Ac225-dota-tate conjugate

Abstract

The present disclosure relates to enriched and stable radiopharmaceutical compositions comprising 225 Ac]Ac-DOTA-TATE.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 550,380, filed February 6, 2024, and U.S. Provisional Application No. 63 / 727,994, filed December 4, 2024, the entire contents of which are hereby incorporated by reference. Background Technology

[0003] DOTA-TATE is an eight-amino acid-long peptide with a covalently bonded DOTA bifunctional chelator (Nockel P. et al., Thyroid. [Thyroid] 2016, 26 (6): 831–5). DOTA-TATE can react with radionuclides such as actinium-225, gallium-68, lutetium-177, and copper-64 to form radiopharmaceuticals for positron emission tomography (PET) imaging or radionuclide therapy. Radionuclide therapy using DOTA-TATE targets the somatostatin receptor (SSR) (Aktolun, C. et al., Nuclear Medicine Therapy: Principles and Clinical Applications. [Nuclear Medicine Therapy: Principles and Clinical Applications] 2012, Springer. [Springer Press] p. 364). Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Since somatostatin regulates cell growth and hormone secretion, the somatostatin receptor (SSTR) has become a valuable target for the treatment of different types of neuroendocrine tumors (NETs).

[0004] One of the major challenges in radiopharmaceutical production is extending the product's shelf life to allow for patient treatment in locations remote from the manufacturer's site. As radionuclides (such as actinium-225) decay, a range of highly reactive chemicals are generated. In some cases, these can react with pharmaceutical substances, for example, causing degradation of drugs containing radioisotopes and increasing radioactive impurities over time.

[0005] Most common radionuclide therapy manufacturing processes require the use of ICH Class 2 solvents, which cannot be injected into the human body, necessitating additional chemical processing and reconstitution steps. However, these extra steps often lead to the degradation of radioligand therapy through radiodegradation. Furthermore, because radioisotopes have short half-lives, the time between production and therapy administration must be minimized. Producing pure, highly radioactive drugs that rapidly track tumors will increase the likelihood of adequate radiation reaching the tumor to induce cell death.

[0006] Therefore, there is still a need to develop radioligand therapies that are radioactively enriched and have prolonged stability. Summary of the Invention

[0007] One of the major challenges in radiopharmaceutical manufacturing is extending the shelf life of the product to allow for patient treatment in locations remote from the manufacturing site. As radionuclides (such as actinium-225) decay, a range of highly reactive chemicals are generated. In some cases, these can react with pharmaceutical substances, for example, causing degradation of drugs containing radioisotopes and increasing radioactive impurities over time. Therefore, in one aspect, this document provides liquid radiopharmaceutical formulations that provide enhanced stability for alpha-emitting radionuclides (such as actinium-225). Thus, this disclosure provides formulations containing […] 225 Ac]Ac-DOTA-TATE radiopharmaceutical compositions address stability issues by being highly enriched and stable for at least 288 hours.

[0008] Therefore, on the one hand, this paper provides a method that includes enrichment [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition having a radiochemical purity (RCP) greater than 98%, wherein [ 225 Ac]Ac-DOTA-TATE has the following structure:

[0009] .

[0010] On the other hand, this paper provides a method that includes enrichment [ 225 Ac]Ac-DOTA-TATE is a radiopharmaceutical composition having a radiochemical purity (RCP) greater than 94%, wherein the RCP is measured by radio-HPLC.

[0011] On the other hand, this paper provides a method that includes [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition, wherein the radiopharmaceutical composition has a radiochemical purity (RCP) greater than 99% and a specific activity of 5 µCi / nmol.

[0012] On the other hand, this article provides a method that includes [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition, wherein the radiopharmaceutical composition has a radiochemical purity (RCP) greater than 95% and a specific activity of 5 µCi / nmol.

[0013] The radiopharmaceutical composition disclosed herein exhibits superior performance compared to previously developed compositions containing [ 225 Stability of the Ac]Ac-DOTA-TATE radiopharmaceutical composition. Attached Figure Description

[0014] Figure 1 The co-injection of DOTATATE and [[ was shown] nat HPLC separation of La]La-DOTA-TATE.

[0015] Figure 2 It shows [ 225 HPLC separation of the Ac]Ac-DOTA-TATE reaction mixture, with indications of the collected fractions. Detailed Implementation

[0016] This article provides information containing enrichment [ 225 Ac]Ac-DOTA-TATE is a radiopharmaceutical composition that exhibits a high level of radiochemical purity (RCP) over an extended period of time.

[0017] Although the desired radiolabeled peptide and the unwanted non-radiolabeled peptide starting materials are similar in structure and properties, the formulations and compositions disclosed herein unexpectedly enrich the desired radiolabeled peptide product. Another unexpected finding of the disclosed formulations is that the addition of a surfactant to the formulations improved the stability of the radiolabeled peptides over a longer period after separation.

[0018] definition

[0019] The following are definitions of various terms used to describe the compositions disclosed herein. These definitions apply to all terms used throughout this specification and claims unless otherwise specified individually or as part of a larger group.

[0020] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Typically, the nomenclature used herein, as well as laboratory procedures in cell culture, organic chemistry, and peptide chemistry, are those well-known and commonly used in the art.

[0021] As used herein, the article “a / an” refers to one or more (i.e., at least one) grammatical objects of the article. For example, “a / an element” means one or more elements. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0022] As used herein, the term “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to measurable values ​​such as quantity, time interval, etc., the term “about” means covering a variation of ±20% or ±10% from the specified value, including ±5%, ±1%, and ±0.1%, because such variation is suitable for performing the disclosed methods.

[0023] As used herein, the term "enriched" refers to a radiolabeled peptide composition in which the ratio of radiolabeled peptides is higher than the ratio of non-radiolabeled peptide starting materials. In the examples, the radiolabeled peptide compositions are enriched by approximately 90%, 95%, 96%, 97%, 98%, or 99% compared to non-radiolabeled peptides.

[0024] As used herein, the term "stabilizing solution" refers to a solution containing a radiodegradation stabilizer. A radiodegradation stabilizer is a substance that prevents or reduces radiodegradation (i.e., the degradation of target molecules by radioactive decay energy).

[0025] As used herein, the term "quencher" or "quenching agent" refers to a molecule or group of molecules that can remove excess radioactive starting material during the synthesis of radiolabeled compounds, including radiolabeled peptides. In a non-limiting example, the quencher is diethylenetriaminepentaacetic acid (DTPA).

[0026] As used herein, “surfactant” refers to an excipient that preferentially adsorbs onto the interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water / air interface, or an organic solvent / air interface. Suitable surfactants include, but are not limited to, fatty alcohols, such as polyethylene glycol (PEG) and cetyl alcohol. In non-limiting embodiments, the surfactant is a polysorbate. Polysorbates are esterifications of ethoxylated sorbitol (a derivative of sorbitol) with fatty acids and include (but are not limited to): polyoxyethylene (20) sorbitol monolaurate, polyoxyethylene (20) sorbitol monopalmitate, polyoxyethylene (20) sorbitol monostearate, and polyoxyethylene (20) sorbitol monooleate. In some embodiments provided herein, the polysorbate is polyoxyethylene (20) sorbitol monolaurate (Tween20).

[0027] The term "buffer solution" refers to a solution whose pH does not change significantly when diluted or supplemented with acid or base at a constant temperature.

[0028] As used herein, the terms “radioactive nuclide” and “radioactive isotope” are used interchangeably and refer to a nuclide with excess nuclear energy that is used in one of three ways: emitted from the nucleus as a gamma emission; transferred to one of its electrons to release it as a converted electron; or used to produce and emit new particles (alpha or beta particles) from the nucleus.

[0029] As used herein, the term "radiochemical purity" or "RCP" is defined as the percentage of total radioactivity in the composition corresponding to a radiolabeled pharmaceutical substance (radiolabeled peptide). In the examples, the radiolabeled peptide is [ 225 Ac]Ac-DOTA-TATE.

[0030] As used in this article, the term "half-life" or "t" refers to the period of time in which the time elapsed. 1 / 2 "This refers to the time it takes for half of the radioactive atoms of a radionuclide to decay."

[0031] As used herein, the term “chromatography” refers to a process in which a chemical mixture carried by a liquid or gas is separated into its components due to the differential distribution of the chemical entities as they flow around or over a stationary liquid or solid phase.

[0032] As used herein, the phrase “liquid chromatography” or “LC” refers to the process in which one or more components in a fluid solution are selectively blocked when a fluid is uniformly passed through a column of finely dispersed material or through a capillary pathway. The blocking is caused by the partitioning of the components of the mixture between one or more stationary phases and the bulk fluid (i.e., the mobile phase) as the fluid moves relative to one or more stationary phases. Examples of “liquid chromatography” include reversed-phase liquid chromatography (RPLC), high-performance liquid chromatography (HPLC), and turbulent liquid chromatography (TFLC) (sometimes referred to as high-turbulence liquid chromatography (HTLC) or high-throughput liquid chromatography).

[0033] During the separation process, the mobile phase composition can be constant (i.e., "isocratic elution" as used herein) or can be varied (i.e., "gradient elution" as used herein). To separate compositions containing components with very different chemical properties, additional solvent can typically be introduced into the column by increasing the proportion of solvent in the mobile phase. In a non-limiting example, the stationary phase is C18 bonded to silica. In a non-limiting example, the mobile phase comprises an aqueous mixture of water and an organic solvent (e.g., ethanol).

[0034] In some embodiments, liquid chromatography is ultra-high performance liquid chromatography (UPLC; the terms “ultra-high performance liquid chromatography” or UHPLC are used interchangeably herein). UPLC, referred to in the art as LC technology, relies on columns with reduced particle size (e.g., less than 2 µm) and increased flow rate to improve chromatographic resolution, efficiency, peak capacity, and sensitivity (see, for example, Plumb, R. et al. (2004) Rapid Commun. Mass Spectrom. [Mass Spectrometry Letters] 18:2331-2337). In some embodiments, UPLC refers to the use of a column with a particle size of less than 2 µm in liquid chromatography. In some embodiments, UPLC refers to the use of a high linear solvent rate in liquid chromatography (e.g., observed when operating at 6000 psi or higher). Exemplary UPLC instruments are commercially available, such as the Waters ACQUITY Premier UPLC Class H (Premier QSM, Premier SM-FTN, CM-A, PDA eλ detector, and SQD 2 mass analyzer).

