Staple peptide and method

Abstract

In particular, this disclosure provides technologies, including I-66 formulations, compositions, and methods, for treating various cancers. This disclosure provides technologies, such as formulations, dosages, and drug regimens, for treating conditions, disorders, or diseases, in particular certain types of cancer. In some embodiments, this disclosure provides high-purity I-66 active pharmaceutical ingredients. In some embodiments, this disclosure provides I-66 pharmaceutical products. In some embodiments, this disclosure provides I-66 formulations, which are liquid compositions in which I-66 has sufficiently high solubility and stability for clinical application.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 471,492, filed on June 6, 2023, and U.S. Provisional Application No. 63 / 510,357, filed on June 26, 2023, both of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background Stapled peptides are useful for a variety of applications. For example, as biologically active drugs, they can be used to modulate various biological functions.

[0003] I-66 is a synthetically produced, helically constrained polypeptide. Various techniques have confirmed that I-66 directly binds to the tumorigenic protein beta-catenin, and that this binding leads to the blockage of beta-catenin:TCF (T cell factor) complex formation, thereby inhibiting the downstream transcriptional program driven by this complex and dramatically inhibiting tumor growth. [Overview of the Initiative]

[0004] In particular, this disclosure provides technologies for treating conditions, disorders or diseases, especially certain types of cancer, such as formulations, dosages, and drug regimens. In some embodiments, this disclosure provides high-purity I-66 active pharmaceutical ingredient. In some embodiments, this disclosure provides I-66 pharmaceutical products. In some embodiments, this disclosure provides I-66 formulations, which are liquid compositions in which I-66 has sufficiently high solubility and stability for clinical application.

[0005] This disclosure also includes a description of a useful clinical development program for I-66 to demonstrate and confirm that I-66 can be used as described herein to treat conditions, disorders, or diseases, including cancer. In some embodiments, the clinical program would include a human, open-label, Phase 1 / 2, multicenter trial to evaluate and confirm the safety, pharmacokinetic (PK), pharmacodynamic (PD), and antitumor activity of I-66. In particular, the objectives of the clinical trial would include demonstrating the safety and tolerability profile of DS-1 in cancer patients, as well as evaluating the antitumor activity of DS-1.

[0006] In some embodiments, the Disclosure provides a method comprising the step of administering or delivering an effective amount of I-66 to a subject, wherein the subject has cancer. In some embodiments, I-66 is administered or delivered as a pharmaceutically acceptable salt. In some embodiments, I-66 is administered or delivered via a pharmaceutical composition described herein. In some embodiments, I-66 is administered or delivered via a formulation described herein. In some embodiments, the subject is a patient with advanced or metastatic microsatellite-stable (MSS) colorectal cancer (CRC). In some embodiments, the subject is a patient with a solid tumor having a WNT pathway-activating mutation (WPAM).

[0007] In some embodiments, the Disclosure provides pharmaceutical compositions comprising or delivering I-66 and a pharmaceutically acceptable carrier. In some embodiments, I-66 is in a pharmaceutically acceptable salt form. In some embodiments, the provided compositions comprise a pharmaceutically acceptable salt form of I-66. In some embodiments, in various compositions and methods, I-66 is provided as one or more pharmaceutically acceptable salt forms.

[0008] In some embodiments, the Disclosure provides a method for modulating the properties, activity, and / or function of beta-catenin, comprising the step of contacting beta-catenin with I-66. In some embodiments, the Disclosure provides a method for modulating the properties, activity, and / or function of beta-catenin in a system comprising beta-catenin, comprising the step of administering an effective amount of I-66 to the system. In some embodiments, the Disclosure provides a method for modulating the properties, activity, and / or function of beta-catenin in a system expressing beta-catenin, comprising the step of administering or delivering an effective amount of I-66 to the system. In some embodiments, the activity in beta-catenin is inhibited or reduced. In some embodiments, the function in beta-catenin is inhibited or reduced. In some embodiments, the properties, activity, and / or function are related to beta-catenin / TCF interactions.

[0009] In some embodiments, the disclosure provides a method for modulating the beta-catenin / TCF interaction. In some embodiments, the disclosure provides a method for modulating the beta-catenin / TCF interaction, comprising the step of contacting beta-catenin with I-66. In some embodiments, the disclosure provides a method for modulating the beta-catenin / TCF interaction in a system comprising beta-catenin and TCF, comprising the step of administering or delivering an effective amount of I-66 to the system. In some embodiments, the disclosure provides a method for modulating the beta-catenin / TCF interaction in a system expressing beta-catenin and TCF, comprising the step of administering or delivering an effective amount of I-66 to the system. In some embodiments, the interaction between beta-catenin and TCF is reduced. In some embodiments, the interaction between beta-catenin and TCF is inhibited.

[0010] In some embodiments, the Disclosure provides a method for inhibiting cell proliferation, comprising the step of administering or delivering an effective amount of I-66 to a population of cells. In some embodiments, the Disclosure provides a method for inhibiting cell proliferation in a system, comprising the step of administering or delivering an effective amount of I-66 to the system. In some embodiments, the Disclosure provides a method for inhibiting cell growth, comprising the step of administering or delivering an effective amount of I-66 to a population of cells. In some embodiments, the Disclosure provides a method for inhibiting cell growth in a system, comprising the step of administering or delivering an effective amount of I-66 to the system. In some embodiments, such cell proliferation is beta-catenin dependent. In some embodiments, such cell growth is beta-catenin dependent. In some embodiments, such proliferation or growth depends on the interaction of beta-catenin with TCF.

[0011] In some embodiments, the Disclosure provides a method for reducing or preventing the activation of the WNT pathway. In some embodiments, the Disclosure provides a method for reducing or preventing the activation of the WNT pathway in a system, the method comprising the step of administering or delivering an effective amount of I-66 to the system.

[0012] In some embodiments, the system is in vitro. In some embodiments, the system is ex vivo. In some embodiments, the system is in vivo. In some embodiments, the system is a cell or contains a cell. In some embodiments, the system is a tissue or contains a tissue. In some embodiments, the system is an organ or contains an organ. In some embodiments, the system is a living organism or contains an organ. In some embodiments, the system is an animal. In some embodiments, the system is a human. In some embodiments, the system is a cell, tissue, or organ associated with a condition, disorder, or disease. In some embodiments, the system is a cancer cell, for example, a colorectal cancer cell, or contains a cell.

[0013] In some embodiments, I-66 is administered as a pharmaceutical composition containing or delivering I-66. In some embodiments, I-66 is provided and / or delivered in one or more pharmaceutically acceptable salt forms. In some embodiments, in a composition (e.g., a liquid composition of a particular pH), I-66 may exist in various forms, including various pharmaceutically acceptable salt forms.

[0014] A further description of a specific embodiment of the technology provided is given below. [Brief explanation of the drawing]

[0015] [Figure 1] 1H NMR of preparation I-66 (DMSO-d6, 373K).

[0016] [Figure 2] The integral of the peaks in the 1H NMR spectrum of the I-66 preparation prepared as described in Example 9 (DMSO-d6, 373K). It will be understood by those skilled in the art that the integral can be further adjusted and / or optimized.

[0017] [Figure 3] 1H NMR of the I-66 preparation. Solvent: methanol-d4. Approx. 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 30.1. Relaxation wait time: 2.5000. Acquisition time: 1.5139. Spectrometer frequency: 900.30 MHz. Spectral width: 10822.5. Minimum frequency: -927.2. Acquired size: 16384. Spectral size: 65536. Digital resolution: 0.17.

[0018] [Figure 4]A region of the 1H NMR spectrum of a preparation of I-66. Top: Approximately 10 mg / 750 uL of I-66 preparation in methanol-d4, 900 MHz 1H at 298 K. Bottom: Approximately 10 mg / 500 uL of I-66 preparation in methanol-d4, 500 MHz 1H at 298 K. As shown, the upper spectrum may provide improved resolution for various peaks.

[0019] [Figure 5] A region of the 1H NMR spectrum of a preparation of I-66. Top: Approximately 10 mg / 750 uL of I-66 preparation in methanol-d4, 900 MHz 1H at 298 K. Bottom: Approximately 10 mg / 500 uL of I-66 preparation in methanol-d4, 500 MHz 1H at 298 K. As shown, the top spectrum may provide improved resolution for various peaks; a certain NH peak at approximately 7.7 ppm observed in the 500 MHz data was not present in the 900 MHz data. As will be understood by those skilled in the art, the NH peak may vary depending on the sample environment.

[0020] [Figure 6] 13C NMR of the I-66 preparation. Solvent: methanol-d4. Approx. 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8108. Receiver gain: 177.2. Relaxation wait time: 1.5000. Acquisition time: 0.3277. Spectrometer frequency: 226.40 MHz. Spectral width: 50000.0. Minimum frequency: -911.8. Acquired size: 16384. Spectral size: 65536. Digital resolution: 0.76.

[0021] [Figure 7]COSY of the I-66 preparation. Solvent: methanol-d4. Approx. 10 mg / 750 uL. Temperature: 298 K. Number of scans: 4. Receiver gain: 30.1. Relaxation wait time: 2.0000. Acquisition time: 0.2272. Spectrometer frequency: (900.30, 900.30). Spectral width: (9014.4, 9009.0). Lowest frequency: (-22.7, -23.3). Nucleus: (1H, 1H). Acquisition size: (2048, 1024). Spectral size: (2048, 1024). Digital resolution: (4.40, 8.80).

[0022] [Figure 8] 1H-13C HSQC preparation of I-66. Solvent: methanol-d4. Approx. 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 177.2. Relaxation wait time: 1.5000. Acquisition time: 0.1137. Spectrometer frequency: (900.30, 226.40). Spectral width: (900.90, 340.13.6). Lowest frequency: (-22.0, 288.5). Nucleus: (1H, 13C). Acquired size: (1024, 512). Spectral size: (1024, 1024). Digital resolution: (8.80, 33.22).

[0023] [Figure 9] 1H-13C HMBC of preparation I-66. Solvent: methanol-d4. Approximately 10 mg / 750 uL. Temperature: 298 K.

[0024] [Figure 10] 1H-1H tocsy of I-66 preparation. Solvent: methanol-d4. Approx. 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 57.7. Relaxation wait time: 2.0000. Acquisition time: 0.2272. Spectrometer frequency: (900.30, 900.30). Spectral width: (9014.4, 9009.0). Lowest frequency: (-21.8, -23.3). Acquired size: (2048, 800). Spectral size: (2048, 1024). Digital resolution: (4.40, 8.80).

[0025] [Figure 11] 1H-1H NOESY of I-66 preparation. Solvent: methanol-d4. Approx. 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 57.7. Relaxation wait time: 2.0000. Acquisition time: 0.2272. Spectrometer frequency: (900.30, 900.30). Spectral width: (9014.4, 9009.0). Minimum frequency: (-5.7, -3.0). Acquired size: (2048, 1024). Spectral size: (2048, 1024). Digital resolution: (4.40, 8.80).

[0026] [Figure 12] Expanded 1H-1H NOESY of preparation I-66. Solvent: methanol-d4. Approx. 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 57.7. Relaxation wait time: 2.0000. Acquisition time: 0.2272. Spectrometer frequency: (900.30, 900.30). Spectral width: (9014.4, 9009.0). Lowest frequency: (-5.7, -3.0). Acquired size: (2048, 1024). Spectral size: (2048, 1024). Digital resolution: (4.40, 8.80). As shown herein, NOE peaks were observed between the olefin protons (111 and 112) of the PL3-B5 staple. In some embodiments, this peak was stronger than the NOE peaks between adjacent aromatic protons of 3Thi (20 and 21) and / or between the p and m protons of the phenyl group of Phe (48 and 47 / 49).

[0027] [Figure 13] Schematic diagram of the trial. APC = adenomatous polyposis coli; CRC = colorectal cancer; GEJ = esophagogastric junction; MSS = microsatellite stability; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; PD = pharmacodynamics; RP2D = recommended dose for phase 2 trial; WPAM = Wnt pathway activating mutation.

[0028] [Figure 14]Microfluidic modulation spectroscopy (MMS) data of the I-66 preparation. (A) Absolute absorbance spectrum of 20 mg / mL I-66 in the amide I band (1588–1712 cm⁻¹ shown). This spectrum was the average of three consecutive measurements. (B) Second derivative plot of the absolute absorbance spectrum. The four highlighted peaks represent the major secondary structure motifs of this peptide molecule. (C) Relative abundance of each secondary structure motif in I-66. [Modes for carrying out the invention]

[0029] Detailed description of a particular embodiment definition When used herein, unless otherwise specified, the following definitions shall apply. For the purposes of this disclosure, chemical elements are defined as those in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Identified according to the ed. Furthermore, the general principles of organic chemistry are “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5 th This is listed in Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001.

[0030] Administration: As used herein, the term “administration” typically refers to the administration of a composition to a subject or system. A variety of routes that may be used for administration to a subject, e.g., a human, in appropriate circumstances will be recognized by those skilled in the art. For example, in some embodiments, administration may be intraocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., by intrabronchial drip infusion), buccal, skin (e.g., one or more of the following, or may include, topical application to the dermis, intradermal, intercutaneous, transdermal, etc.), enteral, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intramedullary, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucous membrane, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal drip infusion), vaginal, intravitreous, etc. In some embodiments, administration may involve intermittent dosing (e.g., multiple dosings spaced out over time) and / or periodic dosing (e.g., individual dosings spaced out over a common period of time). In some embodiments, administration may involve continuous dosing over at least a selected period of time (e.g., perfusion).

[0031] Affinity: As is well known in the art, "affinity" is a criterion for evaluating the closeness of binding of a particular ligand (e.g., a drug) to its partner (e.g., beta-catenin or a part thereof). Affinity can be measured in different ways. In some embodiments, affinity is measured by quantitative assays. In some such embodiments, the concentration of the binding partner can be fixed to be in excess of the ligand concentration to mimic physiological conditions. Alternatively, or in addition to that, in some embodiments, the concentrations of the binding partner and / or the ligand can be varied. In some such embodiments, affinity can be compared to a reference under equivalent conditions (e.g., concentrations).

[0032] Drugs: Generally, the term “drugs” as used herein may be used to refer to any chemical class of compounds or entities, including, for example, polypeptides, nucleic acids, sugars, lipids, small molecules, metals, or combinations or complexes thereof. Where appropriate, as will be apparent to those skilled in the art from the context, the term may be used to refer to cells or organisms, or entities that are or contain fractions, extracts, or components thereof. Alternatively or in addition, as will be apparent from the context, the term may be used to refer to natural products found in nature and / or obtained from nature. In some cases, again, as will be apparent from the context, the term may be used to refer to one or more entities that are artificial in the sense that they are designed, manipulated, and / or produced through human action and / or not found in nature. In some embodiments, drugs may be available in isolated or pure form; in some embodiments, drugs may be available in crude form. In some embodiments, potential drugs may be provided as a collection or library, which can be screened, for example, to identify or characterize the active drugs among them. In some cases, the term “agent” may refer to a compound or entity that is or contains a polymer; in some cases, the term may refer to a compound or entity that contains one or more polymer portions. In some embodiments, the term “agent” may refer to a compound or entity that is not a polymer and / or substantially does not contain any polymer and / or one or more specific polymer portions. In some embodiments, the term may refer to a compound or entity that lacks or substantially contains no polymer portions. In some embodiments, the agent is a compound. In some embodiments, the agent is a staple peptide.

[0033] Amino acid: In its broadest sense, as used herein, refers to any compound and / or substance that can be incorporated into a polypeptide chain, for example, by the formation of one or more peptide bonds. In some embodiments, an amino acid comprises an amino group and a carboxylic acid group. In some embodiments, an amino acid is NH(R a1 )-L a1 -C(R a2 )(R a3 )-L a2The amino acid has a -COOH structure, where each variable is independently as described in this disclosure. In some embodiments, the amino acid has a general structure NH(R')-C(R')2-COOH, where each R' is independently as described in this disclosure. In some embodiments, the amino acid has a general structure H2N-C(R')2-COOH, where R' is as described in this disclosure. In some embodiments, the amino acid has a general structure H2N-C(H)(R')-COOH, where R' is as described in this disclosure. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a non-natural amino acid; in some embodiments, the amino acid is a D-amino acid; in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any of the 20 commonly found standard L-amino acids found in naturally occurring peptides. "Non-standard amino acid" refers to any amino acid other than a standard amino acid, whether synthetically prepared or obtained from a natural source. In some embodiments, amino acids, including carboxyl-terminal and / or amino-terminal amino acids, of a polypeptide may contain structural modifications compared to the general structure described above. For example, in some embodiments, amino acids may be modified compared to the general structure by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., for an amino group, a carboxylic acid group, one or more protons, one or more hydrogens, and / or a hydroxyl group). In some embodiments, such modifications may, for example, alter the cyclic half-life of a polypeptide containing a modified amino acid compared to a polypeptide containing an otherwise identical unmodified amino acid. In some embodiments, such modifications do not significantly alter the relevant activity of a polypeptide containing a modified amino acid compared to a polypeptide containing an otherwise identical unmodified amino acid.As will be apparent from the context, in some embodiments the term "amino acid" may be used to refer to free amino acids; in some embodiments the term may be used to refer to amino acid residues of polypeptides.

[0034] Analogue: As used herein, the term “analogue” refers to a substance that shares one or more specific structural features, elements, components, or parts with a reference substance. Typically, an “analogue” exhibits significant structural similarity with the reference substance, for example, sharing a core or consensus structure, but differing in certain distinct points. In some embodiments, an analogue is a substance that can be produced from a reference substance, for example, by chemically manipulating the reference substance. In some embodiments, an analogue is a substance that can be produced by carrying out a synthetic process substantially similar to (for example, sharing several steps with) that produces the reference substance. In some embodiments, an analogue may be produced or produced by carrying out a synthetic process different from that used to produce the reference substance.

[0035] Animal: As used herein, refers to any member of the animal kingdom. In some embodiments, “animal” refers to a human being of any sex and at any developmental stage. In some embodiments, “animal” refers to a non-human animal at any developmental stage. In certain embodiments, a non-human animal is a mammal (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, and / or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, an animal may be a transgenic animal, a genetically modified animal, and / or a clone.

[0036] Approximately: As used herein, the terms “approximately” or “about” refer to a value similar to the expressed reference value when applied to one or more values ​​of interest. In certain embodiments, unless otherwise specified or it is evident from the context that such a number exceeds 100% of the possible values, the terms “approximately” or “about” refer to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than 1% of the expressed reference value, either greater than or less than the reference value.

[0037] Related to: As used herein, two events or entities are “related” to each other if the presence, level and / or form of one correlates with the presence, level and / or form of the other. For example, a particular entity (e.g., nucleic acid (e.g., genomic DNA, transcripts, mRNA, etc.), polypeptide, gene signature, metabolite, microorganism, etc.) is considered related to that particular disease, disorder, or condition if its presence, level and / or form correlates (e.g., across a relevant population) with the incidence and / or susceptibility of that disease, disorder, or condition.

[0038] Binding: As used herein, the term “binding” will be understood to typically refer to a non-covalent association between drugs (two or more). In many embodiments herein, binding is dealt with in relation to a particular drug and beta-catenin. It will be understood by those skilled in the art that such binding can be evaluated in any of a variety of situations. In some embodiments, binding is evaluated in relation to beta-catenin. In some embodiments, binding is evaluated in relation to one or more amino acid residues of beta-catenin. In some embodiments, binding is evaluated in relation to one or more amino acid residues corresponding to amino acid residues of beta-catenin (e.g., similarly located in three-dimensional space and / or having certain similar properties and / or functions).

[0039] Binding site: As used herein, the term “binding site” refers to a region of the target polypeptide that, in three-dimensional space, contains one, more, or all of the interaction residues of the target polypeptide. In some embodiments, a “binding site” may refer to one or more amino acid residues that contain, or are, one, more, or all of the interaction amino acid residues of the target polypeptide. As will be understood by those skilled in the art, a binding site may include residues adjacent to each other linearly, and / or residues that are distal to each other linearly but approach each other in three-dimensional space when the target polypeptide is folded. A binding site may include amino acid residues and / or sugar residues.

[0040] Carrier: As used herein, refers to a diluent, adjuvant, excipient, or vehicle with which the composition is administered. In some exemplary embodiments, the carrier may include a sterile liquid, such as water, and oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier may be one or more solid components or include them.

[0041] Equivalent: As used herein, the term “equivalent” means two or more sets of agents, entities, situations, conditions, etc., that do not have to be identical to one another, but are similar enough that a reasonable conclusion can be drawn between them, and therefore, on the basis of observed differences or similarities, on the basis of observed differences or similarities, as understood by those skilled in the art. In some embodiments, an equivalent set of conditions, situations, individuals, or groups may feature several substantially identical features and one or a few variable features. The degree of identity required for two or more such sets of agents, entities, situations, conditions, etc., to be considered equivalent in any given situation will be understood by those skilled in the art depending on the situation. For example, a set of situations, individuals, or groups may be considered equivalent if they feature a sufficient number and types of substantially identical features to guarantee a reasonable conclusion that differences in results or observed phenomena obtained under or using different sets of situations, individuals, or groups are caused by or demonstrate variations in those variable features.

[0042] Derivatives: As used herein, the term “derivative” refers to a structural analogue of a reference substance. That is, a “derivative” is a substance that exhibits significant structural similarity to a reference substance, for example, sharing a core or consensus structure, but is distinct in certain distinct respects. In some embodiments, a derivative is a substance that can be produced from a reference substance by chemical manipulation. In some embodiments, a derivative is a substance that can be produced by carrying out a synthetic process that is substantially similar to (for example, sharing several steps with) the process that produces the reference substance.

[0043] Dosage Form or Unit Dosage Form: It will be understood by those skilled in the art that the term “dosage form” may be used to refer to a physically distinct unit of an active agent (e.g., a therapeutic or diagnostic agent) to be administered to a subject. Typically, each such unit contains a predetermined quantity of the active agent. In some embodiments, such quantity is a unit dose (or entire fraction thereof) suitable for administration according to a drug regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., using a therapeutic drug regimen). It will be understood by those skilled in the art that the total amount of a therapeutic composition or agent to be administered to a particular subject may be determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0044] Medication regimen: It will be understood by those skilled in the art that the term “medication regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually, typically at intervals. In some embodiments, a given therapeutic agent has a recommended medication regimen, which may include one or more doses. In some embodiments, a medication regimen includes multiple doses, each separated by time from the others. In some embodiments, the individual doses are separated by periods of equal length from each other; in some embodiments, a medication regimen includes multiple doses, each separated by at least two different periods. In some embodiments, all doses in a medication regimen are administered at the same unit dose. In some embodiments, different doses in a medication regimen are administered in different amounts. In some embodiments, a medication regimen includes a first dose at a first dose, followed by one or more additional doses at a second dose different from the first dose. In some embodiments, the drug regimen includes a first dose of medication followed by one or more additional doses of medication at a second dose equal to the first dose. In some embodiments, the drug regimen correlates with a desired or beneficial outcome when administered across a relevant population (i.e., it is a therapeutic drug regimen).

[0045] “Improved,” “increased,” or “reduced”: As used herein, these terms, or grammatically equivalent comparative terms, indicate a value compared to an equivalent reference measure. For example, in some embodiments, an evaluation value achieved with the drug of interest may be “improved” compared to an evaluation value obtained with an equivalent reference drug. Alternatively, or in addition, in some embodiments, an evaluation value achieved in the object or system of interest may be “improved” compared to an evaluation value obtained in the same object or system under different conditions (e.g., before or after an event such as administration of the drug of interest) or in a different equivalent object (e.g., in a different equivalent object or system than the object or system of interest where one or more indicators of the specific disease, disorder, or condition of interest are present, or where there has been prior exposure to conditions or drugs, etc.). In some embodiments, comparative terms refer to a statistically relevant difference (e.g., one that is widespread and / or large enough to achieve a statistically relevant relationship). A person skilled in the art can recognize or easily determine, in a given situation, the degree and / or extent of the difference necessary or sufficient to achieve such statistical significance.

[0046] Peptides: As used herein, the term "peptide" refers to polypeptides. In some embodiments, peptides are polypeptides having relatively short lengths, for example, less than about 100 amino acids, less than about 50 amino acids, less than about 40 amino acids, less than about 30 amino acids, less than about 25 amino acids, less than about 20 amino acids, less than about 15 amino acids, or less than 10 amino acids. In some embodiments, the lengths are about 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 10-20, 10-19, 10-18, 10-17, 10-16, 10-15, 11-20, 11-19, 11-18, 11-17, 11-16, 11-15, 12-20, 12-19, 12-18, 12-17, 12- 16, 12-15, 13-20, 13-19, 13-18, 13-17, 13-16, 13-15, 14-20, 14-19, 14-18, 14-17, 14-16, 14-15, or approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids.

[0047] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to a formulation in which an active agent is combined with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a therapeutic regimen that demonstrates a statistically significant probability of achieving a given therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those adapted to the following: oral administration, e.g., drench preparations (aqueous solutions, non-aqueous solutions, or suspensions), tablets, e.g., those targeting buccal, sublingual, and systemic absorption, boluses, powders, granules, and pastes for application to the tongue; parenteral administration, e.g., sterile solutions or suspensions, or sustained-release formulations by subcutaneous, intramuscular, intravenous, or epidural injection; topical application, e.g., creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or oral cavity; intravaginal or rectal administration, e.g., vaginal suppositories, creams, or foams; sublingual; intraocular; transdermal; or transnasal, intrapulmonary, and other mucosal surfaces.

[0048] Pharmacologically acceptable: As used herein, the phrase “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that falls within the bounds of good medical judgment, is suitable for use in contact with human and animal tissues, and is free from excessive toxicity, irritation, allergic reactions, or other problems or complications, and is commensurate with a reasonable benefit-risk ratio.

[0049] Pharmacopoeia-acceptable carriers: As used herein, the term “pharmacopoeia-acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulant, that transports or carries the compound of interest from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and does not harm the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository wax; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and dye Examples include oils such as granules; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffers; polyesters, polycarbonates, and / or polyacid anhydrides; and other non-toxic, suitable substances used in pharmaceutical formulations.

