Pharmaceutical compositions for improving oral bioavailability

Abstract

In accordance with this disclosure, a pharmaceutical formulation that improves the oral bioavailability of cyclic peptides has been discovered.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 490,929, filed Mar. 17, 2023, and U.S. Provisional Patent Application No. 63 / 498,207, filed Apr. 25, 2023, both of which are hereby incorporated by reference in their entirety.

[0002] The present disclosure provides a pharmaceutical composition that improves the oral bioavailability of cyclic peptides. Also disclosed is a pharmaceutical composition comprising a macrocyclic compound that binds to PD - L1 and is capable of inhibiting the interaction of PD - L1 with PD - 1 and CD80.

Background Art

[0003] Although there is an increasing trend in drug discovery that favors large molecules such as miramolecules, their low oral bioavailability still hinders their further widespread use. Oral administration of large hydrophilic molecules is challenging due to low intestinal epithelial membrane permeability resulting from pH and interactions with gastric / intestinal enzymes, as well as passive or minimal carrier - mediated transcellular permeation across the phospholipid bilayer, and limitations in paracellular transport through tight junctions. Other variables, such as plasma half - life and therapeutic index, also affect the feasibility of oral delivery of miramolecules.

[0004] In recent years, several cyclic peptides have been reported that block the interaction of PD-L1 with either PD-1 or CD80 (see, for example, Patent Documents 1, 2, 3, and 4). Such compounds are useful for enhancing, stimulating, and / or increasing the immune response in patients and can be used to treat conditions such as septic shock and cancer. Oral delivery of such molecules may offer numerous advantages over injectable delivery of other larger molecules, but the development of oral formulations of such molecules has proven challenging. Therefore, there is a need for oral formulations that improve the bioavailability of larger, biologically active molecules such as cyclic peptides. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] U.S. Patent No. 9,308,263 [Patent Document 2] U.S. Patent No. 9,850,283 [Patent Document 3] U.S. Patent No. 9,879,046 [Patent Document 4] U.S. Patent No. 9,856,292 [Overview of the project] [Problems that the invention aims to solve]

[0006] This disclosure provides a pharmaceutical composition that improves the oral bioavailability of cyclic peptides. [Means for solving the problem]

[0007] In a first embodiment, the present disclosure provides a pharmaceutical composition comprising: a cyclic peptide; and a decanoate. In some embodiments, the decanoate is sodium decanoate. In some embodiments, the cyclic peptide is of formula: [ka] Compound (I) of the same, or a pharmaceutically acceptable salt thereof.

[0008] In certain embodiments, cyclic peptides are present in amounts of approximately 0.1 wt% to approximately 20 wt%. In some embodiments, cyclic peptides are present in amounts of approximately 0.5 wt% to approximately 10 wt%. In some embodiments, cyclic peptides are present in amounts of approximately 6.0 wt% to approximately 9.50 wt%. In some embodiments, cyclic peptides are present in amounts of approximately 0.8 wt% to approximately 5.0 wt%.

[0009] In certain embodiments, decanoate is sodium decanoate. In some embodiments, sodium decanoate is present in amounts of about 15 wt% to about 70 wt%. In some embodiments, sodium decanoate is present in amounts of about 20 wt% to about 55 wt%. In some embodiments, sodium decanoate is present in amounts of about 20 wt% to about 30 wt%. In some embodiments, sodium decanoate is present in amounts of about 27 wt% to about 28 wt%.

[0010] In certain embodiments, the composition is for oral administration. In some embodiments, the composition comprises capsules, tablets, minitablets, or sachets.

[0011] In certain embodiments, this disclosure is: a.Formula: [ka] Compound (I) having, or a pharmaceutically acceptable salt thereof; b. Approximately 27.5 wt% sodium decanoate; c. Approximately 37 wt% to 43 wt% of microcrystalline cellulose; d. Approximately 18 wt% to 22 wt% mannitol; e. Approximately 4 wt% croscarmellose sodium; f. Approximately 2 wt% silicon dioxide; and g. Approximately 2 wt% magnesium stearate The present invention provides a pharmaceutical composition containing the following:

[0012] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.8%. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1.7%. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 3.3%. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 6.7%. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 8.3%.