[0035] As used in this article, the phrase “high performance liquid chromatography” or “HPLC” (sometimes called “high pressure liquid chromatography”) refers to a liquid chromatography method in which resolution is increased by forcing the mobile phase through the stationary phase (typically a densely packed column) under pressure.

[0036] As used herein, the terms "extraction column" and "column" are used interchangeably and refer to a chromatographic column with sufficient plates to separate the substances eluted from a sample. The general purpose of an extraction column is to separate or extract retained and non-retained substances to obtain a purified sample for further analysis. Such a column is typically distinct from an "analytical column," which allows for the determination of the presence or amount of an analyte. As used in this context, the term "about" means ±10%. In a preferred embodiment, the analytical column comprises particles with a diameter of about 5 μm.

[0037] As used herein, the term "radiopharmaceutical composition" refers to a composition comprising at least one active ingredient and a pharmaceutically acceptable carrier or excipient, wherein the form and amount of the active ingredient allow it to be therapeutically effective.

[0038] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and is commensurate with a reasonable benefit / risk ratio (e.g., in accordance with guidelines from government agencies or other regulatory bodies such as the U.S. Food and Drug Administration).

[0039] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to pharmaceutically acceptable materials, compositions, or carriers, such as liquid or solid fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, solvents, or encapsulating materials, which relate to the delivery or transport of compounds that may be used in this disclosure within or into a patient to enable them to perform their intended function. Typically, such constructs deliver or transport compounds 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 other components of the formulation, including compounds that may be used in this disclosure, and is harmless to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic, compatible substances used in pharmaceutical formulations.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts disclosed herein include conventionally non-toxic salts of parent compounds formed from, for example, non-toxic inorganic or organic acids. Pharmaceutically acceptable salts disclosed herein can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media (such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutically acceptable salt" also includes disalts, such as dihydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418, and in the Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0041] As used herein, the terms “effective amount,” “pharmaceutical effective amount,” and “therapeutic effective amount” refer to an amount of a drug that is non-toxic but sufficient to provide the desired biological outcome. The outcome may be a reduction or alleviation of signs, symptoms, or causes of disease, or any other desired alteration of a biological system. In any individual case, the appropriate therapeutic amount can be determined by a person skilled in the art using standard experimental methods.

[0042] As used herein, the terms “patient,” “subject,” and “individual” mean a subject who seeks, needs, requests, receives, expects, or is under the care of a trained (e.g., licensed) professional for a particular disease, disorder, or condition. A patient can include any living organism. Patient treatment can include, but is not limited to, experimental, diagnostic, preventative, and / or therapeutic treatments. Typical patients include, but are not limited to, animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans).

[0043] As used herein, the term "administration" or similar terms refer to the provision of a therapeutic agent to a subject. Various techniques for administering therapeutic agents exist in the art, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration, and topical administration.

[0044] As used in this article, the term "cancer" refers to a disease characterized by abnormal cell growth and division.

[0045] As used in this article, the term "cancer cell" refers to cells that grow and divide in an abnormal and uncontrolled manner.

[0046] As used in this article, the term "tumor" refers to a population of cells that forms in a solid tissue due to abnormal cell growth and division. Benign or "non-cancerous" tumors remain isolated, while malignant or "cancerous" tumors include cells capable of proliferating into surrounding tissues.

[0047] As used herein, the term “therapeutic effective amount” means an amount of a delivered agent that, when administered to a subject who has or is susceptible to a disease, disorder, and / or condition, is sufficient to treat, improve the symptoms of the disease, disorder, and / or condition, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition.

[0048] As used herein, the term “treating / treatment” means suppressing a disease; for example, suppressing the disease, condition, or disorder of an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or disorder (i.e., preventing the further development of the pathology and / or symptoms) or improving the disease; for example, improving the disease, condition, or disorder of an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or disorder (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease.

[0049] As used herein, the term "prevent / preventing / prevention" includes prevention of at least one symptom associated with, or caused by, a state, disease, or disorder that is being prevented.

[0050] Enriched preparations

[0051] On the one hand, this paper provides a method that includes enrichment [ 225 Ac]Ac-DOTA-TATE is a radiopharmaceutical composition having a radiochemical purity (RCP) greater than 98%.

[0052] In one embodiment, the composition is stable for at least 120 hours, as indicated by a greater than 99% RCP. In another embodiment, the composition is stable for at least 168 hours, as indicated by a greater than 98% RCP. In yet another embodiment, the composition is stable for at least 200 hours, as indicated by a greater than 98% RCP. In still another embodiment, the composition is stable for at least 288 hours, as indicated by a greater than 98% RCP.

[0053] In this embodiment, RCP is measured by radioactive-TLC (i-TLC).

[0054] On the other hand, this paper provides a method that includes enrichment [ 225 Ac]Ac-DOTA-TATE is a radiopharmaceutical composition having a radiochemical purity (RCP) greater than 94%, wherein the RCP is measured by radio-HPLC.

[0055] In some embodiments, the composition is stable for at least 120 hours, as indicated by a greater than 94% RCP, i.e., the composition exhibits a greater than 94% RCP after 120 hours of storage. In some embodiments, the composition is stored at 2°C–8°C. In another embodiment, the composition is stable for at least 168 hours, as indicated by a greater than 94% RCP, i.e., the composition exhibits a greater than 94% RCP after 168 hours of storage. In some embodiments, the composition is stored at 2°C–8°C. In yet another embodiment, the composition is stable for at least 288 hours, as indicated by a greater than 94% RCP, i.e., the composition exhibits a greater than 94% RCP after 288 hours of storage. In some embodiments, the composition is stored at 2°C–8°C.

[0056] Specific activity formulations

[0057] As used herein, "specific activity" or "specific molar activity" refers to the activity contained in each total mole of DOTA-TATE. 225 Measurement of radioactivity of compositions or preparations containing Ac-DOTA-TATE. Containing only [ 225 The composition of Ac]Ac-DOTA-TATE will be characterized to have the theoretical maximum specific molar activity. Containing [ 225 Combinations of Ac-labeled and unlabeled DOTA-TATE will be characterized as having specific molar activities less than the theoretical maximum, and the specific molar activity will decrease with increasing ratio of unlabeled compound to radiolabeled compound. Combinations enriched with radiolabeled compound (e.g., by the chromatography described herein) are referred to as “high specific activity”. Unenriched compositions are referred to as “normal specific activity” or “low specific activity”.

[0058] For the purpose of determining specific molar activity, the radioactivity of a composition can be measured using a suitable radiodetector as described in the examples herein. The number of moles of a compound (e.g., expressed in millimoles or micromoles) can be calculated from measurements (such as weight or spectral data) using known methods. For example, spectral data from a UV absorbance detector can be used to quantify the amount of a compound present in a chromatographic eluent. Based on such measurements, the specific molar activity of the compound is calculated. In cases where the radioactivity of a compound can be quantified, but the molar amount of the compound cannot be quantified because the compound is present in an amount or concentration below the detector's limit of quantitation (e.g., by data from a UV absorbance detector), the specific molar activity of the composition can be reported as "greater than" a value (e.g., > 60 µCi / nmol), which is the quotient of the measured radioactivity divided by the limit of quantitation of the device (e.g., the UV absorbance detector). The upper limit of such "greater than" value will be the theoretical maximum specific molar activity. The theoretical maximum specific molar activity of a radiolabeled compound is a function of the activity of the radiolabel and the stoichiometric ratio of the radiolabel to the compound. For example, single radioactively labeled compounds have a stoichiometric ratio of 1:1.

[0059] For example, single 225 The theoretical maximum specific molar activity of Ac-labeled compounds can be calculated as follows:

[0060] • 225 Ac half-life = 9.92 days = 14284.8 min

[0061] • The probability of one atom decaying per minute = Ln(2) / 14284.8 = 0.693 / 14284.8 = 4.85E-5

[0062] • Number of atoms in 1 nmol = 6.022E23 / E9 = 6.022E14

[0063] • Number of decays per nmol per minute = 6.022E14 4.85E-5 = 2.92E10 DPM (decay per minute)

[0064] • 1 mCi = 2.22E9 DPM (unit conversion)

[0065] • Theoretical specific activity = 2.92E10 DPM / nmol = 2.92E10 / 2.22E9 mCi / nmol = 13.2 mCi / nmol.

[0066] Therefore, in some embodiments, [ 225The Ac-DOTA-TATE enriched radiopharmaceutical composition was characterized to have a specific molar activity in the range of 60-13200 µCi / nmol of compound. In some embodiments, the radiopharmaceutical composition has a specific molar activity in the range of 60-13000 µCi / nmol of compound. In some embodiments, the specific molar activity is in the range of 60-100 µCi / nmol of compound. In some embodiments, the specific molar activity is in the range of 60-500 µCi / nmol of compound. In some embodiments, the specific molar activity is in the range of 60-1000 µCi / nmol of compound. In some embodiments, the specific molar activity is in the range of 100-1000 µCi / nmol of compound. In some embodiments, the specific molar activity is in the range of 100-2000 µCi / nmol of compound. In some embodiments, the specific molar activity is in the range of 2000-3000 µCi / nmol of compound. In some embodiments, the specific molar activity is in the range of 3000-4000 µCi / nmol of compound. In some embodiments, the specific molar activity is in the range of 5000-6000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 6000-7000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 7000-8000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 8000-9000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 9000-10000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 10000-11000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 11000-12000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 12000-13000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 2000-4000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 2000-6000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 4000-6000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 4000-8000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 4000-10000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 6000-8000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 6000-10000 µCi / nmol of compounds.In some embodiments, the specific molar activity is in the range of 6000-12000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 8000-10000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 8000-12000 µCi / nmol of compounds. In some embodiments, the specific molar activity is in the range of 10000-13200 µCi / nmol of compounds.