[0050] Pharmacopoeia accommodative salts: The term “pharmacopoeia accommodative salt,” as used herein, refers to a salt of such a compound that is suitable for use in a pharmaceutical context, i.e., a salt that falls within the bounds of good medical judgment, is suitable for use in contact with human and lower animal tissues, does not cause excessive toxicity, irritation, allergic reactions, etc., and has a reasonable benefit-risk ratio. Pharmaceutically accommodative salts are well known. For example, SM Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977) describes pharmaceutically accommodative salts in detail. In some embodiments, non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other known methods such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipines, alginates, ascorbicates, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfons, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanates, glycerophosphates, gluconates, hemisulfates, heptanates, hexanoates, hydroiodides, and 2-hydroxyl sulfates. Examples include ethylethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic base addition salts, such as those formed with a base by the acidic group of the compound provided. Typical alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, and magnesium salts. In some embodiments, pharmaceutically acceptable salts include ammonium salts (e.g., -N(R)3). + ) In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0051] Polypeptide: As used herein, refers to any polymer chain of amino acids. In some embodiments, the polypeptide has a naturally occurring amino acid sequence. In some embodiments, the polypeptide has an amino acid sequence that is not naturally occurring. In some embodiments, the polypeptide has an amino acid sequence that is manipulated in the sense that it is designed and / or made through human action. In some embodiments, the polypeptide may contain or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, the polypeptide may contain or consist of only natural amino acids or only non-natural amino acids. In some embodiments, the polypeptide may contain D-amino acids, L-amino acids, or both. In some embodiments, the polypeptide may contain only D-amino acids. In some embodiments, the polypeptide may contain only L-amino acids. In some embodiments, the polypeptide may include one or more pendant groups or other modifications that modify or are attached to one or more amino acid side chains, for example, at the N-terminus of the polypeptide, at the C-terminus of the polypeptide, or in any combination thereof. In some embodiments, such pendant groups or modifications may be selected from the group consisting of acetylation, amidation, lipid addition, methylation, pegylation, etc., including combinations. In some embodiments, the polypeptide may be cyclic and / or may contain a cyclic portion. In some embodiments, the polypeptide may not be cyclic and / or may not contain a cyclic portion. In some embodiments, the polypeptide may be linear. In some embodiments, the polypeptide may be or may contain a staple polypeptide. In some embodiments, the term “polypeptide” may be affixed to the name of a reference polypeptide, activity, or structure; in such cases, the term is used herein to refer to polypeptides that share a relevant activity or structure and can therefore be considered members of the same class or family of polypeptides.For each such class, exemplary polypeptides are presented herein and / or recognized by those skilled in the art, falling within the range of the class for which the amino acid sequence and / or function is known; in some embodiments, such exemplary polypeptides are reference polypeptides of the polypeptide class or family. In some embodiments, members of the polypeptide class or family exhibit significant sequence homology or identity with the reference polypeptide of that class, and in some embodiments, with all polypeptides within that class, sharing common sequence motifs (e.g., characteristic sequence elements) and / or common activity (in some embodiments, at an equivalent level or within a specified range). For example, in some embodiments, the member polypeptide includes at least one region (e.g., a conserved region which may be or may contain a characteristic sequence element) that exhibits a degree of overall sequence homology or identity with the reference polypeptide of at least about 30–40%, and often above or greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and / or exhibits very high sequence identity which is often above 90%, or even further above 95%, 96%, 97%, 98%, or 99%. Such a conserved region typically comprises at least 3–4 amino acids, and often up to 20 or more amino acids; in some embodiments, the conserved region comprises at least one sequence of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more consecutive amino acids. In some embodiments, the relevant polypeptide may include or consist of a fragment of the parent polypeptide.In some embodiments, a useful polypeptide can comprise or consist of a plurality of fragments, each of which is found in a spatial arrangement relative to each other that is different from that found in the polypeptide of interest in the same parent polypeptide (e.g., fragments that are directly linked in the parent may be spatially separated in the polypeptide of interest, or vice versa, and / or the fragments may be present in a different order in the polypeptide of interest than in the parent), and thus the polypeptide of interest is a derivative of its parent polypeptide.

[0052] Prevent or prophylaxis: As used herein, when used in connection with the occurrence of a disease, disorder, and / or condition, refers to reducing the risk that the disease, disorder and / or condition will occur, and / or delaying the onset of one or more features or symptoms of the disease, disorder or condition. Prophylaxis can be considered complete if the onset of the disease, disorder or condition is delayed over a predefined period.

[0053] Protecting group: The term "protecting group" as used herein is well known in the art and is incorporated herein by reference in its entirety, Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rdThis includes what is described in detail in edition, John Wiley & Sons, 1999. It also includes protecting groups specifically adapted for nucleoside and nucleotide chemistry, as described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al. 06 / 2012, the entirety of Chapter 2 of which is incorporated herein by reference. Suitable amino protecting groups include carbamate methyl, carbamate ethyl, 9-fluorenylmethylcarbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxantyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethylsilylethylcarbamate (Teoc), 2- Phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethylcarbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethylcarbamate (t-Bumeoc), 2-(2'-and 4'-pyridyl)ethylcarbamate (Pyoc), 2-(N,N-Dicyclohexylcarboxamide) ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p- Nitobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzylcarbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethylcarbamate, 2-(p-toluenesulfonyl)ethylcarbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthio Phenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzyl Carbamates, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, phenothiazinyl-(10)-carbonyl derivatives, N'-p-toluenesulfonylaminocarbonyl derivatives, N'-phenylaminothiocarbonyl derivatives, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-Dimethoxycarbonylvinylcarbamate, o-(N,N-dimethylcarboxyamide)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxyamide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcycline butylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate 2,4,6-trimethylbenzylcarbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetamide, (N'-dithiobenzyloxycarbonylamino)acetamide, 3-(p-hydroxyphenyl) Ropanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazofenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrosinamide, N-acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-Dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline (py (roolin)-3-yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzyl Denamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-di Phenylboric acid derivatives, N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramide, dibenzylphosphoramide, diphenylphosphoramide, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-Dinitrobenzenesulfenamide, Pentachlorobenzenesulfenamide, 2-Nitro-4-methoxybenzenesulfenamide, Triphenylmethylsulfenamide, 3-Nitropyridinesulfenamide (Npys), p-Toluenesulfonamide (Ts), Benzenesulfonamide, 2,3,6-Trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-Trimethoxybenzenesulfonamide (Mtb), 2,6-Dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-Tetramethyl-4-methoxybenzenesulfonamide (Mte) Examples include 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracene sulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0054] In some embodiments, preferred monoprotected amines include, but are not limited to, aralkylamines, carbamates, allylamines, and amides. Examples of preferred monoprotected amino moieties include t-butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxocarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethylcarbonyl (-NHFmoc), formamide, acetamide, chloroacetamide, dichloroacetamide, trichloroacetamide, phenylacetamide, trifluoroacetamide, benzamide, and t-butyldiphenylsilyl. In some embodiments, preferred diprotected amines include amines independently substituted with two substituents selected from those listed above as monoprotected amines, and further include cyclic imides such as phthalimide, maleimide, and succinimide. In some embodiments, suitable diprotective amines include pyrrole, 2,2,5,5-tetramethyl-[1,2,5]azadisyloridine, and azides.

[0055] Suitable protected carboxylic acids include, but are not limited to, silyl-protected carboxylic acids, alkyl-protected carboxylic acids, alkenyl-protected carboxylic acids, aryl-protected carboxylic acids, and arylalkyl-protected carboxylic acids. Suitable silyl groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and triisopropylsilyl. Suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, and tetrahydropyran-2-yl. Suitable alkenyl groups include allyl. Suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl), and 2-picolyl and 4-picolyl. In some embodiments, suitable protected carboxylic acids are not limited to these, but may include optionally substituted C 1~6 Examples of such ester groups include aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, and hydrazides. Examples of such ester groups include methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, benzyl esters, and phenyl esters, where each group is optionally substituted. Additional suitable protected carboxylic acids include oxazolines and orthoesters.

[0056] Suitable hydroxyl protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl ( MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl ]-4-methoxypiperidine-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trik Loroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levurinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl L, 3-(imidazole-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazoyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropyl Silyl (DEIPS), dimethyltexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxy Acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (rebrinate), 4,4-(ethylenedithio)pentanoate (rebrinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkylmethyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkylethyl carbonate, alkyl 2,22-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate Alkylallyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6 Examples include dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphodiamide, alkyl N-phenylcarbamate, borate, dimethylphosphinthiole, alkyl 2,4-dinitrophenyl sulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). Regarding the protection of 1,2-diols or 1,3-diols, the protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-Trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester, 1,2-dimethoxy Examples include cylidene orthoesters, α-methoxybenzylidene orthoesters, 1-(N,N-dimethylamino)ethylidene derivatives, α-(N,N'-dimethylamino)benzylidene derivatives, 2-oxacyclopentylidene orthoesters, di-t-butylsilylene groups (DTBS), 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivatives (TIPDS), tetra-t-butoxydisiloxane-1,3-diylidene derivatives (TBDS), cyclic carbonates, cyclic boronates, ethyl boronates, and phenyl boronates.

[0057] In some embodiments, the hydroxyl protecting group is acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl(trityl), 4,4'-dimethoxytrityl, trimethylsilyl , triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), and 4,4',4''-trimethoxytrityl (TMTr), 2-cyanoyl Tyl (CE or Cne), 2-(trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl, 2-(4-nitrophenyl)ethyl (NPE), 2-(4-nitrophenylsulfonyl)ethyl, 3,5-dichlorophenyl, 2,4-dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4,6-trimethylphenyl, 2-(2-nitrophenyl)ethyl, butylthiocarbonyl, 4,4',4''-tris(benzoyloxy)trityl, diphenylcarbamoyl These are levlinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt), 9-phenylxanthene-9-yl (pixyl), or 9-(p-methoxyphenyl)xanthine-9-y1 (MOX). In some embodiments, each of the hydroxyl protecting groups is independently selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and 4,4'-dimethoxytrityl. In some embodiments, the hydroxyl protecting group is selected from the group consisting of trityl, monomethoxytrityl, and 4,4'-dimethoxytrityl groups. In some embodiments, the phosphite linkage protecting group is a group that is attached to the phosphite linkage (e.g., internucleotide linkage) throughout the oligonucleotide synthesis. In some embodiments, the protecting group is attached to the sulfur atom of the phosphorothioate group. In some embodiments, the protecting group is attached to the oxygen atom of the internucleotide phosphorothioate linkage. In some embodiments, the protecting group is attached to the oxygen atom of the internucleotide phosphate linkage. In some embodiments, the protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2-(p-nitrophenyl)ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert-butylcarboxyamide)-1-propyl, 4-oxopentyl, 4-methylthio-1-butyl, 2-cyano-1,1-dimethylethyl, 4-N-methylaminobutyl, 3-(2-pyridyl)-1-propyl, 2-[N-methyl-N-(2-pyridyl)]aminoethyl, 2-(N-formyl,N-methyl)aminoethyl, or 4-[N-methyl-N-(2,2,2-trifluoroacetyl)amino]butyl.

[0058] Protected thiols are well known in the art, including those described in detail by Greene (1999). Suitable protected thiols include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioesters.

[0059] References: When used herein, the standard or control against which the comparison is made is described. For example, in some embodiments, the drug, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control drug, animal, individual, population, sample, sequence, or value. In some embodiments, the test and / or determination of the reference or control is performed substantially simultaneously with the test or determination of interest. In some embodiments, the reference or control is a historical reference or control, embodied in tangible media as necessary. Typically, as will be understood by those skilled in the art, the reference or control is determined or characterized under conditions or circumstances equivalent to those under evaluation. In any case, it will be understood by those skilled in the art whether sufficient similarity exists to justify reliability and / or comparison to a particular possible reference or control.

[0060] Specificity: As is well known in the art, "specificity" is a criterion for evaluating the ability of a particular ligand (e.g., a drug) to distinguish its binding partner (e.g., beta-catenin) from other potential binding partners (e.g., another protein, another part of beta-catenin (e.g., a domain)).

[0061] Subject: As used herein, the terms “subject” or “test subject” refer to any organism to which the provided compound or composition is administered in accordance with this disclosure, for example, for experimental, diagnostic, preventive, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; maggots; etc.) as well as plants. In some embodiments, the subject may be a subject suffering from and / or susceptible to a disease, disorder, and / or condition. In some embodiments, the subject is a human.

[0062] Susceptible to: Individuals who are “suspicious” to a disease, disorder, and / or condition are individuals who are at a higher risk of developing a disease, disorder, and / or condition than members of the general population. In some embodiments, individuals susceptible to a disease, disorder, and / or condition may be individuals who have not been diagnosed with a disease, disorder, and / or condition. In some embodiments, individuals susceptible to a disease, disorder, and / or condition may be individuals who exhibit symptoms of a disease, disorder, and / or condition. In some embodiments, individuals susceptible to a disease, disorder, and / or condition may be individuals who do not exhibit symptoms of a disease, disorder, and / or condition. In some embodiments, individuals susceptible to a disease, disorder, and / or condition may be individuals who develop a disease, disorder, and / or condition. In some embodiments, individuals susceptible to a disease, disorder, and / or condition may be individuals who do not develop a disease, disorder, and / or condition.

[0063] Therapeutic agent: As used herein, the phrase “therapeutic agent” means a substance that, when administered to a subject, has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, reduce, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition.

[0064] Treatment regimen: When the term “treatment regimen” is used herein, it refers to a drug regimen whose administration across a relevant population may correlate with a desired or beneficial treatment outcome.

[0065] Therapeutic dose: As used herein, the term “therapeutic dose” means the amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that, when administered as part of a therapeutic regimen, elicits a desired biological response. In some embodiments, the therapeutic dose of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to the disease, disorder, and / or condition. As will be understood by those skilled in the art, the effective dose of a substance may vary depending on factors such as the desired biological endpoint, the substance being delivered, and the target cells or tissues. For example, the effective dose of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that alleviates, improves, reduces, inhibits, prevents, delays the onset, reduces the severity, and / or reduces the incidence of one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, the therapeutic dose is administered in a single dose; in some embodiments, multiple unit doses are required to deliver the therapeutic dose.

[0066] To treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, improve, reduce, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to subjects who are not showing signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to subjects who are showing only early signs of a disease, disorder, and / or condition, for example, to reduce the risk of developing a condition associated with the disease, disorder, and / or condition.

[0067] Unit Dose: As used herein, the term "unit dose" refers to a single dose and / or an amount administered in a physically distinct unit of a pharmaceutical composition. In many embodiments, a unit dose contains a predetermined quantity of the active agent. In some embodiments, a unit dose contains the entire single dose of the agent. In some embodiments, more than one unit dose is administered to achieve a total single dose. In some embodiments, administration of multiple unit doses is required or anticipated to achieve the intended effect. A unit dose may be, for example, a certain volume of liquid (e.g., an acceptable carrier) containing a predetermined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained-release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It will be understood that a unit dose may exist as a formulation containing any of various components in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc., may be included as follows: In many embodiments, the appropriate total daily dose of a particular therapeutic agent may consist of some or more unit doses, which can be determined, for example, by a physician within the bounds of good medical judgment, as will be understood by those skilled in the art. In some embodiments, a particular effective dose level for any particular subject or organism may depend on a variety of factors, including the disorder being treated and its severity; the activity of the particular active compound used; the particular composition used; the subject's age, weight, overall health, sex, and diet; the timing and rate of administration of the particular active compound used; the duration of treatment; any drugs and / or additional treatments used in combination with or concurrently with the particular compound used, as well as similar factors well known in the field of medicine.

[0068] Unless otherwise specified, the provided compounds include salts, such as pharmaceutically acceptable acid or base addition salts, stereoisomers, and tautomers.

[0069] Where used in this disclosure, unless otherwise evident from the context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising,” “comprise,” “including” (whether used with “not limited to”) and “include” (whether used with “not limited to”) may be understood to encompass the components or steps described item by item, whether shown by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least one additional / second one or more; (v) the terms “about” and “approximately” may be understood to allow for variations in standards understood by those skilled in the art; and (vi) where a range is given, the endpoint is included. WNT pathway activated tumors

[0070] In various cases, secreted WNT ligands have been reported to engage with cell surface receptors (e.g., LRP, FZD, etc.) in multiple cell types during mammalian development and in limited sets of adult cell populations, driving signal transduction pathways that lead to cytosolic stabilization of beta-catenin protein (see, for example, Rim, EY, Clevers H, & Nusse R. The Wnt Pathway: From Signaling Mechanisms to Synthetic Modulators. Annual Reviews in Biochemistry, 2022: 91:15.1-15.28). Engagement of the WNT receptor complex may result in the blockade of a constitutive “destruction complex” that drives proteasome-mediated degradation of beta-catenin in the absence of WNT ligands. In some cases, the "destruction complex" contains multiple proteins, including AXIN, adenomatous polyposis (APC), GSK3, and CK1, which have been reported to cooperate in driving beta-catenin degradation. Cytosolic beta-catenin, after being stabilized, is reported to translocate to the nucleus and activate the transcription program by interacting with members of the TCF transcription factor family (TCF1 / 3 / 4 and LEF1). The beta-catenin:TCF complex can bind to homologous deoxyribonucleic acid (DNA) sequences and drives gene expression programs involved in cell proliferation, stem cell maintenance, and epithelial-mesenchymal transition (EMT).

[0071] Dysregulation of the WNT / beta-catenin pathway is frequently reported in human cancers (see, for example, Zhong Z, Yu J, Virshup DM, Madan B. Wnts and the hallmarks of cancer. Cancer Metastasis Rev. 2020;39(3):625-45; Du P, Han, X. Report R-35. Analysis of the mutation prevalence of Wnt pathway genes and the relationship between APC / CTNNB1 mutations and Microsatellite Instability. 2023). WNT pathway mutations, including APC loss-of-function (LoF) mutations and CTNNB1 (beta-catenin) activating mutations, have been reported to affect cancer cell proliferation, differentiation, and apoptosis (see, for example, Stamos JL, Weis WI. The beta-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5(1):a007898). It has been reported that APC LoF mutations can neutralize the beta-catenin destruction complex, potentially leading to subsequent beta-catenin activation (see, for example, Stamos JL, Weis WI. The beta-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5(1):a007898).LoF mutations in APC and activating mutations in beta-catenin, along with other driver WNT pathway mutations, have been frequently reported in common types of cancer (e.g., Hoadley KA, Yau C, Hinoue T, et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell, 2018;173(2):291-304.E6; Gajos-Michniewicz A, Czyz M. Wnt signaling in melanoma. Int J Mol Sci. 2020;21(14):4852; Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 2014;106(1):djt356; Teeuwssen M, Fodde R. Wnt signaling in ovarian cancer stemness, EMT, and therapy resistance. J Clin Med.) See 2019;8(10):1658, for example.Analysis of the Cancer Genome Atlas (TCGA) dataset revealed that the prevalence of these WNT pathway activating mutations (WPAMs) was 80.7%, 33.1%, 21.1%, and 4.5–7.2% in CRC, liver cancer, gastric cancer, and non-small cell lung cancer (NSCLC), respectively (see, for example, Du P, Han, X. Report R-35. Analysis of the mutation prevalence of Wnt pathway genes and the relationship between APC / CTNNB1 mutations and Microsatellite Instability. 2023; Hoadley KA, Yau C, Hinoue T, et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell, 2018;173(2):291-304.E6).

[0072] The functional relevance of important WPAM mutations to cancer onset and maintenance has been reported preclinically. For example, LoF mutations in the APC gene observed in patient colorectal tumor samples have been reported to drive tumorigenesis in cancer cell and animal models (see, e.g., Bian J, Dannappel M, Wan C, et al. Transcriptional Regulation of Wnt / β-Catenin Pathway in Colorectal Cancer. Cells, 2020: 9:2125). Genetic perturbations of the APC gene in mouse models, particularly in combination with additional cancer driver mutations such as KRAS, TP53, and SMAD4 (all of which have been reported to be commonly observed in CRC patients), have been reported to result in intestinal polyps and tumorigenesis. In preclinical cancer models with APC mutations, it has been reported that repair of wild-type APC or complete blockade of beta-catenin activity (using small hairpin RNA [shRNA] and CRISPR) results in potent inhibition of cancer cells and tumor growth. Furthermore, in tumor cells with activated beta-catenin, knockdown of the TCF protein also inhibits cancer cell proliferation.

[0073] The vast majority of human colorectal cancers (>80%), and many cancers presenting with multiple additional signs (e.g., hepatocellular carcinoma, gastric cancer, endometrial cancer, and non-small cell lung cancer), have been reported to have mutations in the genes of the WNT / beta-catenin pathway. APC and CTNNB1 (encoding β-catenin) are two of the most frequently mutated genes in this pathway. These mutations lead to stabilization of β-catenin at the protein level and hyperactivation of its transcriptional activity as a complex with TCF family proteins in the nucleus of tumor cells.

[0074] The transcriptional program driven by the beta-catenin:TCF complex has been reported to activate multiple biological pathways that promote tumor growth, including cell cycle regulators and the C-MYC transcription factor, which is itself a well-described oncogenetic driver (see, e.g., Rennoll S, Yochum G. 2015. Regulation of MYC gene expression by aberrant Wnt / B-cateninsignaling in colorectal cancer. World J Biol Chem. 6(4):290-300). Directly blocking the β-catenin:TCF interaction provides a useful strategy for treating tumors with WPAM. This has been an area of ​​great interest for decades, yet only a few safe and effective therapeutics have been reported and approved in this area.

[0075] Various in vitro and in vivo assays have confirmed that I-66 can modulate beta-catenin:TCF interactions and inhibit tumor growth, including in various PDX tumor models. In particular, this disclosure provides techniques for treating cancer in human subjects using I-66, such as formulations, dosages, and dosing regimens. I-66

[0076] In some embodiments, this disclosure provides technologies for the manufacture, formulation, and use of I-66 to treat conditions, disorders, or diseases, including cancer.

[0077] The linear sequence of I-66 is Ac-PL3 1 -Asp 2 -Npg 3 -B5 4 -Asp 5 -3COOHF 6 -Aib 7 -Ala 8 -Phe 9 -Lys 10 -PyrS2 11 -3Thi12 -BztA 13 -Glu 14 -Ala 15 -NH2 and PL3 1 and B5 4 Between and B5 4 and PyrS2 11 It has olefin staples between it and Lys 10 and Glu 14 It has lactam staples between them. I-66 has a structure such that it has the NMR spectrum shown in Figures 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and / or 12. In some embodiments, the MeOD of I-66 in the preparation or its composition at 25°C 13¹³C NMR (e.g., 900 MHz Bruker AVANCE III system with cryoprobe, sample concentration 10 mg / 750 uL) contains or consists of the following peaks (chemical shift (δ, ppm)): 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35.8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.1 8, 70.51, 122.71, 123.42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137. 36, 138.06, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08 and 178.58. In some embodiments, the MeOD of I-66 in the preparation or its composition at 25°C. 11H NMR (e.g., 900MHz Bruker AVANCE III with cryoprobe) The system (sample concentration 10 mg / 750 uL) contains the following peaks (chemical shift (δ, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.8 0, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and generally 2.23. In some embodiments, the MeOD of I-66 in the preparation or its composition at 25°C. 1¹H NMR (e.g., 900 MHz Bruker AVANCE III system with cryoprobe, sample concentration 10 mg / 750 uL) included the following peaks (chemical shift (δ, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37(2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), and 2.23(3H), each peak represents 1H unless otherwise specified. In some embodiments, the MeOD of I-66 in the preparation or its composition at 25°C 1¹H NMR (e.g., 900 MHz Bruker AVANCE III system with cryoprobe, sample concentration 10 mg / 750 uL) includes the following peaks (chemical shift (δ, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7. 5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38 , 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69. In some embodiments, the MeOD of I-66 in the preparation or its composition at 25°C. 1¹H NMR (e.g., 900 MHz Bruker AVANCE III system with cryoprobe, sample concentration 10 mg / 750 uL) included the following peaks (chemical shift (δ, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4. 27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3.45, 1.18(2H), 1.36, 1. 55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37(2H), 2.38(2H), 1.80, 1.8 8, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), 2.23(3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, each peak represents 1H unless otherwise specified. As will be readily apparent to those skilled in the art, the chemical shifts of the same compound may differ between different experiments and / or samples; despite slight differences, those skilled in the art can determine whether two NMR results belong to the same compound. The identity of I-66 is confirmed by various techniques, including the NMR described herein. Various stereoisomers may exist, including E / Z isomers of each double bond of the staple. I-66 is an isomer having characterization data, including NMR and HPLC data, as described herein. In some embodiments, I-66 is referred to by the following structure: [ka] In some embodiments, numbering and / or stereochemistry (e.g., one or more of (S), (R), (E), and (Z)) may be omitted. For example: [ka]

[0078] The molecular formula of I-66 is C 102 H 134 N 18 O 25 It is S2. The molecular weight of I-66 is 2076.42.

[0079] In some embodiments, I-66 is 2,2'-((1''S,2R,2'S,5'S,8'S,10''E,12'Z,18''S,21''S,27''S,30''S,33''S,42''S,45''S,48''S)-1-acetyl-42''-(((S)-1-amino-1-oxopropan-2-yl)carbamoyl)-45''-(benzo[b]thiophen-3-ylmethyl)-30''-benzyl-21''-(3-carboxybenzyl)-24'',24'',27''-trimethyl-5'-neopentyl-3',5'',6',16',16'',19'', It is referred to by the chemical name 22'',25'',28'',31'',39'',44'',47'',50'',52''-pentadecaoxo-48''-(thiophen-3-ylmethyl)-6''-oxa-1',4',4'',7',17'',20'',23'',26'',29'',32'',38'',43'',46'',49'',51''-pentadecazadispiro[pyrrolidine-2,15'-cyclohexadecane-8',15''-tricyclo[31.17.2.11,4]tripentacontane]-10'',12'-diene-2',18''-diyl)diacetic acid.