[0013] In certain embodiments, the composition is for oral administration. In some embodiments, the composition comprises capsules, tablets, mini - tablets, or sachets.

[0014] In some embodiments, the pharmaceutical composition comprises sodium decanoate and the sodium decanoate is crystallized.

[0015] In certain embodiments, the present disclosure provides a method for improving the bioavailability of a cyclic peptide in a subject that requires improvement of the bioavailability of the cyclic peptide, comprising formulating the cyclic peptide with sodium decanoate. In some embodiments, the bioavailability is improved by at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, or at least about 1.0%. In some embodiments, the cyclic peptide is a compound (I) having the formula:

Chemical formula

[0016] In certain embodiments, the present disclosure provides a method of inhibiting the growth, proliferation, or metastasis of cancer cells in a subject that requires inhibition of cancer cell growth, proliferation, or metastasis, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer is selected from melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, squamous cell carcinoma of the head and neck, esophageal cancer, gastrointestinal cancer, breast cancer, and hematological malignancies.

[0017] In certain embodiments, the present disclosure provides a method of enhancing, stimulating, and / or increasing an immune response in a subject that requires enhancement, stimulation, and / or increase of an immune response, the method comprising administering to the subject a therapeutically effective amount of a medicament described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] [Figure 1] FIG. 1 shows the plasma concentration of compound (I) over time in cynomolgus monkeys administered 12 mg of compound (I) formulated as described in Example 1. [Figure 2] FIG. 2 shows the plasma concentration of compound (I) over time in dogs treated with 20 mg of compound (I) formulated as described in Example 3. [Figure 3] FIG. 3 shows the plasma concentration of compound (I) over time in dogs treated with 100 mg of compound (I) formulated as described in Examples 5A and 5B. [Figure 4] FIG. 4 shows the plasma concentration of compound (I) over time in dogs treated with 100 mg of compound (I) formulated as described in Examples 5B, 5C, and 5D. DETAILED DESCRIPTION OF THE INVENTION

[0019] This disclosure relates to a pharmaceutical composition comprising a cyclic peptide and a decanoate such as sodium decanoate. This composition can improve the bioavailability of the cyclic peptide.

[0020] I. Definition To make this explanation easier to understand, certain terms are defined first. Additional definitions will be provided throughout the descriptions of the modes for carrying out the invention.

[0021] Unless otherwise specified, any atom whose valence is not met is assumed to have enough hydrogen atoms to satisfy that valence.

[0022] The singular forms “a,” “an,” and “the” refer to multiple objects unless the context specifically indicates otherwise. Therefore, the terms “a” (or “an”), “one or more,” and “at least one” may be used synonymously in this specification. Furthermore, it should be noted that claims may be drafted to exclude any optional elements. Thus, this statement is intended to function as an antecedent for the use of exclusive terminology such as “solely” and “only” in relation to the description of elements of claims or the use of negative limitations.

[0023] The term "or" means logical disjunction (i.e., and / or) and does not indicate exclusive disjunction unless explicitly indicated by terms such as "either one," "unless," "otherwise," or similar phrases.