[0067] On the one hand, this article provides a method that includes [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition, wherein the radiopharmaceutical composition has a radiochemical purity (RCP) greater than 99% and a specific activity of 5 µCi / nmol.

[0068] In the examples, the radiopharmaceutical composition contains approximately 94% RCP. 225 The Ac-DOTA-TATE radiopharmaceutical composition exhibits a radiochemical purity (RCP) greater than 99% and a specific activity of 5 µCi / nmol. In another embodiment, the composition is stable for at least 120 hours, as indicated by an RCP greater than 99%. In yet another embodiment, the composition is stable for at least 168 hours, as indicated by an RCP greater than 99%. In still another embodiment, the composition is stable for at least 288 hours, as indicated by an RCP greater than 99%.

[0069] In this embodiment, RCP is measured by radioactive-TLC (i-TLC).

[0070] On the other hand, this article provides a method that includes [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition, wherein the radiopharmaceutical composition has a radiochemical purity (RCP) greater than 95% and a specific activity of 5 µCi / nmol.

[0071] In the examples, the radiopharmaceutical composition contains approximately 94% RCP. 225 The Ac-DOTA-TATE radiopharmaceutical composition exhibits a radiochemical purity (RCP) greater than 95% and a specific activity of 5 µCi / nmol. In another embodiment, the composition is stable for at least 120 hours, as indicated by an RCP greater than 96%. In yet another embodiment, the composition is stable for at least 168 hours, as indicated by an RCP greater than 96%. In still another embodiment, the composition is stable for at least 288 hours, as indicated by an RCP greater than 95%.

[0072] In the examples, RCP was measured by radioactive-HPLC.

[0073] Pharmaceutical Composition

[0074] The pharmaceutical compositions disclosed herein may also contain additional excipients, including surfactants, polymers, and antioxidants. Surfactants suitable for use in the formulations disclosed herein include surfactants commonly used in pharmaceutical formulations. Examples of surfactants include, but are not limited to, ionic and nonionic surfactants or wetting agents commonly used in pharmaceutical formulations, such as ethoxylated castor oil, polyethylene glycol-modified glyceryl esters, acetylated monoglycerides, sorbitan fatty acid esters, poloxamer, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or their ethoxylated derivatives, diglycerides or their polyoxyethylene derivatives, sodium docusate, sodium lauryl sulfate, cholic acid or its derivatives, lecithin, phospholipids, combinations thereof, etc. Additional surfactants include, but are not limited to, fatty alcohols, such as polyethylene glycol (PEG) and cetyl alcohol.

[0075] Suitable antioxidants for use in formulations disclosed herein include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), sodium metabisulfite, ascorbyl palmitate, potassium metabisulfite, tartaric acid, citric acid, citric acid monohydrate, and sodium sulfite.

[0076] Radiopharmaceuticals and radiopharmaceutical compositions are typically prepared in radiopharmacy or PET centers, where quality control testing is also conducted. Once the drug product has passed the quality control (QC) process and is dispensed to the patient for administration, it can be administered to the patient on-site at a PET scanning facility or transported to a PET scanning facility.

[0077] Regulatory standards for radioligand therapy (RLT) require that it be sterile, pyrogen-free, safe, and effective. One of the key tests in the QC process is the quantitative testing of chemical impurities and the radiochemical purity (RCP) of the drug product. In the United States, the FDA sets a minimum threshold of 90% RCP for all radiopharmaceuticals, including RLTs. Maintaining a high RCP before the point of administration is crucial.

[0078] RCP analysis is routinely performed using high-performance liquid chromatography (HPLC). HPLC achieves the separation of components from liquid compositions due to the different interactions between the components and the stationary phase (typically a silica-based column) and the mobile phase or eluent passing through the column. The chemical properties of each component determine its affinity for the stationary phase based on intermolecular interactions and the time spent on the column before elution.

[0079] This article also provides a pharmaceutical composition (e.g., a radiopharmaceutical composition) comprising a radiolabeled compound as a radiolabeler DOTA-TATE and a stabilizing solution.

[0080] In the embodiments, the pharmaceutical composition (which comprises a stabilizing solution) comprises one or more components selected from the group consisting of: ethanol, L-methionine, selenomethionine, histidine, melatonin, polysorbate, ammonium acetate, ascorbic acid or a pharmaceutically acceptable salt thereof, acetic acid or a pharmaceutically acceptable salt thereof, benzyl alcohol, p-aminobenzoic acid or a pharmaceutically acceptable salt thereof, cysteine, 5-amino-2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof, nicotinic acid or a pharmaceutically acceptable salt thereof, nicotinamide, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentian acid, and inositol.

[0081] In another embodiment, the pharmaceutical composition comprises one or more components selected from the group consisting of ethanol, L-methionine, polysorbate, ascorbic acid or a pharmaceutically acceptable salt thereof, and acetic acid or a pharmaceutically acceptable salt thereof.

[0082] In yet another embodiment, the pharmaceutical composition comprises ascorbic acid or a pharmaceutically acceptable salt thereof, and polysorbate.

[0083] Surprisingly, the presence of polysorbate (e.g., Tween 20), even in small amounts, significantly reduced the amount of ascorbic acid or its pharmaceutically acceptable salts (i.e., radiodegradation stabilizers) without affecting (high) RCP. Therefore, in the examples, ascorbic acid or its pharmaceutically acceptable salts and polysorbate are present in the pharmaceutical composition in amounts sufficient to provide at least 99% RCP for at least 24 hours, at least 48 hours, at least 120 hours, at least 144 hours, at least 168 hours, or at least 288 hours at 2°C–8°C. In specific examples, ascorbic acid or its pharmaceutically acceptable salts and polysorbate are present in the pharmaceutical composition in amounts sufficient to provide at least 99% RCP for at least 168 hours at 2°C–8°C. In the embodiments, ascorbic acid or a pharmaceutically acceptable salt thereof and polysorbate are present in the pharmaceutical composition in an amount sufficient to provide at least 98% RCP for at least 24 hours, at least 48 hours, at least 120 hours, at least 144 hours, at least 168 hours, or at least 288 hours at 2°C-8°C. In specific embodiments, ascorbic acid or a pharmaceutically acceptable salt thereof and polysorbate are present in the pharmaceutical composition in an amount sufficient to provide at least 98% RCP for at least 168 hours at 2°C-8°C. In the embodiments, ascorbic acid or a pharmaceutically acceptable salt thereof and polysorbate are present in the pharmaceutical composition in an amount sufficient to provide at least 96% RCP for at least 24 hours, at least 48 hours, at least 120 hours, at least 144 hours, at least 168 hours, or at least 288 hours at 2°C-8°C. In specific embodiments, ascorbic acid or a pharmaceutically acceptable salt thereof and polysorbate are present in the pharmaceutical composition in an amount sufficient to provide at least 96% RCP for at least 168 hours at 2°C-8°C. In specific embodiments, ascorbic acid or a pharmaceutically acceptable salt thereof and polysorbate are present in the pharmaceutical composition in an amount sufficient to provide at least 94% RCP for at least 24 hours, at least 48 hours, at least 120 hours, at least 144 hours, at least 168 hours, or at least 288 hours at 2°C-8°C. In specific embodiments, ascorbic acid or a pharmaceutically acceptable salt thereof and polysorbate are present in the pharmaceutical composition in an amount sufficient to provide at least 94% RCP for at least 168 hours at 2°C-8°C.

[0084] In the examples, the mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the pharmaceutical composition is 50:1 to 150:1, optionally 80:1 to 120:1, optionally about 100:1. In yet another example, ascorbic acid or a pharmaceutically acceptable salt thereof is present in amounts of ≤ 100 mg / mL, optionally ≤ 80 mg / mL, optionally 30-70 mg / mL, optionally 40-60 mg / mL, optionally about 50 mg / mL.

[0085] In the examples, polysorbate is present in the pharmaceutical composition in amounts of ≤ 0.1% (w / v) (corresponding to ≤ 1 mg / mL), optionally 0.03%-0.07% (w / v) (corresponding to 0.3-0.7 mg / mL), optionally 0.04%-0.06% (w / v) (corresponding to 0.4-0.6 mg / mL), and optionally about 0.05% (w / v) (corresponding to 0.5 mg / mL). In another example, the polysorbate is polyoxyethylene (20) dehydrated sorbitan monolaurate (Tween 20), optionally wherein polyoxyethylene (20) dehydrated sorbitan monolaurate is present in the pharmaceutical composition in amounts of about 0.1 mg / mL to about 1 mg / mL.

[0086] In yet another embodiment, the pharmaceutical composition further comprises L-methionine, optionally wherein L-methionine is present in the pharmaceutical composition at a concentration of about 10 mg / mL to about 30 mg / mL.

[0087] In another embodiment, the pharmaceutical composition further comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein acetic acid or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 0.01 M to about 0.15 M. In an embodiment, acetic acid or a pharmaceutically acceptable salt thereof is ammonium acetate. In another embodiment, the pharmaceutical composition further comprises ethanol, optionally wherein ethanol is present in the pharmaceutical composition at a concentration of about 1% v / v to about 15% v / v, optionally wherein ethanol is present at a concentration of about 5% v / v to about 10% v / v.

[0088] In yet another embodiment, the pharmaceutical composition comprises ethanol, L-methionine, polyoxyethylene sorbitan monooleate, ascorbic acid or a pharmaceutically acceptable salt thereof, and acetic acid or a pharmaceutically acceptable salt thereof. In still another embodiment, the pharmaceutical composition comprises ethanol, ammonium acetate, sodium ascorbate, L-methionine, and polyoxyethylene (20) sorbitan monolaurate.