[0080] In some embodiments, I-66 is provided as a white or slightly colored solid. In some embodiments, the dissociation constant (pKa) is reported to be about 5.0 (for all carboxylic acids). In some embodiments, I-66 is formulated as a salt to provide higher solubility compared to the free acid. Some salts of I-66, e.g., the sodium salt, have a solubility in water greater than 100 mg / mL, compared to less than 26 mg / mL for the free acid. I-66 preparations may be hygroscopic under certain conditions. For example, with respect to the sodium salt preparation, a weight increase of 13% has been reported at RH 40-80%, with a maximum weight increase of about 30%. In some embodiments, the I-66 preparation is amorphous. In some embodiments, the I-66 preparation is an amorphous sodium salt. In some embodiments, the sodium salt is a trisodium salt. Unless otherwise specified, the I-66 sodium salt in this disclosure is a trisodium salt. composition

[0081] In particular, this disclosure provides compositions comprising I-66. In some embodiments, I-66 in the composition exists in salt form. In some embodiments, I-66 in the composition exists in pharmaceutically acceptable salt form. In some embodiments, multiple forms of I-66 may be present in the composition. In some embodiments, I-66 is provided as a trisodium salt, for example, as a prepared active pharmaceutical ingredient.

[0082] In some embodiments, the Disclosure provides techniques for formulating I-66 to provide, for example, a composition of sufficient concentration and stability for clinical use. In some embodiments, the Disclosure provides an I-66 pharmaceutical product. In some embodiments, the I-66 pharmaceutical composition is an I-66 pharmaceutical product. In some embodiments, the composition is a liquid composition.

[0083] In some embodiments, the composition, I-66; Solubilizer; Buffer agent; pH adjuster as needed; and solvent It includes or consists of.

[0084] In some embodiments, the composition, I-66; amino acid; Buffer agent; pH adjuster as needed; and solvent It includes or consists of.

[0085] In some embodiments, the composition, I-66; PEG or surfactant; Buffer agent; pH adjuster as needed; and solvent It includes or consists of.

[0086] In some embodiments, the composition, I-66; PEG; Buffer agent; pH adjuster as needed; and solvent It includes or consists of.

[0087] In some embodiments, the composition, I-66; Surfactants; Buffer agent; pH adjuster as needed; and solvent It includes or consists of.

[0088] In some embodiments, the composition, I-66; amino acid; PEG or surfactant; Buffer agent; pH adjuster as needed; and solvent It includes or consists of.

[0089] In some embodiments, the composition, I-66; amino acid; PEG; Buffer agent; pH adjuster as needed; and solvent It includes or consists of.

[0090] In some embodiments, the composition, I-66; amino acid; Surfactants; Buffer agent; pH adjuster as needed; and solvent It includes or consists of.

[0091] In some embodiments, the composition, I-66; Solubilizer, Buffer agent; pH adjuster as needed; and solvent It includes or consists of.

[0092] In some embodiments, the composition, It includes or consists of.

[0093] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Amino acids at a concentration of approximately 1-20 mg / mL; PEG or surfactant at a concentration of approximately 0.5 w / v% to 5 w / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjuster as needed; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0094] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjuster as needed; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0095] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; pH adjuster as needed; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0096] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0097] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at a concentration of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0098] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at a concentration of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0099] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at a concentration of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-20 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0100] In some embodiments, the composition, I-66 at a concentration of approximately 5-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at a concentration of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-20 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0101] In some embodiments, the composition, I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at a concentration of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-20 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0102] In some embodiments, the composition, I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0103] In some embodiments, the composition, I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of about 3 w / v%; Sodium dihydrogen phosphate at a concentration of about 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Water; comprises or consists of, and the pH of the composition is about 7.0 to 9.0.

[0104] In some embodiments, the composition is I-66 at a concentration of about 10 mg / mL; Arginine at a concentration of about 10 mg / mL; PEG-400 at a concentration of about 3 w / v%; Sodium dihydrogen phosphate at a concentration of about 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Water; comprises or consists of, and the pH of the composition is about 7.0 to 9.0.

[0105] In some embodiments, the composition is I-66 at a concentration of about 1 - 25 mg / mL; Amino acid at a concentration of about 1 - 20 mg / mL; PEG or surfactant at a concentration of about 0.5 w / v% - 5 w / v%; and Buffer; comprises or consists of, and the pH of the composition is about 7.0 to 9.0.

[0106] In some embodiments, the composition is I-66 at a concentration of about 1 - 25 mg / mL; Arginine at a concentration of about 1 - 20 mg / mL; PEG-400 at a concentration of about 0.5 w / v% - 5 w / v%; and Buffer; comprises or consists of, and the pH of the composition is about 7.0 to 9.0.

[0107] In some embodiments, the composition is I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0108] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0109] In some embodiments, the composition, I-66 at a concentration of approximately 5-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0110] In some embodiments, the composition, I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0111] In some embodiments, the composition, I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and buffer; comprises or consists of, and the pH of the composition is about 7.0 to 9.0.

[0112] In some embodiments, the composition I-66 at a concentration of about 5 to 25 mg / mL; arginine at a concentration of about 5 to 20 mg / mL; PEG-400 at a concentration of about 3 w / v%; and a buffer solution; comprises or consists of, and the pH of the composition is about 7.0 to 9.0.

[0113] In some embodiments, the composition I-66 at a concentration of about 5 to 25 mg / mL; arginine at a concentration of about 10 mg / mL; PEG-400 at a concentration of about 3 w / v%; and a buffer solution; comprises or consists of, and the pH of the composition is about 7.0 to 9.0.

[0114] In some embodiments, the composition I-66 at a concentration of about 5 to 15 mg / mL; arginine at a concentration of about 10 mg / mL; PEG-400 at a concentration of about 3 w / v%; and a buffer solution; comprises or consists of, and the pH of the composition is about 7.0 to 9.0.

[0115] In some embodiments, the composition I-66 at a concentration of about 10 mg / mL; arginine at a concentration of about 10 mg / mL; PEG-400 at a concentration of about 3 w / v%; and a buffer solution; comprises or consists of, and the pH of the composition is about 7.0 to 9.0.

[0116] In some embodiments, the composition I-66 at a concentration of about 1 to 25 mg / mL; Amino acids at a concentration of approximately 1-20 mg / mL; PEG or surfactant in a concentration of approximately 0.5 w / v% to 5 w / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjuster as needed; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0117] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjuster as needed; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0118] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; pH adjuster as needed; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0119] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0120] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0121] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0122] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-20 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0123] In some embodiments, the composition, I-66 at a concentration of approximately 5-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-20 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0124] In some embodiments, the composition, I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-20 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0125] In some embodiments, the composition, I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0126] In some embodiments, the composition, I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0127] In some embodiments, the composition, I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and water; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0128] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Amino acids at a concentration of approximately 1-20 mg / mL; PEG or surfactant in a concentration of approximately 0.5 w / v% to 5 w / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0129] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0130] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0131] In some embodiments, the composition, I-66 at concentrations of approximately 1-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0132] In some embodiments, the composition, I-66 at a concentration of approximately 5-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0133] In some embodiments, the composition, I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0134] In some embodiments, the composition, I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0135] In some embodiments, the composition, I-66 at a concentration of approximately 5-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0136] In some embodiments, the composition, I-66 at a concentration of approximately 5-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0137] In some embodiments, the composition, I-66 at a concentration of approximately 5-15 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0138] In some embodiments, the composition, I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer; It contains or consists of, and the pH of the composition is approximately 7.0 to 9.0.

[0139] I-66 in the composition may exist in various forms. In some embodiments, the form of I-66 is a pharmaceutically acceptable salt form. In some embodiments, I-66 exists as one or more dissolved pharmaceutically acceptable salt forms. In some embodiments, two or more forms of I-66 are present in the composition. In some embodiments, the concentration of I-66 is about 1 to 25 mg / mL (evaluated as free acid unless otherwise specified). In some embodiments, the concentration of I-66 is about 10 mg / mL. In some embodiments, the concentration of I-66 is about 20 mg / mL. In some embodiments, the concentration of I-66 is about 25 mg / mL.

[0140] In some embodiments, one solubilizer is present in the composition. In some embodiments, two or more solubilizers are present in the solution. In some embodiments, the solubilizer is an amino acid. In some embodiments, the solubilizer is a basic amino acid. In some embodiments, the solubilizer is arginine. In some embodiments, the solubilizer is PEG. In some embodiments, the solubilizer is PEG-400. In some embodiments, the solubilizer is a surfactant. In some embodiments, the solubilizer is a nonionic surfactant. In some embodiments, the solubilizer is Tween® 80. In some embodiments, each solubilizer is independently selected from amino acids, polyethylene glycol, and surfactants. In some embodiments, each solubilizer is independently selected from amino acids, polyethylene glycol, and nonionic surfactants. In some embodiments, the solubilizer is a basic amino acid. In some embodiments, two solubilizers are present in the composition. In some embodiments, the composition contains two or more solubilizers; for example, in some embodiments, the composition contains both arginine and PEG-400 as solubilizers. In some embodiments, the solubilizer is Tween® 80. In some embodiments, the concentration of the solubilizer is about 1 to 20 mg / mL. In some embodiments, the concentration of the basic amino acid is about 1 to 20 mg / mL. In some embodiments, the concentration of arginine is about 1 to 20 mg / mL. In some embodiments, the concentration of arginine is about 10 mg / mL. In some embodiments, the concentration of the solubilizer, such as PEG or a surfactant, is about 0.5% to 5% (w / v). In some embodiments, the concentration of PEG is about 0.5% to 5% (w / v). In some embodiments, the concentration of PEG is about 2% to 5% (w / v). In some embodiments, the concentration of PEG is about 3% (w / v). In some embodiments, the concentration of PEG-400 is approximately 0.5% to 5% (w / v). In some embodiments, the concentration of PEG-400 is approximately 2% to 5% (w / v). In some embodiments, the concentration of PEG-400 is approximately 3% (w / v). In some embodiments, the concentration of PEG-400 is approximately 3.4% (w / v).For example, as shown in Table E-8, the concentration of PEG-400 is 0.336 mg / mL. In some embodiments, the concentration of the surfactant is about 0.5% to 5% (w / v). In some embodiments, the concentration of PEG is about 2% to 5% (w / v). In some embodiments, the concentration of PEG is about 3% (w / v). In some embodiments, the concentration of Tween® 80 is about 0.01% to 5%, 0.05% to 2%, 0.1% to 2%, 0.5% to 2%, or 0.5% to 1.5% (w / v). In some embodiments, the concentration of Tween® 80 is about 1% (w / v). In some embodiments, the concentrations described herein are, for example, v / v instead of w / v for PEG-400, and in some embodiments, the compositions are otherwise identical except that the concentrations are v / v instead of w / v. In some embodiments, the concentration of the solubilizer, such as PEG or surfactant, is approximately 0.5% to 5% (v / v). In some embodiments, the concentration of PEG is approximately 0.5% to 5% (v / v). In some embodiments, the concentration of PEG is approximately 2% to 5% (v / v). In some embodiments, the concentration of PEG is approximately 3% (v / v). In some embodiments, the concentration of PEG-400 is approximately 2% to 5% (w / v). In some embodiments, the concentration of PEG-400 is approximately 3% (w / v). In some embodiments, the concentration of PEG-400 is approximately 3.4% (w / v). For example, as shown in Table E-8, the concentration of PEG-400 is 0.336 mg / mL. In some embodiments, the concentration of the surfactant is approximately 0.5% to 5% (v / v). In some embodiments, the concentration of PEG is approximately 2% to 5% (v / v). In some embodiments, the PEG concentration is approximately 3% (v / v). In some embodiments, the Tween® 80 concentration is approximately 0.01% to 5%, 0.05% to 2%, 0.1% to 2%, 0.5% to 2%, or 0.5% to 1.5% (v / v). In some embodiments, the Tween® 80 concentration is approximately 1% (v / v).

[0141] In some embodiments, when the density is approximately 1, w / v can be replaced by w / w, and conversely, w / w can be replaced by w / v.

[0142] In some embodiments, the buffering agent is a phosphate. In some embodiments, the buffering agent is sodium dihydrogen phosphate. In some embodiments, the buffering agent is Tris. In some embodiments, the concentration of the buffering agent is about 10 mM.

[0143] In some embodiments, the composition is or comprises a buffer. Various pharmaceutically acceptable buffer systems can be used in accordance with this disclosure. For example, in some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is a Tris buffer.

[0144] In some embodiments, the composition contains a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is not a salt of I-66, a solubilizer, an amino acid, or a buffer. In some embodiments, the pharmaceutically acceptable salt is NaCl. In some embodiments, the pharmaceutically acceptable salt is formed when the pH is adjusted (for example, by adding HCl or NaOH).

[0145] Various pH adjusters can be used in accordance with this disclosure. In some embodiments, the pH adjuster is NaOH. In some embodiments, the pH adjuster is HCl. For example, in some embodiments, the buffer is a sodium dihydrogen phosphate buffer whose pH has been adjusted with NaOH or HCl. Typically, it will be understood by those skilled in the art that pH adjustment is used as needed to adjust the pH.

[0146] In some embodiments, the composition is or comprises a buffer. In some embodiments, the buffer is a phosphate buffer.

[0147] In some embodiments, the pH of the composition is about 6 to 9. In some embodiments, the pH of the composition is about 6.5 to 9.0. In some embodiments, the pH of the composition is about 7.0 to 9.0. In some embodiments, the pH of the composition is about 7.5 to 8.0. In some embodiments, the pH of the composition is about 7.8 to 8.0. In some embodiments, the pH of the composition is about 7.5. In some embodiments, the pH of the composition is about 7.8. In some embodiments, the pH of the composition is about 8.0. In some embodiments, the pH of the composition is about 7.8 to 8.0.

[0148] In some embodiments, the solvent is water.

[0149] In some embodiments, the pharmaceutical composition comprises or consists of I-66, arginine, PEG400, sodium phosphate, NaOH or HCl as needed, and water.

[0150] For example, in some embodiments, the I-66 pharmaceutical product is or contains I-66 at a concentration of 20 mg / mL in a solution of 10 mg / mL arginine / 3% PEG400 (w / v) / 10 mM sodium phosphate and pH=7.8~8.0. In some embodiments, the I-66 pharmaceutical product is or contains I-66 at a concentration of 10 mg / mL in a solution of 10 mg / mL arginine / 3% PEG400 (w / v) / 10 mM sodium phosphate and pH=7.8~8.0. In some embodiments, the I-66 pharmaceutical product is or contains I-66 at a concentration of 20 mg / mL in a solution of 10 mg / mL arginine / 3% PEG400 (v / v) / 10 mM sodium phosphate and pH=7.8~8.0. In some embodiments, the I-66 pharmaceutical product is 10 mg / mL of I-66 in a solution of 10 mg / mL of arginine / 3% PEG400(v / v) / 10 mM sodium phosphate, pH 7.8-8.0, or contains the same. In some embodiments, the composition contains up to 25 mg / mL of I-66 in a solution of 10 mM sodium phosphate, pH 8, 10 mg / mL of arginine, 6% PEG400, or in a solution of 1% Tween® 80 / 99%, 10 mM PBS, pH 7.4.

[0151] In some embodiments, the I-66 pharmaceutical product, I-66 injection, is supplied as a 10 mg / mL liquid in a Type 1 glass vial having a suitable elastomer stopper and aluminum seal. In some embodiments, the I-66 injection contains 10 mg / mL of I-66 in 10 mM sodium phosphate adjusted to pH 8.0, as well as 10 mg / mL of L-arginine and 33.6 mg / mL of PEG400 as excipients.

[0152] In some embodiments, the compositions described herein, such as pharmaceutical products, are prepared and administered using 5% dextrose (e.g., 5% Dextrose Injection, USP). In some embodiments, 5% dextrose is used as a control and vehicle. In some embodiments, the pharmaceutical product is diluted to a predetermined volume for administration using a pharmaceutically acceptable diluent. In some embodiments, the pharmaceutically acceptable dilute is a dextrose solution. In some embodiments, the pharmaceutically acceptable dilute is 5% Dextrose Injection, USP. In some embodiments, the predetermined volume is about 250 mL. In some embodiments, the pharmaceutical product is diluted approximately 1.1 to 200, 1.5 to 150, 1.5 to 100, 1.5 to 50, 2 to 100, 2 to 50, 1.2, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 150, or 200 times, depending on the amount to be administered.

[0153] In some embodiments, the composition, I-66; Solubilizer, Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0154] In some embodiments, the composition, I-66; amino acid; Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0155] In some embodiments, the composition, I-66; PEG or surfactant; Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0156] In some embodiments, the composition, I-66; PEG; Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0157] In some embodiments, the composition, I-66; Surfactants; Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0158] In some embodiments, the composition, I-66; amino acid; PEG or surfactant; Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0159] In some embodiments, the composition, I-66; amino acid; PEG; Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0160] In some embodiments, the composition, I-66; amino acid; Surfactants; Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0161] In some embodiments, the composition, I-66; Solubilizer, Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0162] In some embodiments, the composition, I-66; amino acid; Buffer agent; pH adjuster, if necessary; sugar; and solvent It includes or consists of.

[0163] Useful solubilizers, buffer agents, amino acids, PEG, surfactants, pH adjusters, sugars, and solvents are, for example, as described herein. For example, in some embodiments, the sugar is dextrose. In some embodiments, this disclosure provides the following compositions.

[0164] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0165] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0166] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0167] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0168] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0169] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0170] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0171] In some embodiments, the composition, I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at a concentration of approximately 0.05 w / v% to 2 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02-0.05 mg / mL; and water; It includes or consists of.

[0172] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 w / v% to 3 w / v%; buffer; and Dextrose at a concentration of approximately 0.02–0.05 mg / mL; It includes or consists of.

[0173] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; buffer; and Dextrose at a concentration of approximately 0.02–0.05 mg / mL; It includes or consists of.

[0174] In some embodiments, the composition, I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at a concentration of approximately 0.05 w / v% to 2 w / v%; buffer; and Dextrose at a concentration of approximately 0.02–0.05 mg / mL; It includes or consists of.

[0175] In some embodiments, the composition, I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at a concentration of approximately 0.05 w / v% to 2 w / v%; buffer; and Dextrose at a concentration of approximately 0.02–0.05 mg / mL; It includes or consists of.

[0176] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 v / v% to 3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0177] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0178] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0179] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0180] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0181] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0182] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; water; It includes or consists of.

[0183] In some embodiments, the composition, I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02-0.05 mg / mL; and water; It includes or consists of.

[0184] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 v / v% to 3 v / v%; buffer; and Dextrose at a concentration of approximately 0.02–0.05 mg / mL; It includes or consists of.

[0185] In some embodiments, the composition, I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; buffer; and Dextrose at a concentration of approximately 0.02–0.05 mg / mL; It includes or consists of.

[0186] In some embodiments, the composition, I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; buffer; and Dextrose at a concentration of approximately 0.02–0.05 mg / mL; It includes or consists of.

[0187] In some embodiments, the composition, I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; buffer; and Dextrose at a concentration of approximately 0.02–0.05 mg / mL; It includes or consists of.

[0188] In some embodiments, the concentration of I-66 is approximately 0.1 to 6 mg / mL. In other embodiments, the concentration of I-66 is approximately 0.2 to 5 mg / mL. A specific concentration is presented as an example in Example 3.

[0189] In some embodiments, the concentration of the solubilizer is approximately 0.1 to 6 mg / mL. In some embodiments, the concentration of the amino acid is approximately 0.1 to 6 mg / mL. In some embodiments, the concentration of arginine is approximately 0.1 to 6 mg / mL. In some embodiments, the concentration of arginine is approximately 0.2 to 5 mg / mL. Certain concentrations are presented as examples in Example 3.

[0190] In some embodiments, the PEG concentration is approximately 0.01 v / v% to 3 v / v%. In some embodiments, the PEG-400 concentration is approximately 0.01 v / v% to 3 v / v%. In some embodiments, it is approximately 0.05 v / v% to 2 v / v%. In some embodiments, the PEG concentration is approximately 0.01 w / v% to 3 w / v%. In some embodiments, the PEG-400 concentration is approximately 0.01 v / v% to 3 v / v%. In some embodiments, it is approximately 0.05 w / v% to 2 w / v%. Certain concentrations are presented as examples in Example 3.

[0191] In some embodiments, the concentration of the surfactant is approximately 0.01 v / v% to 3 v / v%. In some embodiments, the concentration of the surfactant is approximately 0.05 v / v% to 2 v / v%. In some embodiments, the concentration of the surfactant is approximately 0.01 w / v% to 3 w / v%. In some embodiments, the concentration of the surfactant is approximately 0.05 w / v% to 2 w / v%.

[0192] In some embodiments, the dextrose concentration is approximately 0.01–0.05 mg / mL. In some embodiments, the dextrose concentration is approximately 0.02–0.05 mg / L. A specific concentration is presented as an example in Example 3.

[0193] In some embodiments, the concentration of the buffer solution or buffer agent or sodium dihydrogen phosphate is about 0.01 to 100 mM. In some embodiments, it is about 0.01 to 50 mM. In some embodiments, it is about 0.01 to 20 mM. In some embodiments, it is about 0.01 to 10 mM. In some embodiments, it is about 0.1 to 10 mM. In some embodiments, it is about 0.2 to 10 mM.

[0194] In some embodiments, the pH of the composition is about 7.0 to 9.0, as described herein.

[0195] In particular, the composition provided offers high solubility of I-66.

[0196] In some embodiments, the disclosure provides a method for preparing a composition, comprising the steps of dissolving various components (e.g., I-66, a solubilizer, an amino acid, arginine, a surfactant, PEG-400, a buffer, sodium dihydrogen phosphate, etc.) and adjusting the pH using a pH adjusting agent. In some embodiments, the components may be available in salt form, for example, a pharmaceutically acceptable salt, for example, a sodium salt form. In some embodiments, the form is water-containing, for example, a hydrate form. In some embodiments, the form is a hydrate of a pharmaceutically acceptable salt. In some embodiments, the Disclosure provides a method for preparing a composition for administration, for example, an IV dose, comprising the step of diluting a composition containing I-66, for example, a higher concentration of I-66, for example, about 1–25 mg / mL, about 5–25 mg / mL, about 5–20 mg / mL, about 5–15 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 15 mg / mL, about 25 mg / mL, etc., using a pharmaceutically acceptable diluent as described herein (e.g., 5% Dextrose for Injection, USP). In some embodiments, the composition for administration provides an amount of I-66 to be administered to a patient as described herein. In some embodiments, the volume of the composition for administration is about 250 mL.

[0197] Various compositions and methods are presented as examples in the examples.

[0198] In some embodiments, the composition, for example, the liquid I-66 composition, is stored at 2-8°C. In some embodiments, the I-66 preparation, for example, the active pharmaceutical ingredient, is stored at -20°C.

[0199] Multiple stereoisomers exist for I-66. In some embodiments, the level of I-66 in the composition is enriched compared to one, more, or all of its stereoisomers. For example, in some embodiments, the stereochemistry of double bonds (E / Z) is enriched. In some embodiments, each double bond is independently enriched. In some embodiments, one stereochemistry is enriched for chiral elements, such as chiral centers. In some embodiments, one stereochemistry is enriched for chiral centers bonded to two staples. In some embodiments, each chiral element is independently enriched. In some embodiments, one stereochemistry is independently enriched for one, more, or all stereochemical elements (e.g., double bonds, chiral elements, etc.). In some embodiments, for each double bond, one stereochemistry is independently enriched at each staple. In some embodiments, for each double bond, at each staple, one stereochemistry is enriched independently, and for the chiral center bonded to two staples, one stereochemistry is enriched. In some embodiments, the enrichment for each double bond is independently E or Z. In some embodiments, the enrichment for each chiral element is independently R or S. In some embodiments, the enrichment for each stereochemical element, e.g., double bond, chiral center, etc., is about or at least about a certain level, e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (percentage of drug). In some embodiments, about or at least a certain level of all molecules sharing the composition of the drug or a salt in the composition, for example, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, is the drug or a salt. In some embodiments, it is about or at least about 85%. In some embodiments, it is about or at least about 90%. In some embodiments, it is about or at least about 95%. In some embodiments, it is about or at least about 96%.In some embodiments, it is about or at least about 97%. In some embodiments, it is about or at least about 98%. In some embodiments, it is about or at least about 99%.

[0200] In some embodiments, the purity of I-66 is approximately or at least approximately 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the purity of I-66 is approximately or at least approximately 85%. In some embodiments, the purity of I-66 is approximately or at least approximately 90%. In some embodiments, the purity of I-66 is approximately or at least approximately 95%. In some embodiments, the purity of I-66 is approximately or at least approximately 96%. In some embodiments, the purity of I-66 is approximately or at least approximately 97%. In some embodiments, the purity of I-66 is approximately or at least approximately 98%. In some embodiments, the purity of I-66 is approximately or at least approximately 99%.

[0201] In some embodiments, the disclosure provides a method comprising the step of comparing I-66 in a preparation to a reference standard. In some embodiments, the method is used to verify the identity of I-66 in a preparation. In some embodiments, the method is used for quality control of an I-66 preparation. In some embodiments, the method is used to release an I-66 preparation (e.g., the purity of the I-66 is above a certain level, and / or impurities are below certain individual and / or total levels). In some embodiments, the reference standard is an I-66 preparation, where I-66 is Ac-PL3 1 -Asp 2 -Npg 3 -B5 4 -Asp 5 -3COOHF 6 -Aib 7 -Ala 8 -Phe 9 -Lys 10 -PyrS2 11 -3Thi 12 -BztA13 -Glu 14 -Ala 15 -Has the structure of NH2, PL3 1 and B5 4 Between and B5 4 and PyrS2 11 An olefin staple exists between them, Lys 10 and Glu 14 A lactam staple exists between and: During MeOD, at 25°C 13 When characterized by 13C NMR, 13 The following peaks (chemical shift (δ, ppm)) were observed in the 13C NMR spectrum: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35. 8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123. 42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 1 Including 38.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58, During MeOD, at 25°C 1 When characterized by 1H NMR, 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, Including 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4 .15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3. 45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2 .07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1. This includes 42, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), and 2.23(3H), with each peak representing 1H unless otherwise specified; or 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3. Including 92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36 , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3.45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.8 1, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3. The peaks include 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified.