[0024] Furthermore, when used herein, “and / or” should be interpreted as a specific disclosure of each of the two designated features or components, whether or not they are accompanied by the other. Thus, the term “and / or” as used in expressions such as “A and / or B” is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in expressions such as “A, B, and / or C” is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0025] Units, prefixes, and symbols are expressed in the format recognized by the International System of Units (SI). Numerical ranges include the digits defining the range. Where a range of values ​​is given, each integer value and fraction of the upper and lower limits of the range are also to be understood as being specifically disclosed, along with each subrange between such values. The upper and lower limits of any range may independently be included in or excluded from that range, and each range that includes either one of the limits, neither, or both is also included within the scope of this disclosure. Thus, ranges described herein are to be understood as abbreviated representations of all values ​​within that range, including the endpoints described. For example, the range 1 to 10 is to be understood as including any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0026] Where a value is explicitly stated, any value that is substantially the same quantity or amount as the stated value should also be understood to be within the scope of this disclosure. Where a combination is disclosed, each partial combination of the elements of that combination is also specifically disclosed and within the scope of this disclosure. Conversely, where different elements or groups of elements are disclosed individually, their combinations are also disclosed. Where, for any element of a disclosure, it is disclosed that there are multiple options, examples of that disclosure with each option excluded one by one, or examples of all combinations with other options, are also disclosed herein; two or more elements of a disclosure may have such exclusions, and all combinations of elements having such exclusions are disclosed herein.

[0027] Those skilled in the art will recognize that amino acids include compounds represented by the following general structure: [ka] (wherein R and R' are as discussed herein). Unless otherwise specified, the term “amino acid” as used herein, either alone or as part of another group, includes, but is not limited to, an amino group and a carboxyl group linked to the same carbon referred to as the “α” carbon, where R and / or R' may be a natural or unnatural side chain including hydrogen. The “S” absolute configuration at the “α” carbon is generally referred to as the “L” or “natural” configuration. When both the “R” and “R'” (prime) substituents are equal to hydrogen, the amino acid is glycine and is not chiral.

[0028] Unless otherwise specified, amino acids described herein may be D- or L-stereochemical and may be substituted as described in other parts of this disclosure. Where stereochemistry is not specified, it should be understood that this disclosure encompasses all stereoisomeric forms, or mixtures thereof, that produce the desired activity. Individual stereoisomers of a compound may be prepared synthetically from commercially available starting materials containing chiral centers, or they may be prepared by separation after preparation of a mixture of enantiomer products, e.g., conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers by chiral chromatography columns. Starting compounds of specific stereochemistrys are commercially available or can be prepared and divided by techniques known in the art.

[0029] As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound, or at least one salt of a compound, or a combination thereof. For example, "compound (I) or a pharmaceutically acceptable salt thereof" includes, but is not limited to, compound (I), a pharmaceutically acceptable salt of compound (I), one or more pharmaceutically acceptable salts of compound (I) and compound (I), and two or more pharmaceutically acceptable salts of compound (I).

[0030] The term "to treat" means to inhibit a disease, disorder, or symptom, i.e., to prevent its onset; (iii) to alleviate a disease, disorder, or symptom, i.e., This refers to causing the regression of a disease, disorder, and / or symptoms, and / or signs associated with a disease, disorder, and / or symptoms.

[0031] II. Pharmaceutical Compositions In certain embodiments, the Disclosure provides compositions comprising cyclic peptides. As used herein, the term “composition” is intended to encompass products comprising a specified component in a specified amount, and any products directly or indirectly derived from a combination of a specified component in a specified amount. With respect to pharmaceutical compositions, such term is intended to encompass products comprising an active component and an inactive component constituting a carrier, and any products directly or indirectly derived from a combination, complexation, or aggregation of any two or more components, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition produced by mixing the compounds of the present invention with a pharmaceutically acceptable carrier. “pharmaceutically acceptable carrier” means that the carrier, diluent, or excipient is compatible with the other components of the formulation and is not harmful to its recipient.

[0032] In some embodiments, the compositions of the Disclosure are suitable for oral administration. These compositions may comprise solid, semi-solid, gel matrix, or liquid dosage forms suitable for oral administration. Oral administration as used herein includes buccal, lingual, and sublingual administration. Suitable oral dosage forms, but are not limited to, tablets, minitablets, bilayer tablets, capsules, pills, lozenges, sachets, pellets, medicinal chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups, or any combination thereof. In some embodiments, the compositions of the Disclosure suitable for oral administration are in the form of tablets or capsules. In some embodiments, the compounds of the Disclosure may be formulated tablets. In some embodiments, tablets may be encapsulated in capsules for administration.