[0089] In the examples, the pH of the stabilization solution is about 6 and / or the pH of the pharmaceutical composition is about 6.

[0090] In another embodiment, the DOTA-TATE of the pharmaceutical composition comprises a radioisotope selected from the following: 111 In、 99m Tc, 94m Tc, 66 Ga、 67 Ga、 68 Ga、 134 Ce、 52 Fe、 169Er、 72 As、 97 Ru、 203 Pb, 61 Cu、 62 Cu、 64 Cu、 67 Cu、 89 Sr、 186 Re、 188 Re、 86 Y、 90 Y、 89 Zr、 51 Cr 52 Mn, 51 Mn, 177 Lu、 169 Yb、 175 Yb、 105 Rh、 166 Dy、 166 Dy、 166 Ho、 153 Sm、 149 Pm, 151 Pm, 172 Tm、 121 Sn、 117m Sn、 212 Bi、 213 Bi、 142 Pr、 143 Pr、 198 Au、 199 Au、 18 F (e.g. [ 18 F]AlF), 149 Tb, 152 Tb, 155 Tb, 161 Tb, 43 Sc、 44 Sc、 47 Sc、 212 Pb, 211 At、 223 Ra、 227 Th、 226 Th、 82 Rb、 32 P, 76 As、 89 Zr、 111 Ag、 165 Er、 225 Ac and 227 Ac. In yet another embodiment, the radiolabeled compound contains 111 In (i.e., radioactive isotopes are) 111 In). In the embodiments, the radiolabeled compound contains.177 Lu (i.e., radioactive isotopes are) 177 Lu). In another embodiment, the radiolabeled compound contains 225 Ac (i.e., radioactive isotopes are) 225 Ac).

[0091] In some embodiments, the radiolabeled compound has an affinity for cell surface proteins. In another embodiment, the affinity (in K... D (in units) ≤ 1.0 nM. In other embodiments, affinity is characterized as: 1.0 nM < K D ≤10 nM, 10 nM < K D ≤ 100 nM, or 100 nM < K D ≤ 300 nM.

[0092] In the embodiments, the pharmaceutical composition has a total activity in the range of 0.01-1000 mCi. In some embodiments, the radioisotope is... 177 Lu, and the total activity of the pharmaceutical composition is in the range of 10-1000 mCi, for example 10-100 mCi, 100-200 mCi, 200-300 mCi, 300-400 mCi, 400-500 mCi, 500-600 mCi, 600-700 mCi, 700-800 mCi, 800-900 mCi, or 900-1000 mCi. In some embodiments, the radioactive isotope is... 225 Ac, and the total activity of the pharmaceutical composition is in the range of 0.01-5 mCi, for example 0.1-5 mCi, 1-5 mCi, 2-5 mCi, 3-5 mCi, 4-5 mCi, 0.01-4 mCi, 0.1-4 mCi, 1-4 mCi, 2-4 mCi, 3-4 mCi, 0.01-3 mCi, 0.1-3 mCi, 1-3 mCi, 2-3 mCi, 0.01-2 mCi, 0.1-2 mCi, 1-2 mCi, 2-3 mCi, 0.01-1 mCi, or 0.1-1 mCi.

[0093] In another embodiment, the pharmaceutical composition has a volume of about 1-100 mL. In one embodiment, the pharmaceutical composition has a volume of about 1-10 mL. In another embodiment, the pharmaceutical composition has a volume of about 11-20 mL. In yet another embodiment, the pharmaceutical composition has a volume of about 15 mL. In one embodiment, the pharmaceutical composition has a volume of about 21-30 mL. In still another embodiment, the pharmaceutical composition has a volume of about 31-40 mL. In one embodiment, the pharmaceutical composition has a volume of about 41-50 mL. In yet another embodiment, the pharmaceutical composition has a volume of about 41 mL.

[0094] In yet another embodiment, the pharmaceutical composition has a volume of about 51-60 mL. In still another embodiment, the pharmaceutical composition has a volume of about 61-70 mL. In one embodiment, the pharmaceutical composition has a volume of about 71-80 mL. In another embodiment, the pharmaceutical composition has a volume of about 81-90 mL. In yet another embodiment, the pharmaceutical composition has a volume of about 91-100 mL.

[0095] In another embodiment, the pharmaceutical composition comprises sodium ascorbate, L-methionine, polyoxyethylene (20) sorbitol monolaurate, ethanol, and acetate.

[0096] In yet another embodiment, the pharmaceutical composition comprises sodium ascorbate at a concentration of about 40 mg / mL to about 60 mg / mL, L-methionine at a concentration of about 10 mg / mL to about 30 mg / mL, polyoxyethylene (20) sorbitan monolaurate at a concentration of about 0.01% w / v to about 0.1% w / v, ethanol at a concentration of about 1% v / v to about 10% v / v, and acetate at a concentration of about 0.01 M to about 0.1 M.

[0097] Therapeutic Diagnostics

[0098] "Therapeutic diagnostics" is a term derived from the combination of therapeutics and diagnostics, and is an emerging medical field in which specific disease-targeting agents, such as radiopharmaceuticals, can be used to simultaneously or sequentially diagnose and treat medical conditions. Therapeutic diagnostic techniques have become an important area of ​​research and development in medical physics, where altering the isotope of a radionuclide present in a given disease-targeting agent (e.g., radioligand therapy) can transform the disease-targeting agent from an imaging probe (by, for example, using β+ or γ emission isotopes to promote positron emission tomography (PET) or single-photon emission computed tomography (CT) imaging, respectively) into a therapeutic probe (by, for example, using α or β-particles or Auger electron emission isotopes to promote targeted radiotherapy). Therefore, the enriched and stable radioligand formulations disclosed herein can be used in therapeutic diagnostic methods.

[0099] Treatment

[0100] In one respect, this article provides a method for treating cancer in a subject in need, the method comprising administering to the individual a therapeutically effective amount of the radiopharmaceutical composition disclosed herein.

[0101] In one embodiment, the cancer is a neuroendocrine tumor. In another embodiment, the cancer is a somatostatin receptor-positive (SSTR+) tumor. In yet another embodiment, the SSTR+ tumor is a gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

[0102] In another embodiment, the cancer is a neuroendocrine carcinoma, lymphoma, pancreatic cancer, pituitary cancer, breast cancer, gastric cancer, medulloblastoma, or neuroblastoma. In some embodiments, the cancer is a neuroendocrine carcinoma, which may optionally be recurrent. In some embodiments, the neuroendocrine carcinoma is refractory to radiotherapy containing a radionuclide that emits beta particles. In some embodiments, the subject has received radiotherapy containing a radionuclide that emits beta particles prior to administration of the radiopharmaceutical composition. The neuroendocrine carcinoma may also be a neuroendocrine lung cancer or a neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine carcinoma is a carcinoid tumor in the lung, gastrointestinal tract, or thymus. In another embodiment, the neuroendocrine carcinoma is a pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, VIP tumor), medullary thyroid carcinoma, Merkel cell carcinoma, pheochromocytoma of the adrenal gland, adrenal carcinoma, small cell carcinoma (e.g., in the lung), or large cell carcinoid tumor (e.g., in the lung).

[0103] In another embodiment, the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, medulloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia. Blood disorders, chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt lymphoma, dysplastic changes (developmental abnormalities and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, colloid carcinoma. Plasma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's lymphoma), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, T-cell or B-cell-derived malignant tumors of the lymphatic system, leukemia, lymphoma, medullary carcinoma, medulloblastoma Cytomas, melanomas, meningiomas, mesotheliomas, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial malformation, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0104] In another embodiment, the cancer is selected from the group consisting of: primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gallbladder cancer, bile duct cancer, small bowel cancer, urethral cancer, and kidney cancer. Cancer, urothelial carcinoma, female reproductive tract cancer, uterine cancer, gestational trophoblastic disease, male reproductive tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary cancer, hemangioma, sarcoma originating from bone and soft tissue, Kaposi's sarcoma, neurocarcinoma, eye cancer, meningeal cancer, glioblastoma, neuroma, neuroblastoma, Schwannoma, solid tumors originating from hematopoietic malignancies (such as leukemia), metastatic melanoma, recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small cell lung cancer, malignant glioma, epithelial ovarian cancer, primary peritoneal serous carcinoma, metastatic liver cancer, neuroendocrine carcinoma, refractory malignant tumors, triple-negative breast cancer, HER2-amplified breast cancer, nasopharyngeal carcinoma, oral cancer, biliary duct cancer. Hepatocellular carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-thyroid medullary carcinoma, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS carcinoma, liposarcoma, leiomyosarcoma, salivary gland carcinoma, mucosal melanoma, acral / lentigines melanoma, paraganglioma, pheochromocytoma, advanced metastatic carcinoma, solid tumors, triple-negative breast cancer, colorectal cancer, sarcoma, melanoma, renal carcinoma, endometrial cancer, thyroid cancer, rhabdomyosarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancies.

[0105] In this embodiment, cancer is selected from the group consisting of: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, urogenital tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver and biliary tract cancer, kidney cancer, medullary disorders, lymphatic system disorders, Hodgkin's lymphoma, pilosarcoma, oral and laryngeal cancer (oral cancer), lip cancer, tongue cancer, oral cancer, laryngeal cancer, small bowel cancer, colon cancer, rectal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, chronic myeloid leukemia (CML), and leukemia.

[0106] In another embodiment, the cancer is selected from the group consisting of myeloma, lymphoma, or cancer selected from gastric cancer, kidney cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin lymphoma, and lung cancer.

[0107] In this embodiment, the cancer is selected from the group consisting of: prostate cancer, colon cancer, lung cancer, head and neck squamous cell carcinoma, esophageal cancer, hepatocellular carcinoma, melanoma, sarcoma, gastric cancer, pancreatic cancer, ovarian cancer, and breast cancer.