[0202] Those skilled in the art will understand, upon reading this disclosure, that various techniques, including analytical chemistry techniques, can be used in accordance with this disclosure. For example, HPLC is used in some embodiments. Various useful HPLC techniques are used as examples in this disclosure. In some embodiments, the HPLC conditions are as described in Example 1. In some embodiments, the HPLC conditions are as described in Table E-7. In some embodiments, the HPLC conditions are as described in Table E-10. In some embodiments, NMR is used. In some embodiments, NMR is used. 1 It is either an H NMR spectrum or includes one. In some embodiments, the NMR spectrum is 13 It is a 1C NMR spectrum or includes one. In some embodiments, the NMR spectrum is15 It is or includes an N NMR. In some embodiments, the NMR is or includes a NOE. In some embodiments, the NMR is or includes a two-dimensional NMR. In some embodiments, the NMR is or includes a multi-dimensional NMR. In some embodiments, each dimension is independently 1 1H NMR or 13 It includes or is 13C NMR. In some embodiments, each dimension is independently, 1 1H NMR, 13 C NMR or 15 It contains or is N NMR. Use and Application

[0203] The technologies provided, for example, I-66, its preparations and compositions, can be used for a variety of purposes.

[0204] In some embodiments, the Disclosure provides a method for treating cancer, comprising the step of administering or delivering an effective amount of I-66 to a human subject having cancer. In some embodiments, the Disclosure provides a method for treating cancer, comprising the step of administering (or) a pharmaceutical composition described herein to a human subject having cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the subject has a solid tumor. In some embodiments, the subject has an advanced and / or metastatic solid tumor. In some embodiments, the subject has a locally advanced tumor. In some embodiments, the subject has a locally advanced solid tumor. In some embodiments, the subject has metastatic cancer. In some embodiments, the subject has a metastatic solid tumor. In some embodiments, the subject has a locally advanced and metastatic solid tumor. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-squamous cell carcinoma. In some embodiments, the lung cancer is squamous cell carcinoma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is metastatic non-small cell lung cancer. In some embodiments, the cancer is stage IIIB non-small cell lung cancer. In some embodiments, the cancer is stage 4 non-small cell lung cancer, TNM. In some embodiments, the cancer is gastroesophageal junction cancer. In some embodiments, the subject has a solid tumor with a Wnt pathway activating mutation (WPAM). In some embodiments, the subject has microsatellite-stable (MSS) colorectal cancer. In some embodiments, the cancer is non-small cell lung cancer with a Wnt pathway activating mutation (WPAM) in APC or beta-catenin. In some embodiments, the cancer is non-small cell lung cancer with a WPAM in APC. In some embodiments, the cancer is non-small cell lung cancer with a WPAM in beta-catenin. In some embodiments, the cancer is gastric / gastric junction (GEJ) cancer with a Wnt pathway activating mutation (WPAM) in APC or beta-catenin. In some embodiments, the cancer is gastric cancer with WPAM in the APC.In some embodiments, the cancer is gastric cancer having a WPAM in beta-catenin. In some embodiments, the cancer is esophagogastric junction cancer having a WPAM in APC. In some embodiments, the cancer is esophagogastric junction cancer having a WPAM in beta-catenin. In some embodiments, the cancer is refractory gastric / esophagogastric junction cancer (GEJ) having a Wnt pathway activating mutation (WPAM) in APC or beta-catenin. In some embodiments, the cancer is refractory gastric cancer having a WPAM in APC. In some embodiments, the cancer is refractory gastric cancer having a WPAM in beta-catenin. In some embodiments, the cancer is refractory esophagogastric junction cancer having a WPAM in APC. In some embodiments, the cancer is refractory esophagogastric junction cancer having a WPAM in beta-catenin. In some embodiments, the subject has a solid tumor having a Wnt pathway activating mutation. In some embodiments, the subject has a solid tumor having a WPAM in APC. In some embodiments, the subject has a solid tumor having a WPAM in beta-catenin. In some embodiments, the solid tumor is non-MSI-H. In some embodiments, the solid tumor is non-dMMR. In some embodiments, the subject has an advanced or metastatic solid tumor that is non-MSI-H or non-dMMR CRC. In some embodiments, the cancer is advanced or metastatic NSCLC having a WPAM mutation in, for example, APC or beta-catenin. In some embodiments, the cancer is refractory advanced or metastatic NSCLC having a WPAM mutation in, for example, APC or beta-catenin. In some embodiments, the NSCLC is non-squamous cell carcinoma. In some embodiments, the NSCLC is squamous cell carcinoma. In some embodiments, the cancer is advanced or metastatic gastric cancer having a WPAM mutation in, for example, APC or beta-catenin. In some embodiments, the cancer is refractory advanced or metastatic gastric cancer having a WPAM mutation in, for example, APC or beta-catenin. In some embodiments, the cancer is advanced or metastatic GEJ having a WPAM mutation in, for example, APC or beta-catenin.In some embodiments, the cancer is a refractory, advanced, or metastatic GEJ having a WPAM mutation in, for example, APC or beta-catenin.

[0205] In some embodiments, the cancer is refractory. In some embodiments, the subject has a refractory, advanced, or metastatic solid tumor with a WPAM mutation.

[0206] In some embodiments, the subject has a WNT pathway activating mutation. In some embodiments, the tumor has a WNT pathway activating mutation. In some embodiments, the tumor is microsatellite stable.

[0207] In some embodiments, the Wnt pathway activating mutation is a mutation in APC. In some embodiments, the Wnt pathway activating mutation is a mutation in beta-catenin. In some embodiments, the Wnt pathway activating mutation is selected from APC loss-of-function mutations (including LOF, frameshift, nonsense, or splice sites), CTNNB1 gain-of-function mutations (including GOF, missense, in-frame insertion, or deletions at codons 32-37, 41, and 45), RNF43 LOF mutations, and RSPO2 and RSPO3 fusions. In some embodiments, the Wnt pathway activating mutation is selected from mutations in APC, CTNNB1, RNF43, RSPO2, and RSPO3. In some embodiments, the Wnt pathway activating mutation is selected from mutations in other Wnt pathway genes, such as AMER1, AXIN1, AXIN2, BCL9, CSNK1A1, GSK3B, LRP5, LRP6, LGR5, TCF7L2, and WIF1.

[0208] In some embodiments, I-66 is administered or delivered intravenously. In some embodiments, I-66 is provided as a sterile solution for intravenous (IV) administration. In some embodiments, I-66 injection, 10 mg / mL, is supplied as a sterile, aseptically treated solution in a disposable vial for intravenous (IV) administration, labeled to be stored at 2–8°C. In some embodiments, I-66 injection is diluted to a predetermined volume for administration, e.g., 250 mL, for intravenous administration, using a pharmaceutically acceptable diluent, e.g., 5% Dextrose Injection, USP. Various I-66 compositions for delivery or administration are described herein. As described herein, I-66 can be delivered or administered in various forms, including pharmaceutically acceptable salts, e.g., sodium salt form. In some embodiments, I-66 is delivered as a trisodium salt. In some embodiments, I-66 is administered as a trisodium salt. In some embodiments, I-66 in the composition is in trisodium salt form. In some embodiments, I-66 in the composition is a dissolved trisodium salt.

[0209] In some embodiments, the administration schedule is weekly. In some embodiments, the administration schedule is weekly in 28-day cycles. In some embodiments, the administration schedule is weekly in 28-day cycles. In some embodiments, I-66 is administered or delivered approximately once a week in consecutive cycles of approximately 21 or approximately 28 days. In some embodiments, I-66 is administered or delivered intravenously approximately once a week in consecutive cycles of approximately 21 or approximately 28 days. In some embodiments, each dose within a cycle contains or delivers approximately the same amount of I-66. In some embodiments, doses in several (e.g., two, three, four, five or more) or all cycles contain or deliver approximately the same amount of I-66. In some embodiments, all doses to the subject are approximately the same. In some embodiments, one dose differs from another (higher or lower dose). In some embodiments, the dose in a cycle differs from the dose in another cycle (higher or lower dose). In some embodiments, the cycle is approximately 21 days. In some embodiments, each cycle is approximately 21 days, independently. In some embodiments, the cycle is approximately 28 days. In some embodiments, each cycle is approximately 28 days, independently. In some embodiments, the dose is approximately 18 mg / m². 2 (Unless otherwise specified, this refers to the dose of I-66 free acid.) In some embodiments, the dose is approximately 36 mg / m². 2 In some embodiments, the dose is approximately 72 mg / m². 2 In some embodiments, the dose is approximately 144 mg / m². 2 In some embodiments, the dose is approximately 240 mg / m². 2 In some embodiments, the dose is approximately 360 mg / m². 2 In some embodiments, the dose is approximately 480 mg / m². 2 In some embodiments, the dose is approximately 600 mg / m². 2 In some embodiments, the cycle dose is approximately 18 mg / m². 2 In some embodiments, the cycle dose is approximately 36 mg / m². 2is. In some embodiments, the dose per cycle is about 72 mg / m 2 is. In some embodiments, the dose per cycle is about 144 mg / m 2 is. In some embodiments, the dose per cycle is about 240 mg / m 2 is. In some embodiments, the dose per cycle is about 360 mg / m 2 is. In some embodiments, the dose per cycle is about 480 mg / m 2 is. In some embodiments, the dose per cycle is about 600 mg / m 2 is. Certain useful techniques for calculating body surface area and the amount of I-66 are described in the Examples. As will be understood by those skilled in the art, in a pharmaceutical composition, e.g., a pharmaceutical product, I-66 can exist in one or more forms including one or more pharmaceutically acceptable salt forms. For example, in some embodiments, I-66 can exist as one or more dissolved salt forms (e.g., sodium salt). In some embodiments, a patient can start at a low dose. In some embodiments, a patient can start at a high dose. In some embodiments, there is one or more loading doses. In some embodiments, there is no loading dose.

[0210] In some embodiments, I-66 is administered or delivered about every two weeks. In some embodiments, I-66 is administered or delivered about every three weeks.

[0211] In some embodiments, the effect of I-66 is evaluated after one or more administrations. In some embodiments, biopsy material can be obtained from a subject and the levels of one or more biomarkers, e.g., transcripts or polypeptides (e.g., of cMyc, Axin2, etc.), can be evaluated. In some embodiments, the evaluation is compared to a baseline.

[0212] In some embodiments, the disclosure provides I-66 compositions for modulating beta-catenin function. In some embodiments, the disclosure provides I-66 compositions for modulating beta-catenin:TCF interaction. In some embodiments, the disclosure provides I-66 compositions for modulating beta-catenin:TCF interaction and related functions.

[0213] In some embodiments, the techniques provided can reduce, suppress, or block one or more of such interactions. In some embodiments, the disclosure provides a method for modulating an interaction between beta-catenin and its binding partner (e.g., a TCF / LEF family member), the method comprising the step of bringing beta-catenin into contact with I-66.

[0214] In some embodiments, the binding of I-66 to beta-catenin competes with or inhibits the binding of another drug. In some embodiments, the binding of I-66 to beta-catenin competes with or inhibits the binding of another drug. In some embodiments, the binding of I-66 to beta-catenin competes with or inhibits the binding of TCF or a fragment thereof.

[0215] In some embodiments, the provided technology can reduce or block interactions between beta-catenin and all TCF family members, E-cadherin, and APC, but does not significantly affect interactions between beta-catenin and ICAT, AXIN, and BCL9. In some embodiments, the provided technology can interfere with beta-catenin / TCF interactions at both the physical interaction level (confirmed by, for example, NanoBRET, co-IP, etc.) and the transcriptional level (confirmed by, for example, a reporter cell line, endogenous gene expression, etc.). In some embodiments, the provided technology does not affect beta-catenin stability.

[0216] In particular, this disclosure provides techniques for modulating the levels and / or activity of a transcript and / or its products. In some embodiments, the levels and / or activity of a transcript and / or its products, such as polypeptides, can be independently modulated, or independently increased, decreased, or maintained at the same or equivalent levels.

[0217] In some embodiments, the reduction is about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. In some embodiments, the increase is about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. In some embodiments, the disclosure provides increases and / or decreases at least several days after the completion of administration, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or thereafter.

[0218] In some embodiments, the system, cells, tissues, organs, or subjects contain or express mutant beta-catenin. In some embodiments, the system, cells, tissues, organs, or subjects contain beta-catenin hyperactivity. In some embodiments, the system, cells, tissues, organs, or subjects contain upregulated beta-catenin transcript levels. In some embodiments, the system, cells, tissues, organs, or subjects contain upregulated beta-catenin polypeptide levels. In some embodiments, the system, cells, tissues, organs, or subjects contain or express mutant c-Myc. In some embodiments, the system, cells, tissues, organs, or subjects contain c-Myc hyperactivity. In some embodiments, the system, cells, tissues, organs, or subjects contain upregulated c-Myc transcription levels. In some embodiments, the system, cells, tissues, organs, or subjects contain upregulated c-Myc polypeptide levels. In some embodiments, the system, cells, tissues, organs, or subjects contain or express mutant N-Myc. In some embodiments, the system, cells, tissues, organs, or subjects contain N-Myc hyperactivity. In some embodiments, the system, cells, tissues, organs, or subjects contain upregulated N-Myc transcription levels. In some embodiments, the system, cells, tissues, organs, or subjects contain upregulated N-Myc polypeptide levels.

[0219] In some embodiments, the provided drug is used in combination with another treatment. In some embodiments, the provided drug is used in combination with another therapeutic agent. In some embodiments, the other treatment or therapeutic agent is administered before the administration or delivery of the provided drug. In some embodiments, the other treatment or therapeutic agent is administered almost simultaneously with the administration or delivery of the provided drug. In some embodiments, the provided drug and the other drug are in the same pharmaceutical composition. In some embodiments, the other treatment or therapeutic agent is administered following the administration or delivery of the provided drug. In some embodiments, the subject is exposed to both the provided drug and the other therapeutic agent. In some embodiments, both the provided drug and the other drug may be detected in the subject. In some embodiments, the provided drug is administered before the other drug and eliminated by the subject, or vice versa. In some embodiments, the provided drug is administered within the half-life of the other drug, or within 2, 3, 4, 5, or 6 times its half-life, or vice versa. In some embodiments, the subject is exposed to the therapeutic effect of both the provided drug and the therapeutic effect of the other therapeutic agent. In some embodiments, the effect of the drug may be obtained after the drug has been eliminated or metabolized by the subject. In some embodiments, procedures, such as surgical procedures or radiation therapy, may produce effects after the completion of the procedure.

[0220] In some embodiments, the alternative treatment is cancer treatment. In some embodiments, the alternative treatment is or includes surgery. In some embodiments, the alternative treatment is or includes radiotherapy. In some embodiments, the alternative treatment is or includes immunotherapy. In some embodiments, the alternative therapeutic agent is or includes a drug. In some embodiments, the alternative therapeutic agent is or includes an oncology drug. In some embodiments, the alternative therapeutic agent is or includes a chemotherapeutic agent. In some embodiments, the alternative therapeutic agent is or includes a hormone therapy agent. In some embodiments, the alternative therapeutic agent is or includes a kinase inhibitor. In some embodiments, the alternative therapeutic agent is or includes a checkpoint inhibitor (e.g., an antibody against PD-1, PD-L1, CTLA-4, etc.). In some embodiments, a provide agent may be administered in lower unit doses and / or total doses compared to when used alone. In some embodiments, one or more side effects associated with the administration of the provide agent and / or the alternative treatment or therapeutic agent are reduced. In some embodiments, combination therapy provides improved results compared to, for example, when each drug is used individually. In some embodiments, combination therapy achieves one or more better results compared to, for example, when each drug is used individually.

[0221] In some embodiments, the other drug is a checkpoint inhibitor, EGFR inhibitor, VEGF inhibitor, VEGFR inhibitor, kinase inhibitor, or anticancer drug.

[0222] In some embodiments, the additional agent is a checkpoint inhibitor. In some embodiments, the additional agent is an immunotumor agent. In some embodiments, the additional agent is an antibody against a checkpoint molecule. In some embodiments, the additional agent is an antibody against PD1, PDL-1, CTLA4, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, TIM-s, C10orf54, etc. In some embodiments, the antibody is an anti-PD1 antibody. In some embodiments, the antibody is an anti-PD-L1 antibody. In some embodiments, the antibody is an anti-CTLA4 antibody.

[0223] In some embodiments, another agent is an EGFR inhibitor, such as erlotinib, gefitinib, lapatinib, panitumumab, vandetanib, or cetuximab. In some embodiments, another agent is a VEGF and / or VEGFR inhibitor, such as pazopanib, bevacizumab, sorafenib, sunitinib, axitinib, ponatinib, regorafenib, vandetanib, cabozantinib, ramucirumab, lenvatinib, or ziv-aflibercept. In some embodiments, another agent is a kinase inhibitor. In some embodiments, another therapeutic agent is a chemotherapeutic agent. In some embodiments, other therapeutic agents include anticancer drugs, such as cyclophosphamide, methotrexate, 5-fluorouracil (5-FU), doxorubicin, mustine, vincristine, procarbazine, prednisolone, dacarbazine, bleomycin, etoposide, cisplatin, epirubicin, capecitabine, folinic acid, actinomycin, all-trans retinoic acid, azacitidine, azathioprine, bortezomib, and others. These include ruboplatin, chlorambucil, cytarabine, daunorubicin, docetaxel, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, mechloretamine, mercaptopurine, mitoxantrone, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, barrubicin, vinblastine, vindesine, vinorelbine, and oxaliplatin.