[0108] In this embodiment, cancer is selected from the group consisting of: tumors, growths, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancers include, but are not limited to, mesotheliomas, leukemias, and lymphomas such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotropic virus (HTLV) (such as adult T-cell leukemia / lymphoma (ATLL)), B-cell lymphomas, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphomas and multiple myeloma, non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Other examples include myelodysplastic syndromes, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas, common adult solid tumors such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal, and esophageal cancers), genitourinary cancers (e.g., prostate, bladder, kidney, uterine, ovarian, and testicular cancers), lung cancers (e.g., small cell and non-small cell carcinomas), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, Göring syndrome-related tumors (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Other exemplary forms of cancers that can be treated with the subject compound include, but are not limited to, cancers of skeletal or smooth muscle, gastric cancer, small bowel cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0109] Other cancers that can be treated with the radiopharmaceutical compositions described herein include, for example, colon cancer, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, or melanoma. Furthermore, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), kidney cancer, renal parenchymal carcinoma, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary system cancer, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), gallbladder cancer, bronchial cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.

[0110] Equivalence principle and scope

[0111] While various disclosed embodiments have been specifically shown and described in this disclosure, those skilled in the art will understand that various changes in form and detail may be made without departing from the spirit and scope of the embodiments disclosed herein and set forth in the appended claims.

[0112] Those skilled in the art will recognize or be able to determine many equivalent forms of the specific embodiments described herein using only conventional experiments. The scope of this disclosure is not intended to be limited to the foregoing description, but rather as set forth in the appended claims.

[0113] Where a range is given, the endpoints are included. Furthermore, it should be understood that, unless otherwise specified or otherwise clearly apparent from the context and to those skilled in the art, numerical values ​​represented as ranges in different embodiments of this disclosure may take any specific value or subrange within the stated range up to one-tenth of the lower limit unit of that range, unless the context otherwise expressly specifies.

[0114] Furthermore, it should be understood that any particular embodiment of the present disclosure within the prior art may be expressly excluded from any one or more claims. Because such embodiments are considered to be known to those skilled in the art, they may be excluded even if such exclusion is not expressly stated herein. Any particular embodiment of the compositions disclosed herein may be excluded from any one or more claims for any reason, whether or not related to the existence of prior art.

[0115] All sources cited, such as references, publications, databases, database entries, and techniques cited herein, are incorporated herein by reference, even if not explicitly stated in the citations. In the event of a contradiction between cited sources and statements in this application, the statements in this application shall prevail.

[0116] Example

[0117] The formulations and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. Unless otherwise indicated, the practices disclosed herein will utilize conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the scope of the art.

[0118] Example 1: Preparation of enriched and stable radiopharmaceutical compositions

[0119] Separating radiolabeled peptides from non-radiolabeled peptides using chromatography is challenging because radiolabeled peptides are often co-eluted with excess non-radiolabeled peptide starting material. The methods outlined below allow for the synthesis and separation of radioligand-based therapies enriched with radiolabeled peptides.

[0120] DOTA-TATE (peptide 1) is available from commercial sources. 225 The IUPAC name of Ac-DOTA-TATE is (2,2′,2″-(10-(2,4(R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-4-(((1S,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-16- (4-hydroxybenzyl)-7-((R)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloeicosano-19-yl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate; Actinide-225(3+)), and it has the following structure:

[0121] .

[0122] synthesis

[0123] Dry actinium-225 (nitric acid) 225 Ac(III) or chloride 225 Ac(III) was reconstituted in weak hydrochloric acid and transferred to a pharmaceutical-grade glass or reinforced plastic reaction vessel. Then, solutions of low molar concentrations (0.04–0.1 M) of hydrochloric acid, sodium acetate buffer, and peptide 1 were prepared.

[0124] HCl, buffer solution, peptide solution, and reconstituted actinium-225 were combined in a sealed glass container and heated at 90°C for 15 minutes in a dry heating block heater. Diethylenetriaminepentaacetic acid (DTPA) was then added to quench the reaction, and the crude reaction mixture was analyzed by iTLC (mobile phase 50 mM EDTA, pH 5.5).

[0125] purification

[0126] Manually inject 100 µl (small-scale) or 5.5 mL (large-scale) aliquots of the crude product mixture into the HPLC injection loop, which is large enough to contain the full volume in a single injection [Small-scale: Waters XSelect Peptide CSH C18; 130A; 3.5 μm; 4.6 x 150 mm (PN 186006957) or similar; Large-scale: Waters XSelect Peptide CSH C18 OBD; 130A 5 μm; 10 x 250 mm (PN 186008267) or similar].

[0127] In the small-scale purification process, an isocratic method was used, with a mobile phase of 80% 1.5 mM ammonium acetate / 20% ethanol; a run time of 45 min; a flow rate of 0.5 mL / min; and an injection volume of 100 μL. The retention time of the purified radiolabeled peptide was simulated using a method similar to that used for the non-radioactive lanthanum peptide (La-DOTA-TATE) and the non-radioactive labeled DOTA-TATE control. The purified radiolabeled DOTA-TATE drug product was then... 225 Ac]Ac-DOTA-TATE was diluted to a certain strength and contained less than 10% v / v of ethanol, methionine, sodium ascorbate, and ammonium acetate buffer to mark the end of synthesis (EOS).

[0128] In the large-scale purification process, an isocratic method was used, with the mobile phase solvent being a 1.5 mM ammonium acetate solution containing 20% ​​v / v ethanol. The retention time of the purified radiolabeled peptide was simulated using a method similar to that used with a non-radioactive lanthanum peptide (La-DOTA-TATE) control. After elution, Tween-20 was added. The purified radiolabeled DOTA-TATE drug product was then... 225 Ac]Ac-DOTA-TATE diluted to a certain strength and containing less than 10% v / v ethanol, methionine, sodium ascorbate and Tween-20 in ammonium acetate buffer to label EOS.

[0129] After separation, the purified radiolabeled DOTA-TATE drug product [225 Ac]Ac-DOTA-TATE was passed through a Millipore Millex GV sterile filter or equivalent to marked end of preparation (EOF). The radiochemical purity (RCP) of the sterile product was then analyzed by analytical HPLC equipped with a fraction collector.

[0130] The following two high-performance liquid chromatography (HPLC) methods were used to determine the purification and RCP analysis.

[0131] 1. Small-scale

[0132] a. Agilent 1260 Infinity II HPLC System

[0133] i. Main Components

[0134] ii.1260 Infinity II Quadridimensional Pump

[0135] iii.1260 Infinity II vial sampler

[0136] iv.1260 Infinity II Diode Array Detector WR

[0137] v.1260 Infinity II Analytical FC

[0138] vi. Equipped with Laura's Flow-RAM for PET

[0139] vii. PMT / NaI - 1" detector

[0140] viii. Well model NaI / PMT

[0141] 2. Large-scale

[0142] a. The automation module, provided by Optimized Radiochemical Applications,

[0143] ORA LLC

[0144] 15 Salette Street

[0145] Neville 5600

[0146] Belgium

[0147] b. Automation Systems: NEPTIS Mosaic RS® Synthesizer and NEPTIS Control System

[0148] c. The HPLC system with its automated module was provided by KNAUER Wissenschaftliche Geräte GmbH.

[0149] 38 Hergowweg Street

[0150] Berlin 14163

[0151] Germany

[0152] d. Isocratic HPLC system: P 4.1S, equipped with a 10 ml pump head and UVD 2.1S

[0153] e. Gradient HPLC system: P 6.1L pump, P 6.1L (LPG), with 10 ml pump head.

[0154] Dispensing and storing radiopharmaceutical compositions / preparations

[0155] Before dosing, batches of drug products [[ 225 Ac]Ac-DOTA-TATE is stored in sealed glass containers at low temperatures (-20°C, 2°C-8°C, or 25°C). An additional RCP analysis is performed before dispensing the enriched, purified product. Following RCP analysis, the purified product is dispensed as a single dose or multiple doses into final product vials (FPVs).

[0156] [with corresponding RCP values] 225 The specific formulations of Ac]Ac-DOTA-TATE are shown in Table 1 below.

[0157] Table 1

[0158]

[0159] iTLC method:

[0160] iTLC mobile phase: 50 mM EDTA, pH 5.5

[0161] iTLC stationary phase: Agilent silicone glass microfiber

[0162] Radioactive HPLC method:

[0163] A = 0.1% formic acid solution

[0164] B = 0.1% Formic acid acetonitrile

[0165] 1-15 minutes 20%-50% B

[0166] 15-20 minutes 90% B

[0167]

[0168] As can be seen in Table 1 above, the radiopharmaceutical compositions disclosed herein exhibit the ability to incorporate cold (non-radioactive) DOTA-TATE precursors into already enriched [ 225 The Ac]Ac-DOTA-TATE product maintains the same stability trend as the enriched product, and it is possible to produce actinium-225 with high RCP stability over a longer period of time. 225 Ac]Ac-DOTA-TATE product.

[0169] Therefore, these compositions extend the product's shelf-life stability from production to distribution and clinical application.

[0170] Furthermore, this disclosure demonstrates that the enrichment process has removed radioactive byproducts (generated by radiodecomposition) that are undetectable by any conventional analytical methods. This is demonstrated by incorporating DOTA-TATE precursors that have not undergone radiosynthetic irritants and radiodecomposition, resulting in the absence of enriched radioactive products but the production of equivalent extended stability.

[0171] Example 2: High specific activity (HSA) 225 Radiochemical methods and formulation development of Ac]Ac-DOTA-TATE

[0172] DOTA-TATE can be purchased from commercial sources.

[0173] I. DOTA-TATE's [ 225 Ac]Ac radioactive labeling

[0174] The reagent consists of the following: 1.0 M sodium acetate buffer (pH 5.5-6.0), a DOTA-TATE precursor dissolved in metal-free water or 0.1 M sodium acetate buffer (pH 5.5) at a concentration of 0.4-1.3 nmol / µL, and actinium-225 (nitric acid) dissolved in 0.04-0.1 M hydrochloric acid at a radioactive concentration of 24.0-8.2 µCi / µL. 225 Ac(III) or chloride 225 Ac(III)). The above reagents were mixed in various proportions to achieve a final concentration range of 0.04–0.15 M sodium acetate, 0.30–0.96 nmol / µL DOTA-TATE, and 1.19–3.16 µCi / µL Actinium-225 in the reaction mixture. The mixture was incubated at 90°C for 15 minutes with shaking at 700 RPM. After 15 minutes, the reaction was briefly cooled, quenched with 0.05 mg / mL DTPA solution, and purified by RP-HPLC in 100 µL aliquots as needed, as described in Part II below. See also Figure 2The reaction conditions are summarized in Table 2. In run #1, the injection activity was 74 µCi, the recovered activity was 67 µCi, the purification yield was 91%, and the process yield was 80%. In run #2, the injection activity was 541 µCi, the recovered activity was 370 µCi, the purification yield was 68%, and the process yield was 58%. In run #3, the injection activity was 76 µCi, the recovered activity was 55 µCi, the purification yield was 73%, and the process yield was 67%.

[0175] Table 2. Initial [ 225 Summary of Ac]Ac-DOTA-TATE radiolabeling reaction conditions

[0176]

[0177] II. Isocratic RP-HPLC Purification and Development

[0178] Isocratic RP-HPLC purification was developed using an Agilent 1260 Infinity II system equipped with a diode array detector (detection at 220 nm). Separations were performed on a Waters XSelect Peptide CSH C18 column (130 Å, 3.5 µm, 4.6 x 150 mm). The strength of a single buffer (1.5 mM ammonium acetate) and two different ethanol concentrations (20% and 30%) were tested at 0.5 mL / min. These solvent compositions produced on-column buffer strengths of 1.20 and 1.05 mM, respectively.

[0179] The internally generated DOTA-TATE and [ nat La-DOTA-TATE was dissolved in water to achieve concentrations of 0.47 and 0.36 nmol / µL, respectively. The compounds were co-injected by mixing them in equal volumes (5 µL).

[0180] Initial testing with 20% ethanol yielded very favorable results, with good resolution and peak shape for both substances. Several co-injections were performed to validate the results, and a DOTA-TATE injection was performed to confirm peak identity. See also Figure 1 .

[0181] III. Formulation Development

[0182] Using the optimized strategy described above, a buffer solution was selected consisting of approximately 50 mg / mL sodium ascorbate, approximately 24 mg / mL L-methionine, approximately 0.05% Tween-20, approximately 75 mM ammonium acetate, and approximately 5% v / v ethanol, and this buffer solution maintained RCP > 90% for 288 hours. During HPLC purification, fractions were collected into 2 mL HPLC vials pre-filled with 0.75 mL of the buffer solution. Each fraction was collected for 30 seconds, yielding approximately 0.25 mL of collected eluent and approximately 1 mL of total fraction volume.

[0183] A study was conducted to determine the stability difference between high specific activity formulations and formulations with reduced specific activity (i.e., “normal specific activity”) (5 µCi / nmol). Precise quantification of the specific molar activity of the high specific activity formulation was unavailable because peptide mass could not be detected at the mass loading used. After purification and re-establishment of long-term equilibration, aliquots of the high specific activity formulation were diluted with sufficient precursor DOTA-TATE to achieve a specific activity of 5 µCi / nmol. Samples were taken at the time points shown in the table below, and RCP was analyzed by iTLC and RP-HPLC.

[0184] Both formulations maintained a high RCP of >90% for up to 288 hours during the testing period. See Tables 3 and 4.

[0185] Table 3. Specific activity (RSA) and HSA of samples stored at 2°C–8°C for up to 288 hours via iTLC. 225 Summary of Ac]Ac-DOTA-TATE %RCP.

[0186]

[0187] Table 4. RSA and HSA levels after 288 hours of RP-HPLC analysis at 2°C–8°C 225 Summary of Ac]Ac-DOTA-TATE %RCP.

[0188]

[0189] IV. RCP Determination

[0190] The analytical conditions used for HPLC and iTLC analysis are described in Tables 5 and 6 below, respectively.

[0191] Table 5. Analytical HPLC conditions.

[0192]

[0193] 1The analysis of DTPA chelation [ 225 Ac]Ac represents unbound [[ in the reaction / formulation mixture]] 225 Ac]Ac.

[0194] Table 6. Analytical iTLC conditions.

[0195]

[0196] 1 The analysis of DTPA chelation [ 225 Ac]Ac represents unbound [[ in the reaction / formulation mixture]] 225 Ac]Ac.

[0197] V.HSA [ 225 Ac]Ac-DOTA-TATE: Comparison of formulations and stability

[0198] A study was conducted to compare [the preparations made according to the methods described herein] 225 The stability of Ac]Ac-DOTA-TATE formulations compared to formulations prepared according to previously known methods. Known methods involve chelating radioactive isotope ions with excess chelating ligands (e.g., DOTA-peptides) in a buffer containing a stabilizer / radioprotectant. These methods produce low specific activity radioactive products that primarily contain unlabeled chelating ligands and impurities derived from the radiolabeling reaction. In contrast, the methods described herein remove excess unlabeled chelating ligands and impurities generated during the radiolabeling reaction conditions.

[0199] Example 13 of U.S. Patent No. 11,819,556 discloses a known method involving heating [ 225 A mixture of Ac]Ac and DOTA-TATE yielded a product with a target molar activity of 5 µCi / nmol. 225 Ac]Ac-DOTA-TATE. Then [ 225 Ac]Ac-labeled DOTA-TATE was mixed with a preparation buffer (composed of sodium ascorbate, DTPA and saline) to obtain a product solution with a radioactivity concentration of 0.033 µCi / µL, and then evaluated by iTLC at different time points (Table 7).

[0200] Table 7.

[0201]

[0202] As described above, [the preparation and formulation were carried out in sodium ascorbate, L-methionine, Tween-20, 75 mM ammonium acetate, and ethanol]. 225A comparative formulation of Ac]Ac-DOTA-TATE was prepared to obtain a product solution with a specific molar activity of 5 µCi / nmol and a radioactivity concentration of 0.033 µCi / µL. The product solution was divided into three fractions, and its stability was assessed by iTLC. See Table 3.

[0203] Example

[0204] E1. A type of enrichment [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition having a radiochemical purity (RCP) greater than 98%, wherein [ 225 Ac]Ac-DOTA-TATE has the following structure:

[0205] .

[0206] E2. A radiopharmaceutical composition as described in E1, wherein the composition is stable for at least 120 hours, as indicated by greater than 99% RCP.

[0207] E3. A radiopharmaceutical composition as described in E1 or E2, wherein the composition is stable for at least 168 hours, as indicated by greater than 98% RCP.

[0208] E4. The radiopharmaceutical composition as described in any one of E1-E3, wherein the composition is stable for at least 200 hours, as indicated by greater than 98% RCP.

[0209] E5. The radiopharmaceutical composition as described in any one of E1-E4, wherein the composition is stable for at least 288 hours, as indicated by greater than 98% RCP.

[0210] E6. The radiopharmaceutical composition as described in any one of E1-E5, wherein the composition is characterized to have the listed RCP after being stored at a temperature of 2°C-8°C for the listed number of hours.

[0211] E7. The radiopharmaceutical composition as described in any one of E1-E6, wherein the RCP is measured by radio-TLC (i-TLC).

[0212] E8. A type of enrichment [ 225 Ac]Ac-DOTA-TATE is a radiopharmaceutical composition having a radiochemical purity (RCP) greater than 94%, wherein the RCP is measured by radio-HPLC.

[0213] E9. A radiopharmaceutical composition as described in E8, wherein the composition is stable for at least 120 hours, as indicated by greater than 94% RCP.

[0214] E10. A radiopharmaceutical composition as described in E8 or E9, wherein the composition is stable for at least 168 hours, as indicated by greater than 94% RCP.

[0215] E11. A radiopharmaceutical composition as described in any one of E8-E10, wherein the composition is stable for at least 288 hours, as indicated by greater than 94% RCP.

[0216] E12. The radiopharmaceutical composition as described in any one of E1-E11, having a specific activity of at least about 5 µCi / nmol.

[0217] E13. The radiopharmaceutical composition as described in E12, having a specific activity of about 5 µCi / nmol.

[0218] E14. The radiopharmaceutical composition as described in E12, having a specific activity greater than about 5 µCi / nmol.

[0219] E15. A radiopharmaceutical composition as described in E14, having a specific activity of about 60 to about 13200 µCi / nmol.

[0220] E16. A type of [ 225 Ac]Ac-DOTA-TATE is a radiopharmaceutical composition having a specific activity of about 5 µCi / nmol and a radiochemical purity (RCP) greater than 99%.

[0221] E17. A radiopharmaceutical composition as described in E16, wherein the composition is stable for at least 120 hours, as indicated by greater than 99% RCP.

[0222] E18. A radiopharmaceutical composition as described in any one of E16-E17, wherein the composition is stable for at least 168 hours, as indicated by greater than 99% RCP.

[0223] E19. The radiopharmaceutical composition as described in any one of E16-E18, wherein the composition is stable for at least 288 hours, as indicated by greater than 99% RCP.

[0224] E20. The radiopharmaceutical composition as described in any one of E16-E19, wherein the RCP is measured by radio-TLC (i-TLC).

[0225] E21. A type of [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition, wherein the radiopharmaceutical composition has a specific activity of about 5 µCi / nmol and a radiochemical purity (RCP) greater than 95%.

[0226] E22. A radiopharmaceutical composition as described in E21, wherein the composition is stable for at least 120 hours, as indicated by greater than 96% RCP.

[0227] E23. The radiopharmaceutical composition as described in any one of E21-E22, wherein the composition is stable for at least 168 hours, as indicated by greater than 96% RCP.

[0228] E24. The radiopharmaceutical composition as described in any one of E21-E23, wherein the composition is stable for at least 288 hours, as indicated by greater than 95% RCP.

[0229] E25. The radiopharmaceutical composition as described in any one of E21-2E4, wherein the RCP is measured by radio-HPLC.