[0224] In particular, this disclosure provides the following embodiments. 1. A composition comprising the following: I-66; PEG; Buffer agent; pH adjuster as needed; and solvent 2. A composition comprising the following: I-66; Surfactants; Buffer agent; pH adjuster as needed; and solvent 3. A composition comprising the following: I-66; Solubilizer, Buffer agent; pH adjuster as needed; and solvent 4. The composition according to Embodiment 3, wherein the solubilizer is an amino acid. 5. A composition comprising the following: I-66; amino acid; Buffer agent; pH adjuster as needed; and solvent 6. A composition according to any one of embodiments 3 to 5, further comprising PEG. 7. A composition according to any one of Embodiments 3 to 6, further comprising a surfactant. 8. The composition according to any one of Embodiments 3 to 5, further comprising another solubilizing agent. 9. The composition according to Embodiment 8, wherein the other solubilizing agent is PEG. 10. The composition according to Embodiment 8, wherein the other solubilizing agent is a surfactant. 11. A composition comprising the following: I-66; amino acid; PEG or surfactant; Buffer agent; pH adjuster as needed; and Solvent A composition comprising the following. I-66; Amino acid; PEG; Buffer agent; Optionally, a pH adjuster; and Solvent A composition comprising the following. I-66; Amino acid; Surfactant; Buffer agent; Optionally, a pH adjuster; and Solvent The composition according to any one of the preceding embodiments, which is a liquid composition. The composition according to any one of the preceding embodiments, comprising I-66 in a pharmaceutically acceptable salt form. The composition according to any one of the preceding embodiments, comprising I-66 in a sodium salt form. 17. I-66 is Ac-PL3 1 -Asp 2 -Npg 3 -B5 4 -Asp 5 -3COOHF 6 -Aib 7 -Ala 8 -Phe 9 -Lys 10 -PyrS2 11 -3Thi 12 -BztA 13 -Glu 14 -Ala 15 -NH2, and there are olefin staples between PL3 1 and B5 4 and between B5 4 and PyrS2 11 and there is a lactam staple between Lys 10 and Glu 14 and, of I-66 in MeOD, at 25°C 13The following peaks (chemical shift (δ, ppm)) were observed in the 13C NMR spectrum: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35.8, 35.96, 36.18 , 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123.42, 123.87, 125.19, 125.2, 12 5.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51, 169.51, 172. A composition according to any one of Embodiments 1 to 16, comprising 38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58, wherein I-66 has a purity of about or at least about 90%. 18. I-66 in MeOD at 25°C 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95 A composition according to any one of Embodiments 1 to 17, comprising 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23. 19. I-66 in MeOD at 25°C 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.3 1, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.1 5, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3.45, 1.18(2 H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H) , 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3 A composition according to any one of Embodiments 1 to 18, comprising .76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), and 2.23(3H), where each peak represents 1H unless otherwise specified. 20. I-66 in MeOD at 25°C 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4. 31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.5 5, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2 A composition according to any one of Embodiments 1 to 19, comprising 0.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69. 21. I-66 in MeOD at 25°C 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89. 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.2 5, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3.45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3 .27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1. 97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07( A composition according to any one of Embodiments 1 to 20, comprising 3H), 1.42(3H), 1.59(3H), 1.33(3H), 2.23(3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, where each peak represents 1H unless otherwise specified. 22. A composition according to any one of the prior embodiments, the identity of which is I-66 is confirmed by comparison with the reference standard. 23. The reference standard is an I-66 preparation, and I-66 is Ac-PL3 1 -Asp 2 -Npg 3 -B5 4 -Asp 5 -3COOHF 6 -Aib 7 -Ala 8 -Phe 9 -Lys 10 -PyrS2 11 -3Thi 12 -BztA 13 -Glu 14 -Ala15 -Has the structure of NH2, PL3 1 and B5 4 Between and B5 4 and PyrS2 11 An olefin staple exists between them, Lys 10 and Glu 14 A lactam staple exists between and: During MeOD, at 25°C 13 When characterized by 13C NMR, 13 The following peaks (chemical shift (δ, ppm)) were observed in the 13C NMR spectrum: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35. 8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123. 42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 1 38.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58; and During MeOD, at 25°C 1 When characterized by 1H NMR, 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, Including 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4 .15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3. 45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2. 07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.4 The peaks include 2, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), and 2.23(3H), with each peak indicating 1H unless otherwise specified. 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3. Including 92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36 , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3.45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.8 1, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3. The peaks include 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified. The composition according to Embodiment 22. 24. The composition according to Embodiment 22 or 23, wherein the comparison is the use of HPLC or includes the use of HPLC. 25. The composition according to Embodiment 24, wherein the HPLC conditions are selected from those in Example 1. 26. The composition according to Embodiment 24, wherein the HPLC conditions are as described in Table E-7. 27. The composition according to Embodiment 24, wherein the HPLC conditions are as described in Table E-10. 28. The composition according to any one of Embodiments 22 to 27, wherein the comparison is the use of NMR or includes the use of NMR. 29. The above comparison is, 1A composition according to any one of embodiments 22 to 28, which involves or includes the use of 1H NMR. 30. The above comparison is 13 A composition according to any one of embodiments 22 to 29, which involves or includes the use of 13C NMR. 31. The composition according to any one of Embodiments 22 to 30, wherein the comparison is the use of two-dimensional or multi-dimensional NMR, or includes the use of two-dimensional or multi-dimensional NMR. 32. The composition according to any one of the prior embodiments, wherein the concentration of I-66 is approximately 1 to 25 mg / mL. 33. The composition according to any one of the prior embodiments, wherein the concentration of I-66 is approximately 10 mg / mL. 34. The composition according to any one of the preceding embodiments, wherein the amino acid is a basic amino acid. 35. The composition according to any one of Embodiments 4 to 34, wherein the amino acid is arginine. 36. The composition according to any one of the prior embodiments, wherein the concentration of the amino acid is approximately 1 to 20 mg / mL. 37. The composition according to any one of the prior embodiments, wherein the concentration of the amino acid is approximately 10 mg / mL. 38. A composition according to any one of the prior embodiments, comprising PEG-400. 39. The composition according to any one of the prior embodiments, wherein the concentration of PEG is approximately 1 w / v% to 5 w / v%. 40. The composition according to Embodiment 39, wherein the concentration of PEG is approximately 3.4 w / v%. 41. The composition according to Embodiment 39, wherein the concentration of PEG is approximately 3 w / v%. 42. The composition according to any one of Embodiments 1 to 38, wherein the concentration of the PEG is approximately 1 v / v% to 5 v / v%. 43. The composition according to Embodiment 39, wherein the concentration of PEG is approximately 3.4 v / v%. 44. The composition according to Embodiment 39, wherein the concentration of PEG is approximately 3 v / v%. 45. A composition according to any one of the prior embodiments, comprising a surfactant. 46. ​​A composition according to any one of the prior embodiments, comprising a nonionic surfactant. 47. A composition according to any one of the prior embodiments, comprising Tween® 80. 48. The composition according to any one of the prior embodiments, wherein the concentration of the surfactant is approximately 0.5 w / v% to 5 w / v%. 49. The composition according to any one of the prior embodiments, wherein the concentration of the surfactant is about 1 w / v%. 50. The composition according to any one of Embodiments 1 to 47, wherein the concentration of the surfactant is approximately 0.5 v / v% to 5 v / v%. 51. The composition according to Embodiment 50, wherein the concentration of the surfactant is about 1 v / v%. 52. The composition according to any one of the prior embodiments, wherein the buffering agent is a phosphate. 53. The composition according to any one of the prior embodiments, wherein the buffering agent is sodium dihydrogen phosphate. 54. The composition according to any one of Embodiments 1 to 49, wherein the buffering agent is Tris. 55. The composition according to any one of the prior embodiments, wherein the concentration of the buffering agent is approximately 10 mM. 56. A composition according to any one of the prior embodiments, comprising a pH adjuster. 57. The composition according to Embodiment 56, wherein the pH adjusting agent is NaOH. 58. The composition according to Embodiment 56, wherein the pH adjusting agent is HCl. 59. The composition according to any one of the preceding embodiments, wherein the solvent is water. A composition according to any one of the prior embodiments, comprising 60.I-66, arginine, PEG-400, sodium phosphate buffer, and water. 61. The composition according to any one of the prior embodiments, wherein the pH of the composition is approximately 7.0 to 9.0. A composition according to any one of the preceding embodiments, comprising 62.I-66, arginine, PEG-400, sodium phosphate, and water, wherein the pH is adjusted to about 7.0 to 9.0 using NaOH and HCl. A composition according to any one of the preceding embodiments, comprising 63.I-66, arginine, PEG-400, sodium phosphate, and water, wherein the pH is adjusted to about 7.0 to 9.0 using NaOH and HCl. 64. A composition according to any one of the prior embodiments, wherein the pH is approximately 8.0. 65. I-66 with a concentration of approximately 1-25 mg / mL; Amino acids at a concentration of approximately 1-20 mg / mL; PEG or surfactant at a concentration of approximately 0.5 w / v% to 5 w / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjuster as needed; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 66. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjuster as needed; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 67. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; pH adjuster as needed; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 68. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 69. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at a concentration of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 70. I-66 at a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at a concentration of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; A composition whose pH is approximately 7.0 to 9.0. 71. The composition according to any one of Embodiments 65 to 70, wherein the concentration of PEG-400 is approximately 3 w / v%. 72. I-66 with a concentration of approximately 1-25 mg / mL; Amino acids at a concentration of approximately 1-20 mg / mL; PEG or surfactant in a concentration of approximately 0.5 w / v% to 5 w / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjuster as needed; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 73. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjuster as needed; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 74. I-66 at a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-100 mM; pH adjuster as needed; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 75. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 76. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 77. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1-50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; A composition whose pH is approximately 7.0 to 9.0. 78. The composition according to any one of Embodiments 65 to 77, wherein the concentration of I-66 is approximately or at least approximately 10 mg / mL. 79. The composition according to any one of Embodiments 65 to 77, wherein the concentration of I-66 is approximately 10 to 25 mg / mL. The composition according to any one of Embodiments 65 to 77, wherein the concentration of 80.I-66 is approximately 10 mg / mL. 81. The composition according to any one of Embodiments 65 to 80, wherein the concentration of the amino acid or arginine is approximately 10 mg / mL. 82. The composition according to any one of Embodiments 72 to 81, wherein the concentration of PEG-400 is approximately 3 v / v%. 83. The composition according to any one of embodiments 65 to 82, wherein the concentration of the buffer agent or sodium dihydrogen phosphate is about 5 to 20 mM. 84. The composition according to any one of embodiments 65 to 82, wherein the concentration of the buffer agent or sodium dihydrogen phosphate is about 10 mM. 85. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 86. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 87. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; A composition whose pH is approximately 7.0 to 9.0. 88. I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 89. I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; A composition whose pH is approximately 7.0 to 9.0. 90. I-66 at a concentration of approximately 1-25 mg / mL; Amino acids at a concentration of approximately 1-20 mg / mL; PEG or surfactants in concentrations of approximately 0.5 w / v% to 5 w / v%; and Includes buffer solution; A composition whose pH is approximately 7.0 to 9.0. 91. I-66 at a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; and Includes buffer solution; A composition whose pH is approximately 7.0 to 9.0. 92. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and Includes buffer solution; A composition whose pH is approximately 7.0 to 9.0. 93. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and Includes buffer solution; A composition whose pH is approximately 7.0 to 9.0. 94. I-66 at a concentration of approximately 5-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and Includes buffer solution; A composition whose pH is approximately 7.0 to 9.0. 95. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and Consists of a buffer solution; A composition whose pH is approximately 7.0 to 9.0. The composition according to any one of Embodiments 90 to 95, wherein the concentration of 96.I-66 is approximately or at least approximately 10 mg / mL. The composition according to any one of Embodiments 90 to 95, wherein the concentration of 97.I-66 is approximately 10 to 25 mg / mL. The composition according to any one of Embodiments 90 to 95, wherein the concentration of 98.I-66 is approximately 10 mg / mL. 99. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 3 w / v% to 5 w / v%; and Includes buffer solution; A composition whose pH is approximately 7.0 to 9.0. 100. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Includes buffer solution; A composition whose pH is approximately 7.0 to 9.0. 101. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Includes buffer solution; A composition whose pH is approximately 7.0 to 9.0. 102. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 3 w / v% to 5 w / v%; and Consists of a buffer solution; A composition whose pH is approximately 7.0 to 9.0. 103. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Consists of a buffer solution; A composition whose pH is approximately 7.0 to 9.0. 104. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Consists of a buffer solution; A composition whose pH is approximately 7.0 to 9.0. 105. I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Includes buffer solution; A composition whose pH is approximately 7.0 to 9.0. 106. I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Consists of a buffer solution; A composition whose pH is approximately 7.0 to 9.0. 107. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 108. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 109. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; A composition whose pH is approximately 7.0 to 9.0. 110. I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; A composition whose pH is approximately 7.0 to 9.0. 111. I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; A composition whose pH is approximately 7.0 to 9.0. 112. I-66 with a concentration of approximately 1-25 mg / mL; Amino acids at a concentration of approximately 1-20 mg / mL; PEG or surfactant in a concentration of approximately 0.5 w / v% to 5 w / v%; and buffer solution Includes; A composition whose pH is approximately 7.0 to 9.0. 113. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; and buffer solution Includes; A composition whose pH is approximately 7.0 to 9.0. 114. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and buffer solution Includes; A composition whose pH is approximately 7.0 to 9.0. 115. I-66 with a concentration of approximately 1-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and buffer solution Includes; A composition whose pH is approximately 7.0 to 9.0. 116. I-66 with a concentration of approximately 5-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and buffer solution Includes; A composition whose pH is approximately 7.0 to 9.0. 117. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and buffer solution Composed of; A composition whose pH is approximately 7.0 to 9.0. 118. The composition according to any one of Embodiments 90 to 95, wherein the concentration of I-66 is approximately or at least approximately 10 mg / mL. 119. The composition according to any one of Embodiments 90 to 95, wherein the concentration of I-66 is approximately 10 to 25 mg / mL. The composition according to any one of Embodiments 90 to 95, wherein the concentration of 120.I-66 is approximately 10 mg / mL. 121. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 3 v / v% to 5 v / v%; and buffer solution Includes; A composition whose pH is approximately 7.0 to 9.0. 122. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer solution Includes; A composition whose pH is approximately 7.0 to 9.0. 123. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer solution Includes; A composition whose pH is approximately 7.0 to 9.0. 124. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 3 v / v% to 5 v / v%; and buffer solution Composed of; A composition whose pH is approximately 7.0 to 9.0. 125. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer solution Composed of; A composition whose pH is approximately 7.0 to 9.0. 126. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer solution Composed of; A composition whose pH is approximately 7.0 to 9.0. 127. I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer solution Includes; A composition whose pH is approximately 7.0 to 9.0. 128. I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and buffer solution Composed of; A composition whose pH is approximately 7.0 to 9.0. 129. The composition according to any one of embodiments 90 to 128, wherein the buffer is a phosphate buffer. 130. The composition according to any one of embodiments 90 to 128, wherein the buffer solution is a sodium phosphate buffer solution. 131. The composition according to any one of embodiments 90 to 128, wherein the buffer solution is a Tris buffer solution. 132. The composition according to any one of embodiments 90 to 131, wherein the concentration of the buffer solution is approximately 5 to 100 mM. 133. The composition according to any one of embodiments 90 to 131, wherein the concentration of the buffer solution is approximately 10 mM. 134.10 mg / mL I-66; 10 mg / mL arginine; 33.6 mg / mL PEG-400; and Contains 10 mM sodium phosphate; The composition has a pH of approximately 8.0. 135.10 mg / mL I-66; 10 mg / mL Arginine; 33.6 mg / mL PEG-400; and It consists of 10 mM sodium phosphate; The composition has a pH of approximately 8.0. 136. I-66 is Ac-PL3 1 -Asp 2 -Npg 3 -B5 4 -Asp 5 -3COOHF 6 -Aib 7 -Ala 8 -Phe 9 -Lys 10 -PyrS2 11 -3Thi 12 -BztA 13 -Glu 14 -Ala 15 -NH2 and PL3 1 and B5 4 Between and B5 4 and PyrS2 11 An olefin staple exists between them, Lys 10 and Glu 14 Lactam staples are present between them, and during MeOD, at 25°C 13 When characterized by 13C NMR, 13The following peaks (chemical shift (δ, ppm)) were observed in the 13C NMR spectrum: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35.8, 35.96, 36.18 , 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123.42, 123.87, 125.19, 125.2, 125 0.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51, 169.51, 172.3 The composition according to any one of Embodiments 65 to 135, comprising 8, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58, wherein I-66 has a purity of about 90% or higher. 137. MeOD at 25°C 1 When characterized by 1H NMR, 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, A composition according to any one of Embodiments 65 to 136, comprising 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23. 138. MeOD at 25°C 1 When characterized by 1H NMR, 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.3 1, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.1 5, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H ), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3. A composition according to any one of embodiments 65 to 137, comprising 76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), and 2.23(3H), where each peak represents 1H unless otherwise specified. 139. MeOD at 25°C 1 When characterized by 1H NMR, 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4. 31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.5 5, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, A composition according to any one of 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or one of Embodiments 65 to 138. 140 MeOD at 25°C 1 When characterized by 1H NMR, 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25 , 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3.45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3. 27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97 , 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H A composition according to any one of Embodiments 65 to 139, comprising ), 1.42(3H), 1.59(3H), 1.33(3H), 2.23(3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, where each peak represents 1H unless otherwise specified. A composition according to any one of embodiments 65 to 140, wherein the identity of I-66 is confirmed by comparison with the reference standard. 142. The above reference standard is an I-66 preparation, and I-66 is Ac-PL3 1 -Asp 2 -Npg 3 -B5 4 -Asp 5 -3COOHF 6 -Aib 7 -Ala 8 -Phe 9 -Lys 10 -PyrS2 11 -3Thi 12 -BztA 13 -Glu 14 -Ala15 -Has the structure of NH2, PL3 1 and B5 4 Between and B5 4 and PyrS2 11 An olefin staple exists between them, Lys 10 and Glu 14 A lactam staple exists between and: During MeOD, at 25°C 13 When characterized by 13C NMR, 13 The following peaks (chemical shift (δ, ppm)) were observed in the 13C NMR spectrum: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35. 8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123 .42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08 and 178.58; and During MeOD, at 25°C 1 When characterized by 1H NMR, 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, Including 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4 .15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3. 45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2. 07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.4 The peaks include 2, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), and 2.23(3H), with each peak representing 1H unless otherwise specified. 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3. Including 92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36 , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3.45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.8 1, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3. The peaks include 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified. The composition described in Embodiment 141. 143. The composition according to Embodiment 141 or 142, wherein the comparison is the use of HPLC or includes the use of HPLC. 144. The composition according to Embodiment 143, wherein the HPLC conditions are selected from those in Example 1. 145. The composition according to Embodiment 143, wherein the HPLC conditions are as described in Table E-7. 146. The composition according to Embodiment 143, wherein the HPLC conditions are as described in Table E-10. 147. A composition according to any one of Embodiments 141 to 146, wherein the comparison is the use of NMR or includes the use of NMR. 148. The above comparison is, 1A composition according to any one of embodiments 141 to 147, which involves or includes the use of 1H NMR. 149. The above comparison is, 13 A composition according to any one of embodiments 141 to 148, which involves or includes the use of 13C NMR. 150. The composition according to any one of Embodiments 141 to 149, wherein the comparison is the use of two-dimensional or multi-dimensional NMR, or includes the use of two-dimensional or multi-dimensional NMR. 151. A composition according to any one of the prior embodiments, further comprising a pharmaceutically acceptable carrier. 152. A composition according to any one of the prior embodiments, further comprising sugar. 153. The composition according to Embodiment 152, wherein the sugar is dextrose. 154. A composition prepared by diluting any one of the compositions described in Embodiments 1 to 153 with a pharmaceutically acceptable diluent to a predetermined volume. 155. The composition according to Embodiment 154, wherein the pharmaceutically acceptable diluent is a sugar solution. 156. The composition according to Embodiment 154, wherein the pharmaceutically acceptable diluent is a dextrose solution. 157. The composition according to Embodiment 154, wherein the pharmaceutically acceptable diluent is 5% Dextrose Injection, USP. 158. The composition according to any one of embodiments 154 to 157, wherein the predetermined volume is 250 mL. The composition according to any one of Embodiments 154 to 158, wherein the concentration of 159.I-66 is approximately 0.05 to 10 mg / mL. The composition according to any one of embodiments 154 to 158, wherein the concentration of 160.I-66 is approximately 0.05 to 6 mg / mL. The composition according to any one of Embodiments 154 to 158, wherein the concentration of 161.I-66 is approximately 0.1 to 5 mg / mL. 162. The composition according to any one of Embodiments 154 to 161, wherein the concentration of the solubilizer, amino acid, or arginine is approximately 0.05 to 10 mg / mL. 163. The composition according to any one of Embodiments 154 to 161, wherein the concentration of the solubilizer, amino acid, or arginine is approximately 0.05 to 6 mg / mL. 164. The composition according to any one of Embodiments 154 to 161, wherein the concentration of the solubilizer, amino acid, or arginine is approximately 0.01 to 5 mg / mL. 165. The composition according to any one of Embodiments 154 to 164, wherein the concentration of the surfactant or PEG is about 0.01 w / v% to 3 w / v%. 166. The composition according to any one of Embodiments 154 to 164, wherein the concentration of the surfactant or PEG is about 0.05 w / v% to 2 w / v%. 167. The composition according to any one of Embodiments 154 to 164, wherein the concentration of the surfactant or PEG is about 0.01 v / v% to 3 v / v%. 168. The composition according to any one of Embodiments 154 to 164, wherein the concentration of the surfactant or PEG is about 0.05 w / v% to 2 v / v%. 169. The composition according to any one of embodiments 154 to 168, wherein the concentration of the buffer agent or buffer solution is about 0.1 to 10 mM. 170. The composition according to any one of Embodiments 154 to 168, wherein the concentration of the buffer agent or buffer solution is about 0.2 to 5 mM. 171. The composition according to any one of embodiments 154 to 170, wherein the buffer agent is sodium dihydrogen phosphate. 172. The composition according to any one of Embodiments 154 to 170, wherein the buffer agent is sodium dihydrogen phosphate. 173. The composition according to any one of embodiments 154 to 170, wherein the buffer is a phosphate buffer. 174. The composition according to any one of embodiments 154 to 170, wherein the buffer solution is a Tris buffer solution. 175. The composition according to any one of Embodiments 154 to 174, wherein the pharmaceutically acceptable diluent is 5% Dextrose Injection, USP, and the dextrose concentration is about 0.02 to 0.05 mg / mL. 176. I-66 at a concentration of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 177. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 178. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 179. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 180. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 181. I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 182. I-66 at concentrations of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 183. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at a concentration of approximately 0.05 w / v% to 2 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02-0.05 mg / mL; and A composition containing water. 184. I-66 at a concentration of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 w / v% to 3 w / v%; buffer; and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 mg / mL. 185. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; buffer; and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 mg / mL. 186. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at a concentration of approximately 0.05 w / v% to 2 w / v%; buffer; and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 mg / mL. 187. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at a concentration of approximately 0.05 w / v% to 2 w / v%; buffer; and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 mg / mL. 188. I-66 at a concentration of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 189. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 190. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 191. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 192. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 193. I-66 with a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 194. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 195. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at a concentration of approximately 0.05 w / v% to 2 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02-0.05 mg / mL; and A composition consisting of water. 196. I-66 with a concentration of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 w / v% to 3 w / v%; buffer; and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 mg / mL. 197. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; buffer; and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 mg / mL. 198. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at a concentration of approximately 0.05 w / v% to 2 w / v%; buffer; and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 mg / mL. 199. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at a concentration of approximately 0.05 w / v% to 2 w / v%; buffer; and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 mg / mL. 200. The concentration of I-66 is approximately 0.2–5 mg / mL; The arginine concentration is approximately 0.2–5 mg / mL; The concentration of PEG-400 is approximately 0.06-1.7 w / v%; and The dextrose concentration is approximately 0.02-0.05 mg / mL. The composition according to any one of embodiments 176 to 199. 201. I-66 at concentrations of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 v / v% to 3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 202. I-66 with a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 203. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 204. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 205. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 206. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 207. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition containing water. 208. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02-0.05 g / mL; and A composition containing water. 209. I-66 at a concentration of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 v / v% to 3 v / v%; buffer; and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 mg / mL. 210. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; buffer; and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL. 211. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; buffer; and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL. 212. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; buffer; and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL. 213. I-66 with a concentration of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 v / v% to 3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 214. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM. pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 215. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 216. I-66 with a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 217. I-66 with a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 218. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 219. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01-0.05 mg / mL; A composition consisting of water. 220. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02-0.05 mg / mL; and A composition consisting of the following. 221. I-66 at a concentration of approximately 0.1-6 mg / mL; Amino acids at a concentration of approximately 0.1 to 6 mg / mL; PEG or surfactant at a concentration of approximately 0.01 v / v% to 3 v / v%; buffer; and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 g / mL. 222. I-66 at a concentration of approximately 0.1-6 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; buffer; and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 g / mL. 223. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.1-6 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; buffer; and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 g / mL. 224. I-66 at a concentration of approximately 0.2-5 mg / mL; Arginine at a concentration of approximately 0.2-5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; buffer; and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 g / mL. 225. The concentration of I-66 is approximately 0.2 to 5 mg / mL; The arginine concentration is approximately 0.2–5 mg / mL; The concentration of PEG-400 is approximately 0.06-1.7 v / v%; and The dextrose concentration is approximately 0.02-0.05 mg / mL. The composition according to any one of embodiments 176 to 199. 226. The composition according to any one of embodiments 176 to 225, wherein the buffer is a phosphate buffer. 227. The composition according to any one of embodiments 176 to 225, wherein the buffer solution is a Tris buffer solution. 228. The composition according to any one of embodiments 176 to 227, wherein the concentration of the buffer solution is approximately 0.01 to 10 mM. 229. The composition according to any one of Embodiments 176 to 227, wherein the concentration of the buffer solution is approximately 0.02 to 5 mM. 230. The composition according to any of embodiments 200 to 229, wherein the pH of the composition is approximately 7.0 to 9.0. 231. A composition according to any of Embodiments 200 to 229, wherein the pH is approximately 8.0. 232. I-66 is Ac-PL3 1 -Asp 2 -Npg 3 -B5 4 -Asp 5 -3COOHF 6 -Aib 7 -Ala 8 -Phe 9 -Lys 10 -PyrS2 11 -3Thi 12 -BztA 13 -Glu 14 -Ala 15 -NH2 and PL3 1 and B5 4 Between and B5 4 and PyrS2 11 An olefin staple exists between them, Lys 10 and Glu 14 Lactam staples are present between them, and during MeOD, at 25°C 13 When characterized by 13C NMR, 13The following peaks (chemical shift (δ, ppm)) were observed in the 13C NMR spectrum: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35.8, 35.96, 36.18 , 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123.42, 123.87, 125.19, 125.2, 125 .37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38 A composition according to any one of Embodiments 176 to 231, comprising 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58, wherein I-66 has a purity of about 90% or higher. 233. I-66 in MeOD at 25°C 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, A composition according to any one of Embodiments 176 to 232, comprising 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23. 234. I-66 in MeOD at 25°C 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.3 1, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.1 5, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H ), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.7 A composition according to any one of Embodiments 176 to 233, comprising 6, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), and 2.23(3H), where each peak represents 1H unless otherwise specified. 235. I-66 in MeOD at 25°C 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.3 1, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.2 A composition according to any one of Embodiments 176 to 234, comprising 2, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69. 236. I-66 in MeOD at 25°C 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7 .38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3.45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.2 7, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H) The composition according to any one of Embodiments 176 to 235, wherein each peak represents 1H unless otherwise specified, including 1.42(3H), 1.59(3H), 1.33(3H), 2.23(3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69. A composition according to any one of embodiments 176 to 236, wherein the identity of 237.I-66 is confirmed by comparison with the reference standard. 238. The reference standard is an I-66 preparation, and I-66 is Ac-PL3 1 -Asp 2 -Npg 3 -B5 4 -Asp 5 -3COOHF 6 -Aib 7 -Ala 8 -Phe 9 -Lys 10 -PyrS2 11 -3Thi 12 -BztA 13 -Glu 14-Ala 15 -Has the structure of NH2, PL3 1 and B5 4 Between and B5 4 and PyrS2 11 An olefin staple exists between them, Lys 10 and Glu 14 A lactam staple exists between and: During MeOD, at 25°C 13 When characterized by 13C NMR, 13 The following peaks (chemical shift (δ, ppm)) were observed in the 13C NMR spectrum: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35. 8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123 .42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08 and 178.58; and During MeOD, at 25°C 1 When characterized by 1H NMR, 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, Including 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4 .15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3. 45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2. 07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.4 The peaks include 2, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), and 2.23(3H), with each peak representing 1H unless otherwise specified. 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3. Including 92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1 .93(2H), 2.38(2H), 2.92, 3.45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3. 31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2. Includes 71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified. The composition according to Embodiment 237. 239. The composition according to Embodiment 237 or 238, wherein the comparison is the use of HPLC or includes the use of HPLC. 240. The composition according to Embodiment 239, wherein the HPLC conditions are selected from those in Example 1. 241. The composition according to Embodiment 239, wherein the HPLC conditions are as described in Table E-7. 242. The composition according to Embodiment 239, wherein the HPLC conditions are as described in Table E-10. 243. A composition according to any one of Embodiments 237 to 242, wherein the comparison is the use of NMR or includes the use of NMR. 244. The above comparison is, 1A composition according to any one of embodiments 237 to 243, which involves or includes the use of 1H NMR. 245. The above comparison is, 13 A composition according to any one of embodiments 237 to 244, which involves or includes the use of 13C NMR. 246. The composition according to any one of embodiments 237 to 245, wherein the comparison is the use of two-dimensional or multi-dimensional NMR, or includes the use of two-dimensional or multi-dimensional NMR. 247. The composition according to any one of embodiments 237 to 246, wherein the comparative volume is approximately 250 mL. 248. A composition identical to the composition described in any one of the prior embodiments, except that the concentration is v / v instead of w / v. 249. A composition identical to any one of Embodiments 1 to 247, except that the concentration is w / w instead of w / v. A composition according to any one of the prior embodiments, wherein 250.I-66 has a purity of about 80% or higher. 251. The composition according to any one of the prior embodiments, wherein I-66 has a purity of about 85% or higher. 252. A composition according to any one of the prior embodiments, wherein I-66 has a purity of about 95% or higher. 253. A method comprising diluting the composition of I-66 with a pharmaceutically acceptable diluent. 254. A step of calculating the volume of composition I-66 to administer the intended dose, The steps include: taking a volume of diluent equivalent to the calculated volume from an infusion bag / container containing a pharmaceutically acceptable diluent; The steps include adding the calculated volume of I-66 composition to the injection bag / container and The method according to embodiment 253, including the method described in embodiment 253. 255. The method according to any one of Embodiments 253 to 254, wherein the concentration of I-66 in the composition is about 1 to 25 mg / mL. 256. The method according to Embodiment 255, wherein the concentration of I-66 in the composition is approximately 5 to 25 mg / mL. 257. The method according to Embodiment 255, wherein the concentration of I-66 in the composition is approximately 10 mg / mL. The method according to any one of Embodiments 253 to 257, wherein the composition of 258.I-66 is the composition described in any one of Embodiments 1 to 153. The method according to any one of Embodiments 253 to 257, wherein the composition of I-66 is the composition described in any one of Embodiments 1 to 150. 260. The method according to any one of embodiments 253 to 259, wherein the pharmaceutically acceptable diluent is 5% Dextrose Injection, USP. 261. The method according to any one of embodiments 253 to 260 for preparing I-66 for administration. A method according to any one of embodiments 253 to 260, for preparing 262.I-66 for intravenous administration. 263. The method according to any one of Embodiments 253 to 262, wherein the composition according to any one of Embodiments 154 to 252 is prepared. 264. A method comprising the step of comparing I-66 in a preparation with a reference standard. 265. The reference standard is an I-66 preparation, and I-66 is Ac-PL3 1 -Asp 2 -Npg 3 -B5 4 -Asp 5 -3COOHF 6 -Aib 7 -Ala 8 -Phe 9 -Lys 10 -PyrS2 11 -3Thi 12 -BztA 13 -Glu 14 -Ala 15 -Has the structure of NH2, PL3 1 and B5 4 Between and B5 4 and PyrS2 11 An olefin staple exists between them, Lys10 and Glu 14 A lactam staple exists between and: During MeOD, at 25°C 13 When characterized by 13C NMR, 13 The following peaks (chemical shift (δ, ppm)) were observed in the 13C NMR spectrum: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35. 8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123 .42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08 and 178.58; and During MeOD, at 25°C 1 When characterized by 1H NMR, 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, Including 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4 .15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38(2H), 2.92, 3. 45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2. 07, 1.37(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.4 The peaks include 2, 1.57, 2.69, 3.76, 3.92, 2.2(2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), and 2.23(3H), with each peak representing 1H unless otherwise specified. 1The following peaks (chemical shift (δ, ppm)) were observed in the 1H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3. Including 92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or the same 1The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR spectrum: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5. 31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1. 65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93(2H), 2.38 (2H), 2.92, 3.45, 1.18(2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.3 7(2H), 2.38(2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55(3H), 1.07(3H), 1.42(3H), 1.59(3H), 1.33(3H), 2.23(3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86 and 7.69 are included, and each peak represents 1H unless otherwise specified. The method according to Embodiment 264. 266. The method of Embodiment 264 or 265, wherein the comparison is the use of HPLC or includes the use of HPLC. 267. The method according to Embodiment 266, wherein the HPLC conditions are selected from those in Example 1. 268. The method according to Embodiment 266, wherein the HPLC conditions are as described in Table E-7. 269. The method according to Embodiment 266, wherein the HPLC conditions are as described in Table E-10. 270. The method according to any one of embodiments 264 to 269, wherein the comparison is the use of NMR or includes the use of NMR. 271. The above comparison is, 1A method according to any one of embodiments 264 to 270, which involves the use of 1H NMR or includes the use of 1H NMR. 272. The above comparison is, 13 A method according to any one of embodiments 264 to 271, which involves the use of 13C NMR or includes the use of 13C NMR. 273. The method according to any one of embodiments 264 to 272, wherein the comparison is the use of two-dimensional or multi-dimensional NMR, or includes the use of two-dimensional or multi-dimensional NMR. 274. A method according to any one of embodiments 264 to 273 for confirming the identity of I-66 in the preparation. 275. A method according to any one of embodiments 264 to 274, used for controlling the quality of the I-66 preparation. 276. A method according to any one of embodiments 264 to 275, used to release the I-66 preparation. 277. The method according to any one of embodiments 264 to 276, wherein the I-66 preparation is a preparation of the I-66 active pharmaceutical ingredient. 278. The method according to any one of embodiments 264 to 276, wherein the I-66 preparation is a preparation of the I-66 pharmaceutical product. 279. The method according to any one of Embodiments 264 to 277, wherein I-66 in the preparation is in or contains a pharmaceutically acceptable salt form. 280. The method according to any one of Embodiments 264 to 279, wherein I-66 in the preparation is in or contains a sodium salt form. 281. The method according to any one of Embodiments 264 to 280, wherein I-66 in the Reference Standard is in a pharmaceutically acceptable salt form or comprises the same. 282. The method according to any one of Embodiments 264 to 281, wherein I-66 in the Reference Standard is in or contains a sodium salt form. 283. A method for modulating the interaction of beta-catenin with a partner in a system, comprising the step of administering or delivering I-66 to the system. 284. The method according to embodiment 283, wherein the partner is TCF4. 285. A method for modulating the TCF-beta-catenin interaction in a system, comprising the step of contacting beta-catenin with I-66. 286. A method for modulating the TCF-beta-catenin interaction in a system, comprising the step of administering or delivering I-66 to the system. 287. A method for inhibiting beta-catenin-dependent cell proliferation, comprising the step of administering or delivering I-66 to the system. 288. A method for reducing beta-catenin polypeptide levels in a system, comprising the step of administering or delivering I-66 to the system. 289. A method for reducing c-Myc polypeptide levels and / or transcript levels in a system, comprising the step of administering or delivering I-66 to the system. The method according to any one of embodiments 288 to 289, wherein the 290.c-Myc polypeptide level is reduced. 291. The method according to any one of embodiments 288 to 290, wherein the c-Myc mRNA level is reduced. 292. The method according to any one of embodiments 288 to 291, wherein the decline is observed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days or later after administration. 293. A method for reducing Axin2 polypeptide levels and / or transcript levels in a system, comprising the step of administering or delivering I-66 to the system. 294. The method according to any one of embodiments 288 to 293, wherein the Axin2 polypeptide level is reduced. 295. The method according to any one of embodiments 288 to 294, wherein the Axin2 mRNA level is reduced. 296. A method for modulating the WNT / beta-catenin pathway in a system, comprising the step of administering or delivering I-66 to the system, thereby modulating nucleic acid expression. 297. A method comprising the step of administering or delivering I-66 to the system, wherein the level of a nucleic acid transcript and / or its product is modulated. 298. A method comprising the step of administering or delivering I-66 to the system, wherein the expression of nucleic acid is modulated. 299. The method according to any one of embodiments 296 to 298, wherein the nucleic acid is a gene or contains one. 300. The method according to any one of Embodiments 283 to 299, wherein the system is an in vitro system. 301. The method according to any one of Embodiments 283 to 299, wherein the system is an in vivo system. 302. The method according to any one of Embodiments 283 to 299, wherein the system is a sample or contains one. 303. The method according to any one of embodiments 283 to 302, wherein the system is a cell, tissue, or organ, or includes one. 304. The method according to any one of Embodiments 283 to 303, wherein the system is a cancer cell or contains one. 305. The method according to any one of embodiments 283 to 305, wherein the system is a tumor or includes one. 306. The method according to any one of embodiments 283 to 305, to which the system is the subject. 307. A method for treating cancer, comprising the step of administering or delivering an effective amount of I-66 to a subject having cancer. 308. A method comprising the step of administering or delivering a certain dose of I-66 to a subject suffering from cancer. 309. The method according to any one of embodiments 307 to 308, wherein the cancer is a solid tumor. 310. The method according to any one of embodiments 307 to 308, wherein the cancer is colorectal cancer. 311. The method according to any one of embodiments 307 to 308, wherein the cancer is gastric cancer. 312. The method according to any one of embodiments 307 to 308, wherein the cancer is lung cancer. 313. The method according to any one of embodiments 307 to 308, wherein the cancer is non-small cell lung cancer. 314. The method according to any one of embodiments 307 to 308, wherein the cancer is metastatic non-small cell lung cancer. 315. The method according to any one of embodiments 307 to 308, wherein the cancer is non-small cell lung cancer stage IIIB. 316. The method according to any one of embodiments 307 to 308, wherein the cancer is a non-small cell carcinoma. 317. The method according to any one of embodiments 307 to 308, wherein the cancer is non-small cell lung cancer, TNM stage 4. 318. The method according to any one of embodiments 307 to 308, wherein the cancer is esophagogastric junction cancer. 319. The method according to any one of embodiments 307 to 318, wherein the tumor is non-MSI-H. 320. The method according to any one of embodiments 307 to 318, wherein the tumor is non-dMMR. 321. The method according to any one of embodiments 307 to 320, wherein the cancer is locally advanced cancer. 322. The method according to any one of embodiments 307 to 321, wherein the cancer is metastatic cancer. 323. The method according to any one of embodiments 307 to 322, wherein the cancer is microsatellite stable. 324. The method according to Embodiment 307, wherein the cancer is advanced or metastatic MSS colorectal cancer. 325. The method according to Embodiment 307, wherein the cancer is advanced or metastatic non-small cell lung cancer. 326. The method according to Embodiment 307, wherein the cancer is advanced or metastatic gastric cancer. 327. The method according to Embodiment 307, wherein the cancer is advanced or metastatic esophagogastric junction cancer. 328. The method according to any one of embodiments 307 to 327, wherein the cancer comprises a Wnt pathway activating mutation (WPAM). 329. The method according to Embodiment 307, wherein the cancer is a WPAM+ solid tumor. 330. The method according to any one of embodiments 307 to 329, wherein the cancer comprises an APC mutation. 331. The method according to any one of embodiments 307 to 330, wherein the cancer comprises a beta-catenin mutation. 332. The method according to Embodiment 307, wherein the cancer is advanced or metastatic non-small cell lung cancer in which WPAM has been demonstrated in APC. 333. The method according to Embodiment 307, wherein the cancer is advanced or metastatic non-small cell lung cancer in which WPAM has been demonstrated with beta-catenin. 334. The method according to Embodiment 307, wherein the cancer is advanced or metastatic gastric cancer in which WPAM has been demonstrated in APC. 335. The method according to Embodiment 307, wherein the cancer is advanced or metastatic gastric cancer in which WPAM has been demonstrated with beta-catenin. 336. The method according to Embodiment 307, wherein the cancer is advanced or metastatic esophagogastric junction cancer in which WPAM has been demonstrated in APC. 337. The method according to Embodiment 307, wherein the cancer is advanced or metastatic esophagogastric junction cancer in which WPAM has been demonstrated with beta-catenin. 338. The method according to any one of Embodiments 307 to 337, comprising a loss-of-function APC mutation, a gain-of-function CTNNB1 mutation, an RNF43 LOF mutation, and a mutation selected from RSPO2 fusions and RSPO3 fusions. 339. The method according to any one of embodiments 307 to 338, comprising a mutation selected from mutations in AMER1, AXIN1, AXIN2, BCL9, CSNK1A1, GSK3B, LRP5, LRP6, LGR5, TCF7L2, and WIF1. 340. The method according to any one of embodiments 307 to 339, which reduces cMyc expression in a tumor sample. 341. The method according to any one of embodiments 307 to 340, wherein the cancer is refractory. The method according to any one of Embodiments 283 to 341, comprising the step of administering I-66 weekly. The method according to any one of Embodiments 283 to 342, comprising the step of administering I-66 weekly in at least about three doses. The method according to any one of Embodiments 283 to 342, comprising the step of administering I-66 weekly in at least about four doses. The method according to any one of Embodiments 283 to 344, comprising the step of administering 345.I-66 as a composition having a volume of approximately 250 mL. The method according to any one of Embodiments 283 to 345, comprising the step of administering 346.I-66 as the composition described in any one of Embodiments 1 to 252. The method according to any one of Embodiments 283 to 345, comprising the step of administering 347.I-66 as the composition described in any one of Embodiments 154 to 252. The method according to any one of Embodiments 283 to 345, comprising the step of administering 348.I-66 as a composition according to any one of Embodiments 176 to 252. The method according to any one of Embodiments 283 to 348, comprising the step of administering or delivering 349.I-66 intravenously. 350.About 18mg / m 2 The method according to any one of embodiments 283 to 349, wherein a dose of I-66 is administered. 351.About 36mg / m 2 The method according to any one of embodiments 283 to 350, wherein a dose of I-66 is administered. 352. Approximately 72mg / m 2 The method according to any one of embodiments 283 to 351, wherein a dose of I-66 is administered. 353.About 144mg / m 2 The method according to any one of embodiments 283 to 352, wherein a dose of I-66 is administered. 354.About 240mg / m 2 The method according to any one of embodiments 283 to 353, wherein a dose of I-66 is administered. 355.About 360mg / m 2 The method according to any one of embodiments 283 to 354, wherein a dose of I-66 is administered. 356.About 480mg / m 2 The method according to any one of embodiments 283 to 355, wherein a dose of I-66 is administered. 357.About 600mg / m 2 The method according to any one of embodiments 283 to 356, wherein a dose of I-66 is administered. The method according to any one of Embodiments 283 to 357, comprising the step of administering or delivering 358.I-66 in a series of cycles at an assigned dose. 359. The method according to Embodiment 358, wherein the allocated doses for each cycle are substantially the same. 360. The method according to any one of embodiments 358 to 359, wherein the allocated dose for one cycle is different from that for another cycle. 361. The method according to any one of embodiments 358 to 360, wherein the cycle is approximately 21 days. 362. The method according to any one of embodiments 358 to 361, wherein the cycle is approximately 28 days. 363. The method according to any one of embodiments 358 to 360, wherein each cycle is independently approximately 21 days long. 364. The method according to any one of embodiments 358 to 360, wherein each cycle is independently approximately 28 days long. 365. The assigned dose for a given cycle is approximately 18 mg / m². 2 The method according to any one of embodiments 358 to 364, which is I-66 of the same. 366. The assigned dose for a given cycle is approximately 36 mg / m². 2 The method according to any one of embodiments 358 to 365, which is I-66 of the same. 367. The assigned dose for a given cycle is approximately 72 mg / m². 2 The method according to any one of embodiments 358 to 366, which is I-66 of the same. 368. The assigned dose for a given cycle is approximately 144 mg / m². 2 The method according to any one of embodiments 358 to 367, which is I-66 of the same. 369. The assigned dose for a given cycle is approximately 240 mg / m². 2 The method according to any one of embodiments 358 to 368, which is I-66 of the same. 370. The assigned dose for a given cycle is approximately 360 mg / m². 2 The method according to any one of embodiments 358 to 369, which is I-66 of the same. 371. The assigned dose for a given cycle is approximately 480 mg / m². 2 The method according to any one of embodiments 358 to 370, which is I-66 of the I-66. 372. The assigned dose for a given cycle is approximately 600 mg / m². 2 The method according to any one of embodiments 358 to 371, which is I-66 of the same. 373. A method according to any one of the prior embodiments, comprising the step of administering or delivering a second therapeutic agent to a subject. 374. A method according to any one of the prior embodiments, comprising the step of administering or delivering a second treatment to a subject. 375. The method according to embodiment 373 or 374, wherein a second therapeutic agent or treatment is administered prior to I-66. 376. The method according to embodiment 373 or 374, wherein a second therapeutic agent or treatment is administered concurrently with I-66. 377. The method according to embodiment 373 or 374, wherein a second therapeutic agent or treatment is administered following I-66. 378. The method according to any one of the prior embodiments, wherein the subject is exposed to a second therapeutic agent or treatment and I-66. 379. The method according to any one of the prior embodiments, wherein the subject is exposed to the therapeutic effect of the second therapeutic agent or treatment and the therapeutic effect of I-66. 380. The method according to any one of the prior embodiments, wherein the second therapeutic agent is a chemotherapeutic agent or comprises the same. 381. The method according to any one of the prior embodiments, wherein the second therapeutic agent is a hormone therapy agent or includes one. 382. The method according to any one of the prior embodiments, wherein the second therapeutic agent is an immunotherapy agent or comprises the same. 383. The method according to any one of the prior embodiments, wherein the second therapeutic agent is a checkpoint inhibitor or comprises one. 384. The method according to any one of the prior embodiments, wherein the second therapeutic agent is an antibody or comprises an antibody. 385. The method according to any one of the prior embodiments, wherein the second therapeutic agent is a CTLA-4, PD-1, or PD-L1 inhibitor, or comprises the same. 386. The method according to any one of the prior embodiments, wherein the second therapeutic agent is a cell or comprises a cell. 387. The method according to any one of the prior embodiments, wherein the second therapeutic agent reduces one or more side effects of I-66. 388. The method according to any one of the prior embodiments, wherein the second treatment is a surgical procedure or includes such procedure. 389. A method according to any one of the prior embodiments, wherein the second treatment is chemotherapy or includes chemotherapy. 390. The method according to any one of the prior embodiments, wherein the second treatment is radiotherapy or includes radiotherapy. 391. The method according to any one of the prior embodiments, wherein the second treatment is hormone therapy or includes hormone therapy. 392. The method according to any one of the prior embodiments, wherein the second treatment is a stem cell transplant or a bone marrow transplant, or includes such a transplant. 393. A method according to any one of the prior embodiments, wherein the second treatment is immunotherapy or includes immunotherapy. 394. A method according to any one of the prior embodiments, wherein the second treatment is T-cell therapy or includes such therapy. 395. A method according to any one of the prior embodiments, wherein the second treatment is CAR T-cell therapy or includes such therapy. 396. A method according to any one of the prior embodiments, wherein the second treatment is the administration of a population of immune cells to the subject, or includes the same. 397. A method according to any one of the prior embodiments, wherein the combination therapy provides higher efficacy than I-66 being administered or delivered alone. 398. The method according to any one of the prior embodiments, wherein the combination therapy provides higher efficacy than when the second therapeutic agent or treatment is administered or delivered alone. [Examples]