[0230] E26. A radiopharmaceutical composition comprising [ 225 Ac]Ac-DOTA-TATE and has a specific activity greater than about 5 µCi / nmol.

[0231] E27. A radiopharmaceutical composition as described in E26, having a specific activity of about 60 to about 13200 µCi / nmol.

[0232] E28. The radiopharmaceutical composition as described in any of the foregoing embodiments, comprising one or more components selected from the group consisting of: ethanol, L-methionine, selenomethionine, histidine, melatonin, polysorbate, ammonium acetate, ascorbic acid or a pharmaceutically acceptable salt thereof, acetic acid or a pharmaceutically acceptable salt thereof, benzyl alcohol, p-aminobenzoic acid or a pharmaceutically acceptable salt thereof, cysteine, 5-amino-2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof, nicotinic acid or a pharmaceutically acceptable salt thereof, nicotinamide, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentianic acid, and inositol.

[0233] E29. The radiopharmaceutical composition as described in any of the preceding embodiments, comprising one or more components selected from the group consisting of ethanol, L-methionine, polysorbate, ascorbic acid or a pharmaceutically acceptable salt thereof, and acetic acid or a pharmaceutically acceptable salt thereof.

[0234] E30. The radiopharmaceutical composition as described in any of the foregoing embodiments, wherein the radiopharmaceutical composition comprises ascorbic acid or a pharmaceutically acceptable salt thereof, and polysorbate.

[0235] E31. The radiopharmaceutical composition as described in E30, wherein the mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the radiopharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1, optionally about 100:1.

[0236] E32. The radiopharmaceutical composition as described in any one of E30-E31, wherein the ascorbic acid or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition in an amount of ≤ 100 mg / mL, optionally ≤ 80 mg / mL, optionally 30-70 mg / mL, optionally 40-60 mg / mL, optionally about 50 mg / mL.

[0237] E33. The radiopharmaceutical composition as described in any one of E30-E32, wherein the polysorbate is present in the radiopharmaceutical composition in an amount of ≤ 1 mg / mL, optionally 0.3-0.7 mg / mL, optionally 0.4-0.6 mg / mL, optionally about 0.5 mg / mL.

[0238] E34. The radiopharmaceutical composition of any one of E30-E33, wherein the polysorbate is polyoxyethylene (20) sorbitan monolaurate, optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the radiopharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL.

[0239] E35. The radiopharmaceutical composition of any one of E30-E34, wherein the radiopharmaceutical composition comprises L-methionine, optionally wherein the L-methionine is present in the pharmaceutical composition at a concentration of about 10 mg / mL to about 30 mg / mL.

[0240] E36. The radiopharmaceutical composition of any one of E30-E35, wherein the radiopharmaceutical composition comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 0.01 M to about 0.15 M.

[0241] E37. The radiopharmaceutical composition as described in any one of E30-E36, wherein the acetic acid or a pharmaceutically acceptable salt thereof is ammonium acetate.

[0242] E38. The radiopharmaceutical composition of any one of E30-E37, wherein the radiopharmaceutical composition comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 1% (v / v) to about 15% (v / v), or optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 5% (v / v) to about 10% (v / v).

[0243] E39. The radiopharmaceutical composition as described in any of the foregoing embodiments, wherein the pH of the radiopharmaceutical composition is about 6.

[0244] E40. A radiopharmaceutical composition comprising [ 225 Ac]Ac-DOTA-TATE, ascorbic acid or its pharmaceutically acceptable salts, and polysorbate.

[0245] E41. The radiopharmaceutical composition as described in E40, wherein the ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in an amount sufficient to provide at least 94% RCP (as measured by HPLC) for at least 168 hours at 2°C-8°C, or at least 98% RCP (as measured by radio-HPLC) for at least 168 hours at 2°C-8°C.

[0246] E42. The radiopharmaceutical composition as described in E40 or E41, wherein the mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the radiopharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1, optionally about 100:1.

[0247] E43. The radiopharmaceutical composition of any one of E40-E42, wherein the ascorbic acid or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition in an amount of ≤ 100 mg / mL, optionally ≤ 80 mg / mL, optionally 30-70 mg / mL, optionally 40-60 mg / mL, optionally about 50 mg / mL.

[0248] E44. The radiopharmaceutical composition of any one of E40-E43, wherein the ascorbic acid or pharmaceutically acceptable salt is sodium ascorbate, optionally wherein the sodium ascorbate is present in the radiopharmaceutical composition in an amount of about 30 mg / mL to about 70 mg / mL.

[0249] E45. The radiopharmaceutical composition of any one of E40-E44, wherein the polysorbate is present in the radiopharmaceutical composition in an amount of ≤ 1 mg / mL, optionally 0.3-0.7 mg / mL, optionally 0.4-0.6 mg / mL, optionally about 0.5 mg / mL.

[0250] E46. The radiopharmaceutical composition of any one of E40-E45, wherein the polysorbate is polyoxyethylene (20) sorbitan monolaurate, optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the radiopharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL.

[0251] E47. The radiopharmaceutical composition of any one of E40-E46, wherein the radiopharmaceutical composition further comprises L-methionine, optionally wherein the L-methionine is present in the pharmaceutical composition at a concentration of about 10 mg / mL to about 30 mg / mL.

[0252] E48. The radiopharmaceutical composition of any one of E40-E47, wherein the radiopharmaceutical composition further comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 0.01 M to about 0.15 M.

[0253] E49. The radiopharmaceutical composition as described in any one of E40-E48, wherein the acetic acid or a pharmaceutically acceptable salt thereof is ammonium acetate.

[0254] E50. A radiopharmaceutical composition as described in any one of E40-E49, wherein the radiopharmaceutical composition comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 1% (v / v) to about 15% (v / v), optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 5% (v / v) to about 10% (v / v).

[0255] E51. The radiopharmaceutical composition as described in any one of E40-E50, wherein the pH of the radiopharmaceutical composition is about 6.

[0256] E52. A method for preparing [ 225 A method for constructing a radiopharmaceutical composition of Ac-DOTA-TATE, the method comprising reacting DOTA-TATE with [Ac-DOTA-TATE] in the presence of acetic acid or a salt thereof. 225 Ac contact to obtain [ 225 Ac]Ac-DOTA-TATE.

[0257] E53. The method as described in E52, wherein the method comprises reacting DOTA-TATE with acetic acid or a salt thereof in the presence of hydrochloric acid. 225 Ac contact.

[0258] E54. The method of any one of E52-E53, wherein the contact includes heating.

[0259] E55. The method as described in any one of E52-E54, wherein the [ 225 Ac]Ac-DOTA-TATE was purified by chromatography.

[0260] E56. The method of any one of E52-E55, wherein the [method] is prepared using a formulation buffer containing one or more radioactive stabilizers. 225 Ac]Ac-DOTA-TATE, to obtain [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition.

[0261] E57. The method as described in E56, wherein the formulation buffer further comprises a surfactant.

[0262] E58. The method of any one of E56-E57, wherein the formulation buffer comprises ascorbic acid or a pharmaceutically acceptable salt thereof, and polysorbate.

[0263] E59. The method of any one of E56-E58, wherein the formulation buffer further comprises L-methionine.

[0264] E60. The method as described in any one of E56-E59, wherein the formulation buffer further comprises ethanol.

[0265] E61. The method as described in any one of E56-E60, wherein the radiopharmaceutical composition comprises [ 225 Ac]Ac-DOTA-TATE, sodium ascorbate, polyoxyethylene (20) dehydrated sorbitol monolaurate, L-methionine, ammonium acetate, ethanol and water.

[0266] E62. A radiopharmaceutical composition prepared according to any one of E52-E61.

[0267] E63. A method for treating cancer in a subject in need, the method comprising administering to the subject an effective amount of a radiopharmaceutical composition as described in any one of E1-E51 and E62.

[0268] E64. As described in E63, wherein the cancer is a neuroendocrine tumor.

[0269] E65. As described in E63 or E64, wherein the cancer is a somatostatin receptor-positive (SSTR+) tumor.

[0270] E66. The method as described in E65, wherein the SSTR+ tumor is a gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

[0271] Although the methods and pharmaceutical compositions disclosed herein have been described in considerable detail by way of illustration and example for purposes of clarity, those skilled in the art will understand that certain changes and modifications may be made within the scope of the appended claims. Furthermore, every reference mentioned in this specification (including all U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications) is incorporated herein by reference in its entirety to the extent that it does not contradict this specification. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A type of enrichment [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition having a radiochemical purity (RCP) greater than 98%, wherein [ 225 Ac]Ac-DOTA-TATE has the following structure: 。 2. The radiopharmaceutical composition of claim 1, wherein, The composition is stable for at least 120 hours, as indicated by greater than 98% RCP.

3. The radiopharmaceutical composition according to claim 1 or 2, wherein, The composition is stable for at least 168 hours, as indicated by greater than 98% RCP.

4. The radiopharmaceutical composition according to any one of claims 1-3, wherein, The composition is stable for at least 200 hours, as indicated by greater than 98% RCP.

5. The radiopharmaceutical composition according to any one of claims 1-4, wherein, The composition is stable for at least 288 hours, as indicated by greater than 98% RCP.

6. The radiopharmaceutical composition according to any one of claims 1-5, wherein, The composition is characterized to have the listed RCP after being stored at a temperature of 2°C–8°C for the listed number of hours.

7. The radiopharmaceutical composition according to any one of claims 1-6, wherein, The RCP was measured by radioactive TLC (i-TLC).

8. A type of enrichment [ 225 Ac]Ac-DOTA-TATE is a radiopharmaceutical composition having a radiochemical purity (RCP) greater than 94%, wherein the RCP is measured by radio-HPLC.

9. The radiopharmaceutical composition of claim 8, wherein, The composition is stable for at least 120 hours, as indicated by greater than 94% RCP.