[0225] Example Those skilled in the art will understand that various technologies are available for manufacturing and evaluating the technologies provided pursuant to this disclosure. A specific example is described below.

[0226] (Example 1) Manufacturing of the I-66.

[0227] Those skilled in the art will understand that I-66, including the active pharmaceutical ingredient and pharmaceutical product according to this disclosure, can be prepared using various synthesis techniques. Some specific useful techniques are listed below as examples. For example, the various techniques described in WO2022 / 261257 are also useful for the preparation of I-66.

[0228] In some embodiments, the Disclosure provides, for example, a technique for producing I-66 for use as an active pharmaceutical ingredient.

[0229] As an example, some useful starting materials are listed below. Table E-1. Useful starting materials for I-66 preparation [Table E-1-1] [Table E-1-2]

[0230] In some embodiments, I-66 is manufactured as follows, for example:

[0231] In some embodiments, the production of the I-66 API involves three steps. In the first step, I-66 is synthesized using a solid-phase peptide synthesis (SPPS) method with a standard Fmoc protecting strategy. Here, all synthetic operations, including the introduction of olefin and lactam staples, are carried out on a solid support. The synthesis proceeds from the C-terminus to the N-terminus, starting with the binding of the C-terminal amino acid residue to an insoluble support (resin). After the initial binding, subsequent Fmoc-protected amino acid derivatives are bound sequentially to extend the protected peptide anchored to the resin. The second step involves cleavage from the resin. In the third step, the crude peptide is purified by preparative reverse-phase chromatography, and the fraction containing the product is freeze-dried to obtain the I-66 API.

[0232] The following Schemes 1 and 2 illustrate the synthesis process for use in both non-GMP and GMP clinical batches for GLP toxicity testing, including the amide formation step and the crucial stapling step. Certain useful starting materials are listed in Table E-1.

[0233] Scheme 1. SPPS synthesis of I-66 to AA2, including the introduction of the first staple (Phase 1). [ka] [ka]

[0234] Scheme 2.I-66: Final step (stage 1) of SPPS synthesis. [ka] [ka]

[0235] Typically, each peptide synthesis cycle step includes deblocking, coupling, and capping steps. Lactam stapling is performed after the first 10 amino acids have been assembled. Lactam stapling is carried out using palladium-mediated deprotection conditions, respectively. 10 and Glu 14 This is done by deprotecting the alloc and allyl groups, and then forming an amide bond using a standard coupling agent (e.g., PyAOP, EDC, CDMT, etc.). After further extending the peptide chain to AA2, a first ring-closing metathesis is performed to produce an (i,i+7) staple (e.g., the E-olefin isomer in various preparations). Then, the last amino acid is introduced, capped, and a second ring-closing metathesis is performed to produce an (i,i+3) staple (e.g., the Z-olefin isomer in various preparations). Typically, for example, one isomer is shown in the scheme.

[0236] After the completion of the Step 1 (SPPS) process, I-66 is cleaved from the solid support using TFA / water, neutralized, and solid-phase extracted using Sepabed (Step 2). The extracted peptide is recovered by filtration for the purification process. I-66 is purified by multi-step reverse-phase chromatography (Step 3). After the purified drug substance is salt-exchanged to obtain the desired counterions, the purified solution is dried by lyophilization (Step 4) to obtain the substance, which can then be packaged in amber glass containers with Teflon®-lined polypropylene screw caps and stored at -20°C ± 5°C. A complete outline of an example of the manufacturing process is illustrated in Scheme 3 below.

[0237] Scheme 3. Overview of all manufacturing stages. [ka]

[0238] Solid-phase peptide synthesis (SPPS) of the I-66 API can be carried out according to well-developed and commonly used procedures and protocols for peptide synthesis. SPPS typically consists of sequentially assembling protected amino acid derivatives to synthesize a peptide anchored to a solid support (resin). In some embodiments, the addition of amino acids to grow the peptide generally involves the following steps: removal of the protective N-terminal Fmoc group from the previous amino acid; washing; coupling of the next activated amino acid; washing; acetylation (if necessary); and washing. These steps, typically proceeding from the C-terminus to the N-terminus, are repeated for each amino acid until the desired linear peptide is assembled on the resin.

[0239] In various preparations, when initiating the synthesis of the I-66 drug substance, a Rink-amide MBHA resin is prepared by a deblocking reaction using piperidine / dimethylformamide (DMF), and then the C-terminal amino acid (Fmoc-Ala-OH·H2O) is loaded onto the resin in the presence of DMF / Oxymapure / diisopropylcarbodiimide (DIC). Unreacted sites on the resin are capped by an acetylation reaction, for example, using DMF / diisopropylethylamine (DIPEA) / acetic anhydride. A substitution test is performed after the loading reaction to ensure acceptable loading of Fmoc-Ala-OH·H2O onto the resin. The peptide is grown by adding each of the subsequent protected amino acids by carrying out two reactions: [1] a deblocking reaction to remove the Fmoc group from the N-terminal amino acid derivative; and [2] a coupling reaction to attach the next amino acid derivative. If necessary, a capping reaction, such as an acetylation reaction, is carried out. These reactions are repeated iteratively to grow the peptide. The deblocking reaction is carried out in the presence of piperidine / DMF. The coupling reaction is carried out in the presence of oxymapure / DIC / DMF. The acetylation reaction is carried out in the presence of DMF / DIPEA / acetic anhydride. In-process checks (e.g., ninhydrin test or chloranil test, and / or LC analysis) are performed after each reaction to ensure the integrity of each reaction. At the end of each reaction, a washing step is applied to remove any remaining reaction reagents and solvents and to prepare for the next reaction.

[0240] Fmoc-Asp 5 After the bonding of (OtBu)-OH, an allyl deprotection reaction is carried out, followed by a lactamation reaction, and then Lys 10 and Glu 14The peptide is crosslinked. The allyl deprotection reaction is carried out in the presence of tetrakis(triphenylphosphine palladium (Pd(PPh3)4) / triphenylphosphine (PPPh3) / dimethylbarbituric acid (DMBA) / dichloromethane (DCM). The lactamation reaction is carried out in the presence of (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) / DMF / DIPEA. In-step checks are performed after each reaction to ensure the completeness of each reaction. After the lactamation reaction, peptide synthesis is resumed.

[0241] Fmoc-Asp 2 After bonding of (OtBu)-OH, a ring-closing metathesis (RCM) reaction is carried out in the presence of a Hoveyda-Grubbs catalyst, resulting in B5 4 and PyrS2 11 Connect them. Perform in-process checks to ensure the integrity of each reaction. Fmoc-PL3 at the N-terminus. 1 The peptide synthesis continues again with the addition of -OH and its acetylation. The second RCM reaction is carried out, B5 4 and PL3 1 Connect them. Dry the peptide-resin under reduced pressure and high temperature.

[0242] Peptide cleavage and solid-phase extraction (SPE) from resins

[0243] Crude I-66 active pharmaceutical ingredient is cleaved from the resin and deprotected by acid hydrolysis in the presence of trifluoroacetic acid (TFA) / H2O to remove the side-chain protecting groups. The spent resin is removed by filtration, the filtrate is neutralized and subjected to solid-phase extraction (SPE) using Sepabeads resin in the presence of ACN / NH4OAc. In-process checks are performed to ensure the integrity of the extraction. The resin is collected and washed. The crude peptide is released from the resin in the presence of ACN / H2O and separated from the spent resin by filtration for the purification step. Various stereoisomers may be formed, and I-66 is an isomer exhibiting the various characterization data (e.g., NMR, HPLC, etc.) described herein, and I-66 is purified. [ka]

[0244] Purification by reverse-phase chromatography

[0245] The crude I-66 active pharmaceutical ingredient is purified by a three-step reversed-phase chromatography (RPC) process (e.g., RPC1, RPC2, and RPC3). The crude peptide (in solution) is diluted 1:4 with ACN / NH4HCO3, then filtered through a 2.4 μm filter and applied to a prepared HPLC column. The effluent from the column is monitored for UV absorption, and the fraction is collected once the product begins to elute. The fraction is evaluated by analytical HPLC and pooled to ensure that the purity meets the in-process control requirements. The fractions that meet the purity requirements are pooled for the next purification step. Sub-fractions that do not meet the purity requirements are pooled and the purification step is repeated, or discarded.

[0246] The first purification step (RPC1) is performed by preparative HPLC using a washed, reverse-phase column pre-equilibriumized with ACN / NH4HCO3. The adsorbed peptide is eluted from the column by applying an ACN / NH4HCO3 gradient. Once the product begins to elute from the column, the fraction is collected and the peptide purity is analyzed by analytical HPLC. RPC1 fractions that meet the specified in-process control (IPC1) purity tolerance criteria (e.g., 85% or higher) are pooled for RPC2 and maintained at 2-8°C until RPC2. RPC1 sub-fractions that do not meet the purity tolerance criteria are either pooled and RPC1 is repeated, or discarded.

[0247] The main pool from RPC1 is diluted with an equal volume of NH4HCO3 and applied to a preparative HPLC column equilibrated with ACN / NH4HCO3. The adsorbed peptide is eluted from the column by applying an ACN / NaH2PO4, pH 8.0 gradient. Once the product begins to elute from the column, the fraction is collected and analyzed for peptide purity by analytical HPLC. RPC2 fractions that meet the in-process control (IPC2) purity acceptance criteria (e.g., 94% or higher in the pre-pool and 95% or higher in the main pool) are pooled for RPC3 and maintained at 2-8°C until RPC3. RPC2 sub-fractions that do not meet the purity acceptance criteria are pooled and RPC2 is repeated, pooled and RPC1 is repeated, or discarded. The pooled sub-fractions are maintained at 2-8°C until their respective next steps.

[0248] The main pool from RPC2 is diluted with an equal volume of USP purified water and applied to a preparative HPLC column equilibrated with ACN / NaH2PO4, pH 8.0. The adsorbed peptide is eluted from the column by applying an ACN / NH4HCO3 gradient. Once the product begins to elute from the column, the fraction is collected and analyzed for peptide purity by analytical HPLC. RPC3 fractions that meet the in-process control (IPC3) purity acceptance criteria (e.g., pre-pool 94.5% or higher and main pool 95.0% or higher) are pooled for the sodium conversion step and maintained at ambient temperature until the sodium conversion step. RPC3 sub-fractions that do not meet the purity acceptance criteria are pooled and RPC2 is repeated, pooled and RPC1 is repeated, or discarded. The pooled sub-fractions are maintained at 2-8°C until their respective next steps.

[0249] Sodium salt conversion and isolation of the final product

[0250] The main pool from RPC3 is combined, diluted 1:1 with Sterile Water for Irrigation (USP) to the target peptide concentration range, and added to an appropriate amount of filtered sodium hydroxide solution required to convert the product to its trisodium form. The sodium form of the product is filtered through a 0.2 μm filter for final lyophilization.

[0251] After the final freeze-drying is complete, the finished I-66 active pharmaceutical ingredient (in powder form) is packaged in an amber glass container, sealed with a Teflon®-lined polypropylene screw cap, and stored at -20°C ± 5°C.

[0252] In some cases, lyophilized I-66 APIs that do not meet the desired acceptance criteria specified in the desired API specifications can be subjected to re-purification. Re-purification is performed by restoring the peptide to a suitable solvent and then repeating the above purification step(s). After re-purification, the obtained material is subjected to final lyophilization as described above.

[0253] In some embodiments, lyophilized I-66 APIs that do not meet the desired acceptable criteria for residual solvent, salt, or water content as specified in the peptide API specifications can be subjected to refreeze-drying. Refreeze-drying is performed by restoring the peptide and then repeating the lyophilization step described above.

[0254] In some embodiments, the following method is used to evaluate I-66 purity; in some embodiments, this method is used for in-process control of preparative HPLC fractions.

[0255] Table E-2. Useful HPLC protocols [Table E-2]

[0256] Other in-process controls used during the manufacturing process include monitoring to ensure that each of the synthetic coupling reactions in the assembly of the protected peptide-resin precursor is complete using ninhydrin and / or chloranil tests and / or RP-HPLC analysis; verifying the purity / impurity profile of the product by RP-HPLC after the crude product has been cleaved from the resin; and verifying the identity of the product by LC-MS after the crude product has been cleaved from the resin.

[0257] In some embodiments, I-66 was isolated as a sodium salt, and the isolation was achieved by freeze-drying it as an amorphous solid.

[0258] Characterization

[0259] I-66 is characterized by various technologies. A specific characteristic is presented as an example.

[0260] The monoisotopic mass of the I-66 drug substance can be verified using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). The sample was analyzed using a Waters Xevo G2-XS QToF mass spectrometer to confirm the monoisotopic mass of the preparation. The theoretical monoisotopic mass is 2074.93 Da(C). 102 H 134 N 18 O 25 (As S2) During mass spectrometry, charged molecular ions [M+2H] 2+ The observed values ​​were: m / z calculated value 1038.4677; measured value 1038.47. From these results, the theoretical molecular mass of I-66 is confirmed.

[0261] The amino acid sequence of I-66 can be verified using matrix-assisted absorption and desorption / ionization time-of-flight tandem mass spectrometry (MALDI-TOF MS / MS). The sample was analyzed using a Bruker ultrafleXtreme MALDI-TOF Mass Spectrometer to confirm the monoisotopic mass and peptide sequence. The results confirm the amino acid sequence of I-66.

[0262] Chiral amino acid analysis (e.g., using GC / MS) can be performed to determine the chiral purity of various constituent amino acid residues, such as Ala, Npg, Asp, Phe, Lys, and BztA. In the analysis, the peptide is hydrolyzed in a 6N deuterated solvent (DCl / D2O), preferably derivatized, and analyzed using GC-MS to determine the enantiomers of each amino acid. Racemization between hydrolysis and derivatization (sample prep) is paralleled with deuterium exchange at the α-position (deuterium labeling). The proportion of epimerized amino acids present in the I-66 sample is expressed as the relative amount of the unlabeled form monitored by mass spectrometry. The results of this analysis confirm that all standard L-amino acids present in the I-66 drug substance have high chiral and isomeric purity.

[0263] Table E-3. Amino acid enantiomer purity by analysis [Table E-3]

[0264] In some embodiments, the present disclosure provides I-66 preparations having approximately the above chiral amino acid purity. In some embodiments, the enantiomer purity of Ala is approximately 99.9% or higher, the enantiomer purity of Npg is approximately 99.8% or higher, the enantiomer purity of Asp is approximately 99.9% or higher, the enantiomer purity of Phe is approximately 99.9% or higher, the enantiomer purity of Lys is approximately 99.9% or higher, and / or the enantiomer purity of BztA is approximately 99.7% or higher.

[0265] Preparations of I-66 may contain counterions. In some embodiments, the sodium and ammonium content of the prepared batches was evaluated by ion chromatography to confirm the identity of the counterions and determine their quantity. For preparations prepared as sodium salts, the identity of sodium counterions equivalent to approximately 3 equivalents per molecule was confirmed, and no ammonium was detected. For preparations prepared as ammonium salts before freeze-drying, the ammonium content was below the theoretical level of the stoichiometric salt, thus suggesting the possibility of salt disproportionation during freeze-drying.

[0266] To confirm I-66 identity and evaluate I-66 preparations, 1 H- and 13 Nuclear magnetic resonance (NMR) spectroscopy (NMR) techniques are used. For example, for preparations, the sample was dissolved in methanol-d4. A 900 MHz Bruker AVANCE III system equipped with a cryoprobe was used. 1 H, 13 C, COSY, TOCSY, NOESY, HSQC, and HMBC data were obtained. The sample concentration was 10 mg / 750 μl. 1 H and 13 The C signal is shown in columns 3 and 4 of Table E-4. Possible allocations are also included in columns 1 and 2 of Table E-4, but are not limited to those.

[0267] Table E-4. 1 H and 13 C signal and possible assignments (MeOD, 25°C) [Table E-4-1] [Table E-4-2] [Table E-4-3] [Table E-4-4]

[0268] A strong and distinct NOE peak is observed between olefin protons 111 and 112. This peak is stronger than the NOE peaks between adjacent aromatic protons 20 and 21, or between 48 and 47 / 49. Without being bound by theory, the distance between adjacent aromatic protons is approximately 2.5 Å, so the distance between 111 and 112 may be shorter than 2.5 Å. These two protons are depicted in cis configuration in the various chemical structures of this disclosure to represent these findings. Both the proton and carbon peaks of 88 and 89 have similar chemical shift values ​​at a 900 MHz instrument. Conventional NOE experiments have provided little information regarding the stereochemistry between these two protons. By combining homonuclear decoupling experiments and simulations, it has been shown that the coupling constant between protons 88 and 89 is approximately 14 Hz. These two protons are depicted in trans configuration in the various chemical structures of this disclosure to represent these findings. Although stereoisomers exist, it will be readily apparent to those skilled in the art that the identity of I-66 can be established and confirmed by various data presented herein, such as NMR and HPLC.

[0269] The structure of I-66 was characterized using X-ray crystallography. The obtained data confirmed the helical nature of I-66 when it binds to β-catenin. The primary sequence of I-66 was also confirmed by X-ray.

[0270] The secondary structure of I-66 was analyzed using microfluidic modulation spectroscopy (MMS). 20 mg / mL of I-66 was analyzed using the AQS3® pro MMS production system (RedShiftBio, Boxborough, MA) as a formulation (10 mg / mL arginine; 33.6 mg / mL PEG-400; 1.2 mg / mL sodium dihydrogen phosphate; pH 8). The absolute absorbance spectra and second derivative plots of the peptide from one batch are shown in Figures 14(A) and (B), respectively. 1662 cm⁻¹ -1 The major peaks in the region indicate that the secondary structure of the protein is predominantly helical, and that it exhibits characteristics of an α-helix and 3 10 -The presence of helical properties is evident. This is consistent with the crystal structure of I-66. A quantitative analysis of the fractional contribution to the higher-order structure (HOS) (Figure 14, (C)) was performed by Gaussian curve deconvolution of baseline-corrected second-order differential plots, based on the secondary structure element notation shown below: [Table 1]

[0271] As shown in Figure 14(C), roughly 56% of the batch structure is 3 10 - It is a helix, and 13% of the structure is α-helix, with a total helix content of 69%. The total percentage of the helical structure is also consistent with the crystal structure, and therefore it is shown that 12 of the 18 amide carbonyl groups (67%) form H bonds that carry the helical structure. Compared to α-helix, 3 10 -A relatively high helix content indicates that some of the amide carbonyl is 3 10This can be explained by the crystal structure, which shows the potential for H-bonding (based on calculated distances) with both i+3 and i+4 amines, resulting in a mixture of -helix and α-helix properties. In solution, MMS measurements revealed that these H-bonding interactions are dynamic and may shift to one property or exceed the other depending on the level of hydration. α- / 3 in the I-66 crystal structure 10 - As an example of the coexistence of helical properties and elongated helical chains, Ac 0 and Npg 3 / B5 4 H bond formation between Npg 3 and 3COOHF 6 / Aib 7 H bond formation between and the 3Thi residue of the elongated chain. 12 BztA 13 , and Glu 14 These are some examples.

[0272] In a specific preparation, I-66 was isolated by lyophilization, and neither crystalline nor polymorphic forms were observed. For example, a sample of the preparation (sodium salt) was evaluated by XRPD at ambient temperature, in transmission mode, held between low-density polyethylene films, using a Panalytical Empyrean diffraction system with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The following parameters were used: range 3–40°²θ, step size 0.01313°, counting time 48 seconds, run time approximately 10 minutes, counting time 23 seconds, run time approximately 5 minutes. The sample was rotated at 60 rpm during data acquisition. XRPD patterns were sorted and manipulated using HighScore Plus v4.9 software. Crystallinity was not explicitly shown, and the sample was found to be amorphous.

[0273] I-66 preparations can be evaluated using thermal analysis. For example, the glass transition temperature of I-66 preparations was determined by performing Hyper-DSC. The glass transition temperature of amorphous materials was not detected by thermogram. Hyper-DSC analysis was performed using a Perkin Elmer DSC8500 differential scanning calorimeter. Accurately weighed samples were placed in crimped aluminum pans, which were closed but not airtight. Each sample was heated and cooled under nitrogen for two cycles at a rate of 300°C per minute, using a set temperature range of -50°C to 160°C. Indium metal was used as a calibration standard.

[0274] I-66 preparations can be evaluated using thermogravimetric differential thermal analysis (TG-DTA). Thermogravimetric analysis of the preparations revealed a significant weight loss, which may be due to the loss of volatile components. A 9% weight loss was observed between 60°C and 170°C, corresponding to 11.7 moles of water. No melting point was detected in the DTA tracking, which is consistent with amorphous behavior. Thermogravimetric analysis was performed using a Mettler Toledo TGA / DSC1 STARe. Calibration standards were indium and tin. The sample was placed in an aluminum sample pan, inserted into the TG furnace, and accurately weighed. Under a nitrogen flow, the heat flow signal was stabilized at 30°C for 1 minute at a rate of 10°C per minute, and then heated to 300°C.

[0275] I-66 preparations can be evaluated using Dynamic Vapor Sorption (DVS). For example, the hygroscopicity and adsorption properties of I-66 preparations were determined using Dynamic Vapor Sorption (DVS). The sample showed continuous water uptake, with a constant weight increase between 40 and 90% RH. From isothermal plots, the total weight increase observed between ambient (40% RH) and 80% RH was 13.3 w / w%, indicating that the sample was hygroscopic based on the European Pharmacopoeia classification. The desorption rate was equivalent to the adsorption rate, with only slight hysteresis observed. Post-DVS XRPD analysis showed that the resulting XRPD pattern was consistent with that of the supply material, thus indicating no significant physical changes. Dynamic Vapor Sorption (DVS) was performed using an SMS DVS Intrinsic Vapor Sorption Balance. Approximately 30 mg of the sample was placed in an aluminum weighing pan, loaded onto a vapor adsorption balance, and maintained at 25°C ± 0.1°C. The sample was subjected to a two-cycle step profile of 40-90-0-90-0-40%RH in 10% increments. The equilibrium standard was set to ∂m / ∂t = 0.002% per minute, with a minimum of 60 minutes and a maximum of 5 hours for each 10% increment. Monitoring the weight change during the adsorption cycle allowed for the determination of the sample's hygroscopic nature. The data acquisition interval was several seconds.

[0276] The specific rotation of the preparation of I-66 is [α] with respect to I-66, according to USP<781S>. D 25 It was determined that the temperature was -73.4° (c = 1% acetic acid / 0.1% in water).

[0277] Dissociation constant and isoelectric point. One pKa value of 5.0 was measured for the I-66 preparation. Further determination of the pKa value was hindered by precipitation. The calculated theoretical isoelectric point of I-66 is 5.0.

[0278] Ultraviolet-visible spectroscopy (UV-Vis). Absorbance peaks at approximately 200 nM and 230 nM were observed from the UV-Vis spectra of I-66 at a concentration of 0.05 mg / mL (24 mM). The maximum absorbance / associated absorbance and corresponding molar extinction at various concentrations in methanol are listed below.

[0279] Table E-5. UV-Vis spectral results of I-66 in methanol (190-800 nm) [Table E-5]

[0280] Solubility Profile: The solubility of I-66 was estimated in 18 solvent systems using the aliquot addition method. These included four aqueous / organic mixtures. At ambient temperature, the solubility of I-66 exceeded 25 mg / mL in 9 of the solvents and 3 of the aqueous mixtures. The obtained solubility data is shown below as an example. In these experiments where solubility was not shown in approximately 40 volumes, two temperature cycles were performed.

[0281] Table E-6. Estimated solubility of I-66 free acid at 20°C [Table E-6]

[0282] All batches of I-66 prepared for evaluation were of high purity, exceeding 95% of the GMP purity specification. In some embodiments, the purity of the I-66 preparation is approximately 93% or higher. In some embodiments, the purity of the I-66 preparation is approximately 94% or higher. In some embodiments, the purity of the I-66 preparation is approximately 95% or higher. In some embodiments, the I-66 preparation contains one or more I-66 isomers. In some embodiments, the I-66 preparation contains one or more peaks with an RRT close to that of I-66 and having the same mass as I-66. For example, without being bound by theory, in some embodiments, impurities eluting close to I-66 (e.g., RRT 1.02, 1.04; RRT of I-66 is 1.00) were identified as olefin isomer impurities formed during the ring-closing metathesis step of the (i,i+3) and (i,i+7) staples. In some embodiments, the preparation or composition includes a fraction having an RRT of 1.02 and the same mass as I-66, and a fraction having an RRT of 1.04 and the same mass as DS-2. In some embodiments, each fraction is independently a single component. In some embodiments, the fraction with an RRT of 1.02 is about 1.5% to 2.5% or about 1.5% to 2.5% or less, for example, about 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, or 1.8% to 2.3%, or about 1.5% or less, 1.6% or less, 1.7% or less, 1.8% or less, 1.9% or less, 2.0% or less, 2.1% or less, 2.2% or less, 2.3% or less, or 1.8% to 2.3% or less.In some embodiments, the fraction with RRT = 1.04 is approximately 0.9% to 3.0%, or less than approximately 0.9% to 3.0%, for example, approximately 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.9%, 0.9% to 2.9%, 2.0% to 3.0%, Alternatively, these could be approximately 1.0% or less, 1.1% or less, 1.2% or less, 1.3% or less, 1.4% or less, 1.5% or less, 1.6% or less, 1.7% or less, 1.8% or less, 1.9% or less, 2.0% or less, 2.1% or less, 2.2% or less, 2.3% or less, 2.4% or less, 2.5% or less, 2.6% or less, 2.7% or less, 2.8% or less, 2.9% or less, 3.9% or less, 0.9% to 2.9% or less, 2.0% to 3.0% or less, etc.

[0283] In some embodiments, the I-66 preparation does not contain Class 1 or Class 2A elemental impurities. The I-66 preparation can be prepared to meet the elemental impurity levels according to the ICH Q3D limits. In some embodiments, the ruthenium level is about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, 10 ppm, 11 ppm, 12 ppm, 13 ppm, 14 ppm, 15 ppm, 16 ppm, 17 ppm, 18 ppm, 19 ppm, 20 ppm, 25 ppm, 30 ppm, 35 ppm, 40 ppm, 45 ppm or 50 ppm, or about 1 ppm or less, 2 ppm or less, 3 ppm or less The levels are less than or equal to ppm, less than or equal to 4 ppm, less than or equal to 5 ppm, less than or equal to 6 ppm, less than or equal to 7 ppm, less than or equal to 8 ppm, less than or equal to 9 ppm, less than or equal to 10 ppm, less than or equal to 11 ppm, less than or equal to 12 ppm, less than or equal to 13 ppm, less than or equal to 14 ppm, less than or equal to 15 ppm, less than or equal to 16 ppm, less than or equal to 17 ppm, less than or equal to 18 ppm, less than or equal to 19 ppm, less than or equal to 20 ppm, less than or equal to 25 ppm, less than or equal to 30 ppm, less than or equal to 35 ppm, less than or equal to 40 In some embodiments, the ruthenium level is about 20 ppm or less. In some embodiments, the ruthenium level is about 15 ppm or less. In some embodiments, the ruthenium level is about 10 ppm or less.In some embodiments, the palladium level is approximately 0.01 ppm, 0.02 ppm, 0.03 ppm, 0.04 ppm, 0.05 ppm, 0.1 ppm, 0.2 ppm, 0.5 ppm, 1.0 ppm, 1.5 ppm, 2 ppm, 5 ppm, 10 ppm, 15 ppm, 20 ppm, 25 ppm, 30 ppm, 40 ppm, or 50 ppm, or approximately 0.01 ppm or less. The following are the palladium levels: below 0.02 ppm, below 0.03 ppm, below 0.04 ppm, below 0.05 ppm, below 0.1 ppm, below 0.2 ppm, below 0.5 ppm, below 1.0 ppm, below 1.5 ppm, below 2 ppm, below 5 ppm, below 10 ppm, below 15 ppm, below 20 ppm, below 25 ppm, below 30 ppm, below 40 ppm, or below 50 ppm. In some embodiments, the palladium level is about 50 ppm or below. In some embodiments, the palladium level is about 20 ppm or below. In some embodiments, the palladium level is about 10 ppm or below. In some embodiments, the palladium level is about 5 ppm or below. In some embodiments, the palladium level is about 2 ppm or below. In some embodiments, the palladium level is about 1 ppm or less. In some embodiments, the palladium level is about 0.5 ppm or less. In some embodiments, the palladium level is about 0.2 ppm or less. In some embodiments, the palladium level is about 0.1 ppm or less. In some embodiments, the palladium level is about 0.05 ppm or less. In some embodiments, the palladium level is about 0.02 ppm or less.

[0284] Evaluate the I-66 preparation using the analytical procedures listed in the official compendium. For example, identity by mass spectrometry, USP <736> ;Moisture content, USP <921> Sodium content, USP <1065> ; Ammonium content, USP <1065> Trifluoroacetic acid content, USP<503.1> / <1065> ; Acetic acid content, USP <503> Residual solvent, USP <467> Elemental impurities, USP <232> / <233> Bioburden, USP <61> / <62> Endotoxin, USP <85> ;Optical rotation, USP <781> etc.

[0285] Assays and related substance testing methods.

[0286] Table E-7 shows the operating conditions for the identity, purity, and related substances test methods for the I-66 active pharmaceutical ingredient.

[0287] Table E-7. Conditions for RP-UHPLC equipment for determining the identity, purity, and related substances of I-66. [Table E-7]

[0288] Peptide content determined by elemental analysis.

[0289] The peptide content is determined by elemental analysis of the I-66 active pharmaceutical ingredient using an elemental analyzer. An appropriate amount of sample is introduced into the elemental analyzer, where it is converted into a gas by combustion at a very high temperature (e.g., 900°C) under ultra-high purity oxygen. Nitrogen is converted to NO x It is converted to , reduced to N2, separated by a GC column, and detected using a thermal conductivity detector (TCD). Using the nitrogen content (%), the peptide content of the sample is calculated using the following formula:

number

[0290] Here, the theoretical nitrogen content is calculated based on anhydrous, counterion-free material. That is, the empirical formula for I-66: C 102 H 134 N 18 O 25 Based on S2 (free acid) MW 2076.42, the value is 12.14%.

[0291] Potency determination

number

[0292] When the % peptide purity by RP-HPLC is 93.65 and the % peptide content is 90.9, the % assay value is 85.1%.

[0293] In some embodiments, this disclosure provides techniques for manufacturing I-66 pharmaceutical products. A specific preparation is described below as an example.

[0294] In some embodiments, the I-66 pharmaceutical product is supplied as a 10 mL liquid filled in a Type 1 glass vial having a suitable elastomer stopper, aluminum seal, and flip cap. The glass vial is labeled to be stored under refrigerated conditions (2-8°C). Based on supportive testing, drug administration by IV infusion can be performed at room temperature. The I-66 injection solution contains 10 mg / mL of I-66, 10 mg / mL of L-arginine, 33.6 mg / mL of PEG-400, and 10 mM sodium phosphate adjusted to pH 8.0. An example formulation of the I-66 pharmaceutical product is shown below.

[0295] Table E-8. Formulation of I-66 Pharmaceutical Products [Table E-8]

[0296] To identify a suitable formulation, various formulations were evaluated. The evaluation included those related to stability and solubility. In some embodiments, histidine buffer, phosphate buffer, or Tris buffer in the pH range of 6.5–8.0 was evaluated. Tris and phosphate were preferably at pH 7.5 or 8.0. In some embodiments, tonicity modifiers, such as sodium chloride or trehalose, were evaluated. In some embodiments, trehalose was selected based on the achievement of higher drug solubility. In some embodiments, various amino acid excipients were evaluated. In some embodiments, glycine, proline, and arginine were evaluated. In some embodiments, arginine was selected based on higher drug solubility. In some embodiments, the addition of other excipients or co-solvents was evaluated to improve solubility, for example, to over approximately 10 mg / mL. For example, PEG-400, PEG-300, NMP, DMSO, and ethanol were evaluated. In some embodiments, PEG-400 and NMP resulted in a greater increase in solubility. In some embodiments, stable concentrations of I-66 exceeding 25 mg / mL were achieved by combining PEG-400 (e.g., about 3%) and arginine (e.g., about 10 mg / mL) in a suitable pH, for example, phosphate buffer or Tris buffer (e.g., about 10 mM) at pH 7.5 or 8.0.

[0297] Mixing tests were conducted to establish the compatibility and stability of I-66 injection solution, 10 mg / mL, when diluted with 5% Dextrose Injection, USP (D5W) in a polyolefin IV mixing bag with a PVC port. The dilution concentration was set to the lowest worst-case concentration of 0.24 mg / mL in the D5W bag. The mixing tests showed no incompatibility, degradation, or potency reduction between the D5W solution and the polyolefin bag or PVC port at this concentration. The mixture was shown to be stable for at least 24 hours under ambient room temperature conditions, and no degradation or decrease in potency was observed over the test period.

[0298] I-66 injection solution, 10 mg / mL, is prepared by adding the I-66 active pharmaceutical ingredient to a solution of PEG-400 and L-arginine in the following quantities in sterile water for injection, sodium phosphate, and pH 9.0 ± 0.2. The pH is adjusted to pH 8.0 ± 0.2 using 1N hydrochloric acid, and the solution is diluted to the target concentration of 10 mg / mL with sterile water for injection. The solution is then sterilized by double filtration through 0.22 μm and aseptically filled into sterile vials sealed with aluminum flip-off seals.

[0299] Table E-9. Batch formulation of I-66 injection, 10 mg / mL, for a batch size of 18 L. [Table E-9]

[0300] The I-66 active pharmaceutical ingredient, stored at -20°C in a refrigeration unit, is brought to room temperature and warmed before compounding. Compounding of the active pharmaceutical ingredient and all excipients is performed in a downflow booth. Compounding is performed in a Grade C area. Approximately 60 w / w% WFI (13.2 kg ± 0.1 kg) is added to a disposable 30 L compounding container containing a LevMixer stirrer. To the stirred WFI, PEG-400 (604.8 g ± 1%), followed by L-arginine (180.0 g ± 1%) and sodium dihydrogen phosphate monohydrate (21.6 g ± 1%) are added at ambient temperature, stirring for at least 10 minutes between each addition to ensure complete dissolution. The pH of the solution is then adjusted to 9.0 ± 0.2 using either 1 N HCl or 1 N NaOH, if necessary. Next, 180.0 g of the I-66 active pharmaceutical ingredient (corrected based on the assay) is added to the formulation container in aliquots of buffer solution at ambient temperature, while the ingredient is being slurryed. The stirred bulk mixture is adjusted to pH 8.0 ± 0.2 using 1N HCl or 1N NaOH to obtain a clear solution at this point. Finally, WFI is added to a final net weight of 18.2 ± 0.2 kg, and the final formulation solution is mixed within 15 minutes. The final pH of the mixture is measured. Samples are taken for density, appearance, assay, and pre-filtration bioburden analysis.

[0301] In some embodiments, the identification of the active pharmaceutical ingredient in the I-66 pharmaceutical product is performed based on relative retention times by assay and related substance testing using RP-HPLC (reverse-phase high-performance liquid chromatography).

[0302] Testing of related substances by assay and HPLC.

[0303] In some embodiments, the operating conditions for identity, purity, and related substance testing methods for I-66 pharmaceutical products, such as I-66 injection solution, 10 mg / mL, are presented below.

[0304] Table E-10. RP-HPLC instrument conditions for determining the i...

Claims

1. I-66; buffer agent; pH adjusters as needed; and solvent; A composition containing the following:

2. The composition according to claim 1, comprising PEG.

3. A composition according to any one of the preceding claims, further comprising an amino acid.

4. A composition according to any one of the preceding claims, further comprising a surfactant.

5. The composition according to claim 1, further comprising a solubilizing agent.

6. The composition according to any one of claims 3 to 5, further comprising a solubilizing agent.

7. The composition according to claim 6, wherein the solubilizer is PEG or a surfactant.

8. A liquid composition, as described in any one of the preceding claims.

9. A composition according to any one of the preceding claims, comprising I-66 in a pharmaceutically acceptable salt form.

10. A composition according to any one of the preceding claims, comprising I-66 in sodium salt form.

11. I-66 is Ac-PL3 １３ -Asp ２ -Npg ３ -B5 ４ -Asp ５ -3COOHF ６ -Aib ７ -Ala ８ -Phe ９ -Lys １０ -PyrS2 １１ -3Thi １２ -BztA １３ -Glu １４ -Ala １５ -NH ２ and where PL3 １ and B5 ４ there is an olefin staple between and B5 ４ and PyrS2 １１ and there is a lactam staple between Lys １０ and Glu １４ ; I-66 in MeOD at 25°C １３ The following peaks (chemical shift (δ, ppm)) were observed in the ¹³C NMR: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35.8, 35.96, 3 6.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123.42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51 , including 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58, wherein I-66 has a purity of about or at least about 90%; and / or I-66 in MeOD at 25°C １ ¹H NMR showed the following peaks (chemical shift (δ, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4. 31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3 .15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 ( 2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.6 Including 9, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), and 2.23 (3H), each peak representing 1H unless otherwise specified; or I-66 in MeOD at 25°C. １ The following peaks (chemical shifts (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.

36. , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.8 1, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3. The peaks include 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified. The composition according to any one of the preceding claims.

12. The identity of I-66 is confirmed by comparison with a reference standard, the reference standard is an I-66 preparation, and I-66 is Ac-PL3 １ - Asp ２ -Npg ３ - B5 ４ - Asp ５ -3COOHF ６ - Aib ７ - Ala ８ -Phe ９ -Lys １０ - PyrS2 １１ -3Th １２ - BztA １３ -Glu １４ - Ala １５ -NH ２ It has the structure of PL3 １ and B5 ４ Between and B5 ４ and PyrS2 １１ Olefin staples are present between them, Lys １０ and Glu １４ A lactam staple exists between and: During MeOD, at 25°C １３ When characterized by 13C NMR, １３ The following peaks (chemical shift (δ, ppm)) were observed in the ¹³C NMR: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35 8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 12 3.42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.0 6, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08 and 178.58; and / or During MeOD, at 25°C １ When characterized by H NMR, １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, Including 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23, or the same １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4 .15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3. 45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2. 07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.4 The peaks include 2, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), and 2.23 (3H), with each peak representing 1H unless otherwise specified. １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3. Including 92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or the same １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.

36. , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.8 1, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3. The peaks include 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified. The composition according to any one of the preceding claims.

13. The comparison described above is whether it involves the use of HPLC, or includes the use of HPLC, as necessary. The composition according to claim 12, wherein the HPLC conditions are selected from those in Example 1, as shown in Table E-7 or Table E-10.

14. Whether the comparison is the use of NMR, or includes the use of NMR, and if necessary, the NMR is １ H NMR, １３ The composition according to any one of claims 12 to 13, wherein the NMR is C14 and / or two-dimensional or multi-dimensional NMR.

15. The composition according to any one of the preceding claims, wherein the concentration of I-66 is about 1 to 25 mg / mL, preferably about 10 mg / mL.