10. The radiopharmaceutical composition of claim 8 or 9, wherein, The composition is stable for at least 168 hours, as indicated by greater than 94% RCP.

11. The radiopharmaceutical composition according to any one of claims 8-10, wherein, The composition is stable for at least 288 hours, as indicated by greater than 94% RCP.

12. The radiopharmaceutical composition according to any one of claims 1-11, having a specific activity of at least about 5 µCi / nmol.

13. The radiopharmaceutical composition of claim 12, having a specific activity of about 5 µCi / nmol.

14. The radiopharmaceutical composition of claim 12, having a specific activity greater than about 5 µCi / nmol.

15. The radiopharmaceutical composition of claim 14, having a specific activity of about 60 to about 13200 µCi / nmol.

16. A method comprising [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition, wherein the radiopharmaceutical composition has a specific activity of about 5 µCi / nmol and a radiochemical purity (RCP) greater than 99%.

17. The radiopharmaceutical composition of claim 16, wherein, The composition is stable for at least 120 hours, as indicated by greater than 99% RCP.

18. The radiopharmaceutical composition according to any one of claims 16-17, wherein, The composition is stable for at least 168 hours, as indicated by greater than 99% RCP.

19. The radiopharmaceutical composition according to any one of claims 16-18, wherein, The composition is stable for at least 288 hours, as indicated by greater than 99% RCP.

20. The radiopharmaceutical composition according to any one of claims 16-19, wherein, The RCP was measured by radioactive TLC (i-TLC).

21. A kind of [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition, wherein the radiopharmaceutical composition has a specific activity of about 5 µCi / nmol and a radiochemical purity (RCP) greater than 95%.

22. The radiopharmaceutical composition of claim 21, wherein, The composition is stable for at least 120 hours, as indicated by greater than 96% RCP.

23. The radiopharmaceutical composition according to any one of claims 21-22, wherein, The composition is stable for at least 168 hours, as indicated by greater than 96% RCP.

24. The radiopharmaceutical composition according to any one of claims 21-23, wherein, The composition is stable for at least 288 hours, as indicated by greater than 95% RCP.

25. The radiopharmaceutical composition according to any one of claims 21-24, wherein, The RCP was measured by radioactive HPLC.

26. A radiopharmaceutical composition comprising [ 225 Ac]Ac-DOTA-TATE and has a specific activity greater than about 5 µCi / nmol.

27. The radiopharmaceutical composition of claim 26, having a specific activity of about 60 to about 13200 µCi / nmol.

28. The radiopharmaceutical composition of any one of the preceding claims, comprising one or more components selected from the group consisting of: ethanol, L-methionine, selenomethionine, histidine, melatonin, polysorbate, ammonium acetate, ascorbic acid or a pharmaceutically acceptable salt thereof, acetic acid or a pharmaceutically acceptable salt thereof, benzyl alcohol, p-aminobenzoic acid or a pharmaceutically acceptable salt thereof, cysteine, 5-amino-2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof, nicotinic acid or a pharmaceutically acceptable salt thereof, nicotinamide, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentianic acid, and inositol.

29. The radiopharmaceutical composition of any of the preceding claims, comprising one or more components selected from the group consisting of ethanol, L-methionine, polysorbate, ascorbic acid or a pharmaceutically acceptable salt thereof, and acetic acid or a pharmaceutically acceptable salt thereof.

30. The radiopharmaceutical composition as claimed in any of the preceding claims, wherein, The radiopharmaceutical composition comprises ascorbic acid or a pharmaceutically acceptable salt thereof, and polysorbate.

31. The radiopharmaceutical composition of claim 30, wherein, The mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the radiopharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1, and optionally about 100:

1.

32. The radiopharmaceutical composition according to any one of claims 30-31, wherein, The ascorbic acid or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition in an amount of ≤ 100 mg / mL, optionally ≤ 80 mg / mL, optionally 30-70 mg / mL, optionally 40-60 mg / mL, optionally about 50 mg / mL.

33. The radiopharmaceutical composition according to any one of claims 30-32, wherein, The polysorbate is present in the radiopharmaceutical composition in an amount of ≤1 mg / mL, optionally 0.3-0.7 mg / mL, optionally 0.4-0.6 mg / mL, optionally about 0.5 mg / mL.

34. The radiopharmaceutical composition according to any one of claims 30-33, wherein, The polysorbate is polyoxyethylene (20) sorbitan monolaurate, optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the radiopharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL.

35. The radiopharmaceutical composition according to any one of claims 30-34, wherein, The radiopharmaceutical composition comprises L-methionine, optionally wherein the L-methionine is present in the pharmaceutical composition at a concentration of about 10 mg / mL to about 30 mg / mL.

36. The radiopharmaceutical composition according to any one of claims 30-35, wherein, The radiopharmaceutical composition comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 0.01 M to about 0.15 M.

37. The radiopharmaceutical composition according to any one of claims 30-36, wherein, The acetic acid or its pharmaceutically acceptable salt is ammonium acetate.

38. The radiopharmaceutical composition according to any one of claims 30-37, wherein, The radiopharmaceutical composition comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 1% (v / v) to about 15% (v / v), or optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 5% (v / v) to about 10% (v / v).

39. The radiopharmaceutical composition as claimed in any of the preceding claims, wherein, The pH of the radiopharmaceutical composition is approximately 6.

40. A radiopharmaceutical composition comprising [ 225 Ac]Ac-DOTA-TATE, ascorbic acid or its pharmaceutically acceptable salts, and polysorbate.

41. The radiopharmaceutical composition of claim 40, wherein, The ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in an amount sufficient to provide at least 94% RCP (as measured by HPLC) for at least 168 hours at 2°C-8°C, or at least 98% RCP (as measured by radio-HPLC) for at least 168 hours at 2°C-8°C.

42. The radiopharmaceutical composition of claim 40 or 41, wherein, The mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the radiopharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1, and optionally about 100:

1.

43. The radiopharmaceutical composition according to any one of claims 40-42, wherein, The ascorbic acid or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition in an amount of ≤ 100 mg / mL, optionally ≤ 80 mg / mL, optionally 30-70 mg / mL, optionally 40-60 mg / mL, optionally about 50 mg / mL.

44. The radiopharmaceutical composition according to any one of claims 40-43, wherein, The ascorbic acid or pharmaceutically acceptable salt is sodium ascorbate, optionally wherein the sodium ascorbate is present in the radiopharmaceutical composition in an amount of about 30 mg / mL to about 70 mg / mL.

45. The radiopharmaceutical composition according to any one of claims 40-44, wherein, The polysorbate is present in the radiopharmaceutical composition in an amount of ≤1 mg / mL, optionally 0.3-0.7 mg / mL, optionally 0.4-0.6 mg / mL, optionally about 0.5 mg / mL.

46. ​​The radiopharmaceutical composition according to any one of claims 40-45, wherein, The polysorbate is polyoxyethylene (20) sorbitan monolaurate, optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the radiopharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL.

47. The radiopharmaceutical composition according to any one of claims 40-46, wherein, The radiopharmaceutical composition further comprises L-methionine, optionally wherein the L-methionine is present in the pharmaceutical composition at a concentration of about 10 mg / mL to about 30 mg / mL.

48. The radiopharmaceutical composition according to any one of claims 40-47, wherein, The radiopharmaceutical composition further comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 0.01 M to about 0.15 M.

49. The radiopharmaceutical composition according to any one of claims 40-48, wherein, The acetic acid or its pharmaceutically acceptable salt is ammonium acetate.

50. The radiopharmaceutical composition according to any one of claims 40-49, wherein, The radiopharmaceutical composition comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 1% (v / v) to about 15% (v / v), or optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 5% (v / v) to about 10% (v / v).

51. The radiopharmaceutical composition according to any one of claims 40-50, wherein, The pH of the radiopharmaceutical composition is approximately 6.

52. A method for preparing [ 225 A method for assembling a radiopharmaceutical composition of Ac-DOTA-TATE, the method comprising reacting DOTA-TATE with [Ac-DOTA-TATE] in the presence of acetic acid or a salt thereof. 225 Ac contact to obtain [ 225 Ac]Ac-DOTA-TATE.

53. The method of claim 52, further comprising reacting DOTA-TATE with acetic acid or a salt thereof and hydrochloric acid in the presence of acetic acid or a salt thereof and hydrochloric acid. 225 Ac contact.

54. The method according to any one of claims 52-53, wherein, The contact includes heating.

55. The method according to any one of claims 52-54, wherein, The [ 225 Ac]Ac-DOTA-TATE was purified by chromatography.

56. The method according to any one of claims 52-55, wherein, The above is prepared using a formulation buffer containing one or more radioactive stabilizers. 225 Ac]Ac-DOTA-TATE, to obtain [ 225 Ac]Ac-DOTA-TATE radiopharmaceutical composition.

57. The method of claim 56, wherein, The formulation buffer further contains a surfactant.

58. The method according to any one of claims 56-57, wherein, The formulation buffer contains ascorbic acid or a pharmaceutically acceptable salt thereof, and polysorbate.

59. The method according to any one of claims 56-58, wherein, The formulation buffer further contains L-methionine.

60. The method according to any one of claims 56-59, wherein, The formulation buffer further contains ethanol.

61. The method according to any one of claims 56-60, wherein, The radiopharmaceutical composition comprises [ 225 Ac]Ac-DOTA-TATE, sodium ascorbate, polyoxyethylene (20) dehydrated sorbitol monolaurate, L-methionine, ammonium acetate, ethanol and water.

62. A radiopharmaceutical composition prepared according to any one of claims 52-61.

63. A method of treating cancer in a subject in need, the method comprising administering to the subject an effective amount of the radiopharmaceutical composition as described in any one of claims 1-51 and 62.

64. The method of claim 63, wherein, The cancer in question is a neuroendocrine tumor.

65. The method of claim 63 or 64, wherein, The cancer in question is a somatostatin receptor-positive (SSTR+) tumor.

66. The method of claim 64, wherein, The SSTR+ tumor is a gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

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