16. The composition according to any one of claims 3 to 15, wherein the amino acid is a basic amino acid.

17. The composition according to any one of claims 3 to 16, wherein the amino acid is arginine.

18. The composition according to any one of claims 3 to 17, wherein the concentration of the amino acid is about 1 to 20 mg / mL, preferably about 10 mg / mL.

19. A composition according to any one of the prior claims, comprising PEG-400.

20. The composition according to any one of the preceding claims, wherein the concentration of PEG is about 1 w / v% to 5 w / v% or 1 v / v% to 5 v / v%, preferably the concentration of PEG is about 3.4 w / v%, about 3 w / v%, about 3.4 v / v%, or about 3 v / v%.

21. A composition according to any one of the preceding claims, comprising a nonionic surfactant.

22. A composition according to any one of the preceding claims, comprising Tween® 80.

23. The composition according to any one of the preceding claims, wherein the concentration of the surfactant is about 0.5 w / v% to 5 w / v% or about 0.5 v / v% to 5 v / v%, preferably the concentration of the surfactant is about 1 w / v% or 1 v / v%.

24. The composition according to any one of the preceding claims, wherein the buffer is a phosphate, and preferably the buffer is sodium dihydrogen phosphate.

25. The composition according to any one of claims 1 to 23, wherein the buffering agent is Tris.

26. The composition according to any one of the preceding claims, wherein the concentration of the buffer is about 10 mM.

27. A composition according to any one of the preceding claims, comprising a pH adjuster.

28. The composition according to claim 27, wherein the pH adjusting agent is NaOH or HCl.

29. The composition according to any one of the preceding claims, wherein the solvent is water.

30. A composition according to any one of the preceding claims, comprising I-66, arginine, PEG-400, sodium phosphate buffer, and water.

31. A composition according to any one of the preceding claims, comprising or consisting of I-66, arginine, PEG-400, sodium phosphate, and water, wherein the pH is adjusted to about 7.0 to 9.0 using NaOH and HCl.

32. A composition according to any one of the preceding claims, comprising I-66, arginine, PEG-400, sodium phosphate, and water, wherein the pH is adjusted to about 7.0 to 9.0 using NaOH or HCl.

33. The composition according to any one of the preceding claims, wherein the pH of the composition is about 7.0 to 9.0, or about 8.

0.

34. I-66 at concentrations of approximately 1–25 mg / mL; Amino acids at a concentration of approximately 1–20 mg / mL; PEG or surfactant in a concentration of approximately 0.5 w / v% to 5 w / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjusters as needed; and Water; containing A composition having a pH of approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjusters as needed; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1 to 100 mM; pH adjuster, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1 to 50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1 to 50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Water; contains The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 1 to 50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Amino acids at a concentration of approximately 1–20 mg / mL; PEG or surfactant in a concentration of approximately 0.5 v / v% to 5 v / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjusters as needed; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; A buffering agent with a concentration of approximately 1 to 100 mM; pH adjusters as needed; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1 to 100 mM; pH adjusters as needed; and water; The pH of the composition is approximately 7.0 to 9.0; the composition, or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1 to 50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1 to 50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 1 to 50 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Water; contains The composition has a pH of approximately 7.0 to 9.

0.

35. The composition according to claim 34, wherein the concentration of PEG-400 is approximately 3 w / v%.

36. The composition according to any one of claims 34 to 35, wherein the concentration of I-66 is about or at least about 10 mg / mL, or about 10 to 25 mg / mL.

37. The composition according to any one of claims 34 to 36, wherein the concentration of the amino acid or arginine is about 10 mg / mL.

38. The composition according to any one of claims 34 to 37, wherein the concentration of PEG-400 is approximately 3 v / v%.

39. The composition according to any one of claims 34 to 38, wherein the concentration of the buffer agent or sodium dihydrogen phosphate is about 5 to 20 mM, or about 10 mM.

40. I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v% to 5 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Amino acids at a concentration of approximately 1–20 mg / mL; PEG or surfactant in a concentration of approximately 0.5 w / v% to 5 w / v%; and a buffer included; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 w / v% to 5 w / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 5–25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 w / v% to 5 w / v%; and Consists of a buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 3 w / v% to 5 w / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0, or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0, or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 3 w / v% to 5 w / v%; and Consists of a buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Consists of a buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Consists of a buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 w / v%; and Consists of a buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at concentrations of approximately 3 v / v% to 5 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and Contains water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; and It consists of water; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Amino acids at a concentration of approximately 1–20 mg / mL; PEG or surfactant in a concentration of approximately 0.5 v / v% to 5 v / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 0.5 v / v% to 5 v / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 1-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 1–25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at concentrations of approximately 5–25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-20 mg / mL; PEG-400 at concentrations of approximately 2 v / v% to 5 v / v%; and Consists of a buffer solution; The pH of the composition is approximately 7.0 to 9.0, or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 3 v / v% to 5 v / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0, or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0, or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0, or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at concentrations of approximately 3 v / v% to 5 v / v%; and Consists of a buffer solution; The pH of the composition is approximately 7.0 to 9.0, or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 5-15 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and Consists of a buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10-25 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and Consists of a buffer solution; The pH of the composition is approximately 7.0 to 9.0; or I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and Includes buffer solution; The pH of the composition is approximately 7.0 to 9.0, or I-66 at a concentration of approximately 10 mg / mL; Arginine at a concentration of approximately 10 mg / mL; PEG-400 at a concentration of approximately 3 v / v%; and Consists of a buffer solution; The composition has a pH of approximately 7.0 to 9.

0.

41. The composition according to claim 40, wherein the concentration of I-66 is approximately 10 mg / mL.

42. The composition according to claim 40, wherein the concentration of I-66 is about or at least about 10 mg / mL, or about 10 to 25 mg / mL.

43. The composition according to any one of claims 40 to 42, wherein the system comprises a buffer, the buffer being a phosphate buffer, and optionally a sodium phosphate buffer.

44. The composition according to any one of claims 40 to 42, wherein the system includes a buffer, and the buffer is a Tris buffer.

45. The composition according to any one of claims 40 to 46, wherein the system includes a buffer, and the concentration of the buffer is about 5 to 100 mM, and optionally about 10 mM.

46. 10mg / mL I-66; 10 mg / mL arginine; 33.6 mg / mL PEG-400; and Contains 10 mM sodium phosphate; The pH of the composition is approximately 8.0, or 10mg / mL I-66; 10 mg / mL arginine; 33.6 mg / mL PEG-400; and It consists of 10 mM sodium phosphate; The composition has a pH of approximately 8.

0.

47. I-66 is Ac-PL3 １ - Asp ２ -Npg ３ - B5 ４ - Asp ５ -3COOHF ６ - Aib ７ - Ala ８ -Phe ９ -Lys １０ - PyrS2 １１ -3Th １２ - BztA １３ -Glu １４ - Ala １５ -NH ２ PL3 １ and B5 ４ Between and B5 ４ and PyrS2 １１ Olefin staples are present between them, Lys １０ and Glu １４ A lactam staple exists between them, and I-66 in MeOD at 25°C １３ The following peaks (chemical shifts (δ, ppm)) were observed in the ¹³C NMR: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35.8 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123.42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13 , including 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08 and 178.58 and I-66, I-66 has a purity of approximately or at least approximately 90%; and / or I-66 in MeOD at 25°C １ ¹H NMR showed the following peaks (chemical shift (δ, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4. 31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3 .15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 ( 2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.6 Including 9, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), and 2.23 (3H), each peak representing 1H unless otherwise specified, or I-66 in MeOD at 25°C. １ The following peaks (chemical shifts (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.

36. , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.8 1, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3. The peaks include 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified. The composition according to any one of claims 34 to 46.

48. The identity of I-66 was confirmed by comparison with a reference standard, the reference standard being an I-66 preparation, and I-66 being Ac-PL3 １ -Asp ２ -Npg ３ -B5 ４ -Asp ５ -3COOHF ６ -Aib ７ -Ala ８ -Phe ９ -Lys １０ -PyrS2 １１ -3Thi １２ -BztA １３ -Glu １４ -Ala １５ -NH ２ having the structure of, and PL3 １ and B5 ４ between and B5 ４ and PyrS2 １１ there being an olefin staple between, and Lys １０ and Glu １４ there being a lactam staple between, and: During MeOD, at 25°C １３ When characterized by 13C NMR, １３ The following peaks (chemical shift (δ, ppm)) were observed in the ¹³C NMR: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35 8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 12 3.42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.0 6, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08 and 178.58; and During MeOD, at 25°C １ When characterized by H NMR, １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, Including 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23, or the same １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4 .15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3. 45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2. 07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.4 The peaks include 2, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), and 2.23 (3H), with each peak representing 1H unless otherwise specified. １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3. Including 92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or the same １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.

36. , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.8 1, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3. The peaks include 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified. The composition according to any one of claims 34 to 47.

49. Whether the comparison described above involves the use of HPLC, or includes the use of HPLC, as necessary. The composition according to claim 48, wherein the HPLC conditions are selected from those in Example 1, as shown in Table E-7 or Table E-10.

50. Whether the comparison is the use of NMR, or includes the use of NMR, and if necessary, the NMR is １ H NMR, １３ The composition according to any one of claims 48 to 49, wherein the NMR is C14 and / or two-dimensional or multi-dimensional NMR.

51. The composition according to any one of the preceding claims, further comprising a pharmaceutically acceptable carrier.

52. The composition according to any one of the preceding claims, further comprising a sugar, wherein the sugar is optionally dextrose.

53. A composition prepared by diluting the composition according to any one of claims 1 to 52 with a pharmaceutically acceptable diluent to a predetermined volume.

54. The composition according to claim 53, wherein the pharmaceutically acceptable diluent is a sugar solution, and optionally the pharmaceutically acceptable diluent is a dextrose solution, and optionally the pharmaceutically acceptable diluent is 5% Dextrose Injection, USP.

55. The composition according to any one of claims 53 to 54, wherein the predetermined volume is 250 mL.

56. The composition according to any one of claims 53 to 55, wherein the concentration of I-66 is about 0.05 to 10 mg / mL, or about 0.05 to 6 mg / mL, or about 0.1 to 5 mg / mL.

57. The composition according to any one of claims 53 to 56, wherein the concentration of the solubilizer, amino acid, or arginine is about 0.05 to 10 mg / mL, or about 0.05 to 6 mg / mL, or about 0.01 to 5 mg / mL.

58. The composition according to any one of claims 53 to 57, wherein the concentration of the surfactant or PEG is about 0.01 w / v% to 3 w / v%, or about 0.05 w / v% to 2 w / v%, or about 0.01 v / v% to 3 v / v%, or about 0.05 v / v% to 2 v / v%.

59. The composition according to any one of claims 53 to 58, wherein the concentration of the buffer agent or buffer solution is about 0.1 to 10 mM, or about 0.2 to 5 mM.

60. The composition according to any one of claims 53 to 59, wherein the buffer agent is sodium dihydrogen phosphate, or the buffer is a phosphate buffer, or the buffer is a Tris buffer.

61. The composition according to any one of claims 53 to 60, wherein the pharmaceutically acceptable diluent is 5% Dextrose Injection, USP, and the dextrose concentration is about 0.02 to 0.05 mg / mL.

62. I-66 at concentrations of approximately 0.1–6 mg / mL; Amino acids at a concentration of approximately 0.1–6 mg / mL; PEG or surfactant in a concentration of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; and A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.2–5 mg / mL; PEG-400 at concentrations of approximately 0.05 w / v% to 2 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02–0.05 g / mL; and A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Amino acids at a concentration of approximately 0.1–6 mg / mL; PEG or surfactant in a concentration of approximately 0.01 w / v% to 3 w / v%; Buffer, and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Buffer, and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.05 w / v% to 2 w / v%; Buffer, and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.2–5 mg / mL; PEG-400 at concentrations of approximately 0.05 w / v% to 2 w / v%; Buffer, and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at concentrations of approximately 0.1–6 mg / mL; Amino acids at a concentration of approximately 0.1–6 mg / mL; PEG or surfactant in a concentration of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.2–5 mg / mL; PEG-400 at concentrations of approximately 0.05 w / v% to 2 w / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02–0.05 mg / mL; and A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Amino acids at a concentration of approximately 0.1–6 mg / mL; PEG or surfactant in a concentration of approximately 0.01 w / v% to 3 w / v%; Buffer, and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 mg / mL; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 w / v% to 3 w / v%; Buffer, and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 mg / mL; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.05 w / v% to 2 w / v%; Buffer, and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 mg / mL; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.2–5 mg / mL; PEG-400 at concentrations of approximately 0.05 w / v% to 2 w / v%; Buffer, and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 mg / mL; or I-66 at concentrations of approximately 0.1–6 mg / mL; Amino acids at a concentration of approximately 0.1–6 mg / mL; PEG or surfactants at a concentration of approximately 0.01 v / v%–3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition containing water; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.2–5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02–0.05 g / mL; and A composition containing water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Amino acids at a concentration of approximately 0.1–6 mg / mL; PEG or surfactant in a concentration of approximately 0.01 v / v% to 3 v / v%; Buffer, and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Buffer, and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; Buffer, and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.2–5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; Buffer, and A composition containing dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at concentrations of approximately 0.1–6 mg / mL; Amino acids at a concentration of approximately 0.1–6 mg / mL; PEG or surfactant in a concentration of approximately 0.01 v / v% to 3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; A buffering agent with a concentration of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; pH adjuster, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at concentrations of approximately 0.01 to 100 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.1–10 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.01–0.05 mg / mL; A composition consisting of water; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.2–5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; Sodium dihydrogen phosphate at a concentration of approximately 0.2–5 mM; Sodium hydroxide, if necessary; Hydrochloric acid, if necessary; Dextrose at a concentration of approximately 0.02–0.05 g / mL; and A composition consisting of water; or I-66 at concentrations of approximately 0.1–6 mg / mL; Amino acids at a concentration of approximately 0.1–6 mg / mL; PEG or surfactant in a concentration of approximately 0.01 v / v% to 3 v / v%; Buffer, and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at concentrations of approximately 0.1–6 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.01 v / v% to 3 v / v%; Buffer, and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.1–6 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; Buffer, and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 g / mL; or I-66 at a concentration of approximately 0.2–5 mg / mL; Arginine at a concentration of approximately 0.2–5 mg / mL; PEG-400 at concentrations of approximately 0.05 v / v% to 2 v / v%; Buffer, and A composition comprising dextrose at a concentration of approximately 0.02 to 0.05 g / mL.

63. The concentration of I-66 is approximately 0.2–5 mg / mL; The arginine concentration is approximately 0.2–5 mg / mL; The concentration of PEG-400 is approximately 0.06 to 1.7 w / v%; and The dextrose concentration is approximately 0.02–0.05 mg / mL; or The concentration of I-66 is approximately 0.2–5 mg / mL; The arginine concentration is approximately 0.2–5 mg / mL; The concentration of PEG-400 is approximately 0.06 to 1.7 v / v%; and The dextrose concentration is approximately 0.02–0.05 mg / mL. The composition according to claim 62.

64. The composition according to any one of claims 62 to 63, wherein the buffer is a phosphate buffer or a Tris buffer, and / or the concentration of the buffer is about 0.01 to 10 mM or about 0.02 to 5 mM.

65. The composition according to any one of claims 62 to 64, wherein the pH of the composition is about 7.0 to 9.0, or the pH of the composition is about 8.

0.

66. I-66 is Ac-PL3 １ - Asp ２ -Npg ３ - B5 ４ - Asp ５ -3COOHF ６ - Aib ７ - Ala ８ -Phe ９ -Lys １０ - PyrS2 １１ -3Th １２ - BztA １３ -Glu １４ - Ala １５ -NH ２ PL3 １ and B5 ４ Between and B5 ４ and PyrS2 １１ Olefin staples are present between them, Lys １０ and Glu １４ A lactam staple exists between and: I-66 in MeOD at 25°C １３ The following peaks (chemical shift (δ, ppm)) were observed in the ¹³C NMR: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35.8, 35.96, 3 6.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123.42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51 , including 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58, wherein I-66 has a purity of about or at least about 90%; and / or I-66 in MeOD at 25°C １ ¹H NMR showed the following peaks (chemical shift (δ, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4. 31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3 .15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 ( 2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.6 Including 9, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), and 2.23 (3H), each peak representing 1H unless otherwise specified, or I-66 in MeOD at 25°C. １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.

36. , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.8 1, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3. The peaks include 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified. The composition according to any one of claims 62 to 65.

67. The identity of I-66 is confirmed by comparison with a reference standard, the reference standard is an I-66 preparation, and I-66 is Ac-PL3 １ - Asp ２ -Npg ３ - B5 ４ - Asp ５ -3COOHF ６ - Aib ７ - Ala ８ -Phe ９ -Lys １０ - PyrS2 １１ -3Th １２ - BztA １３ -Glu １４ - Ala １５ -NH ２ It has the structure of PL3 １ and B5 ４ Between and B5 ４ and PyrS2 １１ Olefin staples are present between them, Lys １０ and Glu １４ A lactam staple exists between and: During MeOD, at 25°C １３ When characterized by 13C NMR, １３ The following peaks (chemical shift (δ, ppm)) were observed in the ¹³C NMR: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35 8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 12 3.42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.0 6, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08 and 178.58; and During MeOD, at 25°C １ When characterized by H NMR, １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, Including 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23, or the same １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4 .15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3. 45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2. 07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.4 The peaks include 2, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), and 2.23 (3H), with each peak representing 1H unless otherwise specified. １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3. Including 92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or the same １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.

36. , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41 , 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53 , 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2. 81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3 This includes 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified. The composition according to any one of claims 62 to 66.

68. Whether the comparison described above involves the use of HPLC, or includes the use of HPLC, as necessary. The composition according to claim 67, wherein the HPLC conditions are selected from those in Example 1, as shown in Table E-7 or Table E-10.

69. Whether the comparison is the use of NMR, or includes the use of NMR, and if necessary, the NMR is １ H NMR, １３ The composition according to any one of claims 67 to 68, wherein the NMR is C14 and / or two-dimensional or multi-dimensional NMR.

70. The composition according to any one of the preceding claims, wherein I-66 has a purity of about 80%, 85%, 95%, or higher.

71. The process includes the step of diluting the composition of I-66 with a pharmaceutically acceptable diluent, if necessary, A step of calculating the volume of composition I-66 to administer the intended dose, The steps include taking out a volume of diluent corresponding to the calculated volume from an infusion bag / container containing a pharmaceutically acceptable diluent, The steps include adding the calculated volume of I-66 composition to the injection bag / container, A method including, as needed, The concentration of I-66 in the composition is approximately 1 to 25 mg / mL, approximately 5 to 25 mg / mL, or approximately 10 mg / mL; The composition of I-66 is the composition according to any one of claims 1 to 54; and / or The pharmaceutically acceptable diluent is 5% Dextrose Injection, USP; If necessary, the method prepares I-66 for administration, and if necessary for intravenous administration; and If necessary, the method prepares the composition according to any one of claims 55 to 72. method.

72. A method comprising the step of comparing I-66 in a preparation with a reference standard, If necessary, the reference standard is the I-66 preparation, and I-66 is Ac-PL3 １ - Asp ２ -Npg ３ - B5 ４ - Asp ５ -3COOHF ６ - Aib ７ - Ala ８ -Phe ９ -Lys １０ - PyrS2 １１ -3Th １２ - BztA １３ -Glu １４ - Ala １５ -NH ２ It has the structure of PL3 １ and B5 ４ Between and B5 ４ and PyrS2 １１ Olefin staples are present between them, Lys １０ and Glu １４ A lactam staple exists between and: During MeOD, at 25°C １３ When characterized by 13C NMR, １３ The following peaks (chemical shift (δ, ppm)) were observed in the ¹³C NMR: 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35. 8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123. 42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 1 38.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58; and During MeOD, at 25°C １ When characterized by H NMR, １ ¹H NMR showed the following peaks (chemical shift (δ, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, Including 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23, or the same １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4 .15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3. 45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2 .07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1. This includes 42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), and 2.23 (3H), where each peak represents 1H unless otherwise specified; or １ The following peaks (chemical shift (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.2 7, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3. Including 92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, or the same １ The following peaks (chemical shifts (δ, ppm)) were observed in the ¹H NMR: 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.

36. , 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.8 1, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3. This includes 40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, with each peak representing 1H unless otherwise specified; If necessary, the comparison may include the use of HPLC or the use of HPLC, if necessary. As described in Table E-7 or Table E-10, the HPLC conditions are selected from those in Example 1; and If necessary, the comparison may involve the use of NMR, or include the use of NMR, and if necessary, the NMR may be １ H NMR, １３ C NMR, and / or two-dimensional or multi-dimensional NMR; If necessary, the method confirms the identity of I-66 in the preparation; as needed, The method described above is used to control the quality of the I-66 preparation; and / or The method described above is used to release the I-66 preparation; as needed, The I-66 preparation is a preparation of the I-66 active pharmaceutical ingredient; or The I-66 preparation is a preparation of the I-66 pharmaceutical product; and as needed, The I-66 in the preparation is in or contains a pharmaceutically acceptable salt form, or the I-66 in the preparation is in or contains a sodium salt form, or the I-66 in the reference standard is in or contains a pharmaceutically acceptable salt form, or the I-66 in the reference standard is in or contains a sodium salt form, method.

73. A method for modulating the interaction of beta-catenin with a partner in a system, comprising the step of administering or delivering I-66 to the system, wherein the partner is optionally TCF4; or A method for modulating the TCF-beta-catenin interaction in a system, comprising the step of contacting beta-catenin with I-66; or A method for modulating the TCF-beta-catenin interaction in a system, comprising the step of administering or delivering I-66 to the system; or A method for inhibiting beta-catenin-dependent cell proliferation, comprising the step of administering or delivering I-66 to the system; or A method for reducing beta-catenin polypeptide levels in a system, comprising the step of administering or delivering I-66 to the system; or A method for reducing the levels of c-Myc polypeptide and / or transcript in a system, comprising the step of administering or delivering I-66 to the system, wherein, if necessary, the levels of c-Myc polypeptide and / or c-Myc mRNA are reduced, and / or, if necessary, the reduction is observed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days or later after administration; or A method for reducing Axin2 polypeptide levels and / or transcript levels in a system, comprising the step of administering or delivering I-66 to the system, wherein, if necessary, the Axin2 polypeptide levels and / or Axin2 mRNA levels are reduced; or A method for modulating the WNT / beta-catenin pathway in a system, comprising the step of administering or delivering I-66 to the system, thereby modulating nucleic acid expression; or A method comprising the step of administering or delivering I-66 to the system, wherein the levels of nucleic acid transcripts and / or their products are modulated; or A method for preparing I-66, comprising the step of administering or delivering I-66 to a system, thereby modulating nucleic acid expression.

74. Nucleic acids are either genes or contain genes. The system is an in vitro system; The system is an in vivo system; The system is either a sample or contains one; The system is a cell, tissue, or organ, or includes one; The system is cancerous, or contains cancer cells; The system is a tumor or contains a tumor; and / or The system is the object. The method according to claim 73.

75. A method for treating cancer, comprising the step of administering or delivering an effective amount of I-66 to a subject suffering from cancer.

76. The method according to claim 75, wherein the cancer is a solid tumor.

77. The cancer is colorectal cancer, gastric cancer, lung cancer, non-small cell lung cancer, metastatic non-small cell lung cancer, non-small cell lung cancer stage IIIIB, non-small cell carcinoma, non-small cell lung cancer, TNM stage 4, or esophagogastric junction cancer, or the cancer is advanced or metastatic MSS colorectal cancer, advanced or metastatic non-small cell lung cancer, advanced or metastatic gastric cancer, or advanced or metastatic esophagogastric junction cancer, or the cancer is advanced or metastatic non-small cell lung cancer, beta, demonstrated WPAM in APC - The method according to claim 75, wherein the cancer is an advanced or metastatic non-small cell lung cancer in which WPAM has been demonstrated in catenin, an advanced or metastatic gastric cancer in which WPAM has been demonstrated in APC, an advanced or metastatic gastric cancer in which WPAM has been demonstrated in beta-catenin, an advanced or metastatic gastroesophageal junction cancer in which WPAM has been demonstrated in APC, or an advanced or metastatic gastroesophageal junction cancer in which WPAM has been demonstrated in beta-catenin, and optionally the cancer comprises a mutation selected from loss-of-function mutations in APC, gain-of-function mutations in CTNNB1, RNF43 LOF mutations, RSPO2 fusions and RSPO3 fusions, or a mutation selected from mutations in AMER1, AXIN1, AXIN2, BCL9, CSNK1A1, GSK3B, LRP5, LRP6, LGR5, TCF7L2 and WIF1.

78. The aforementioned tumor is non-MSI-H; The aforementioned tumor is non-dMMR; The aforementioned cancer is locally advanced cancer; The cancer is metastatic cancer; and / or The aforementioned cancer is microsatellite stable. The method according to any one of claims 75 to 77.

79. The method according to any one of claims 75 to 78, wherein the cancer comprises a Wnt pathway activating mutation (WPAM), the cancer comprises an APC mutation and / or a beta-catenin mutation, and / or the cancer is refractory.

80. Steps include administering or delivering I-66 weekly; A step of administering or delivering I-66 approximately weekly in at least three or four doses; The step of administering or delivering I-66 approximately weekly in a continuous cycle of 21 or 28 days; A step of administering or delivering I-66 as a composition having a volume of approximately 250 mL; The step of administering or delivering I-66 as a composition according to any one of claims 1 to 72; and / or Steps to administer or deliver I-66 intravenously The method according to any one of claims 73 to 79, including the method described in any one of claims 73 to 79.

81. Approximately 18mg / m ２ Administer I-66 at the specified dose; Approximately 36mg / m ２ Administer I-66 at the specified dose; Approximately 72mg / m ２ Administer I-66 at the specified dose; Approximately 144mg / m ２ Administer I-66 at the specified dose; Approximately 240mg / m ２ Administer I-66 at the specified dose; Approximately 360mg / m ２ Administer I-66 at the specified dose; Approximately 480mg / m ２ Administer I-66 in the dose of ; and / or Approximately 600mg / m ２ Administer I-66 at the specified dose; The method according to any one of claims 73 to 80.

82. The method according to any one of the preceding claims, comprising the step of administering or delivering a second therapeutic agent or a second treatment to a subject.

83. The composition or method according to any one of Embodiments 1 to 398.

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