[0033] The tablets of this disclosure may be in the form of compressed tablets, wet tablets, chewable lozenges, fast-dissolving tablets, multilayer compressed tablets, enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that protects the active ingredient from the acidic environment of the stomach, as they are resistant to gastric acid but dissolve or disintegrate in the intestines. Examples of enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammonia-modified shellac, and cellulose phthalate acetate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in masking unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets coated with a thin layer or film of a water-soluble material. Examples of film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose phthalate acetate. Film coatings can impart the same general characteristics as sugar coatings. Multilayer compression tablets are compression tablets manufactured by two or more compression cycles, and include multilayer tablets, compression-coated tablets, or core tablets.

[0034] In some embodiments, the compounds of the Disclosure may be in tablet form. In some embodiments, the compounds of the Disclosure may be in compressed tablet form. In some embodiments, the compounds of the Disclosure may be in enteric-coated tablet form.

[0035] In some embodiments, the compositions of the Disclosure may be prepared by dry granulation of the compounds of the Disclosure with one or more pharmaceutically acceptable carriers, media, and / or excipients. In some embodiments, the compositions of the Disclosure may be prepared by wet granulation.

[0036] In some embodiments, the compositions of this disclosure may be in the form of soft or hard capsules that can be produced from gelatin, methylcellulose, starch, and / or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), may consist of two sections, one of which slips over the other, thus completely enclosing the active ingredient. Flexible capsules (SECs) are flexible spherical shells, such as gelatin shells, which are plasticized by the addition of glycerin, sorbitol, or similar polyols. In some embodiments, the flexible gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include, but are not limited to, methylparaben and propylparaben, sorbic acid, and combinations thereof, as described herein. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated within capsules. Suitable liquid and semi-solid dosage forms include, but are not limited to, solutions and suspensions in propylene carbonate, vegetable oils, triglycerides, and combinations thereof. Furthermore, the capsules may be coated, as is known to those skilled in the art, to modify the active ingredient or to allow it to remain dissolved.

[0037] Colorants and flavoring agents can be used in all of the above dosage forms. In addition, flavoring agents and sweeteners may be particularly useful in the formation of chewable tablets and lozenges.

[0038] In certain embodiments, the compositions of the present disclosure may be formulated as immediate-release or modified-release formulations, including delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release forms.

[0039] The compositions of this disclosure may contain other active ingredients that do not confer therapeutic or prophylactic efficacy to the compositions, and / or substances that enhance or supplement the efficacy of the compositions.

[0040] The compositions described herein are typically part of a mixture with appropriate pharmaceutical diluents, excipients, and / or carriers (collectively referred to herein as pharmaceutical carriers) that are appropriately selected with respect to the intended dosage form and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, an active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier. Furthermore, as desired or required, appropriate binders, lubricants, surfactants, disintegrants, fluidizers, flavoring agents, and colorants can also be incorporated into the mixture. Examples of this type of additive include, but are not limited to, cholesterol, caprylocaproyl macrogol-8 glyceride / caprylocaproyl polyoxyl-8 glyceride, calcium phosphate, calcium sulfate, natural starch, pregelatinized starch, sodium starch glycolate, methylcellulose, microcrystalline cellulose, croscarmellose, croscarmellose sodium, cross-linked carboxymethylcellulose sodium, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, and crospovidone. Examples include crosslinked polymers such as (crospovidone), crosslinked polyvinylpyrrolidone, sodium alginate, clay, rubber, silica, silicon dioxide, talc, starch, aluminum magnesium silicate, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaxomer, bile salts, glyceryl monostearate, copolymers of ethylene oxide, propylene oxide, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, zinc stearate, wax, and talc, as well as combinations thereof.In some embodiments, the compositions described herein include cholesterol, caprylocaproyl macrogol-8 glyceride / caprylocaproyl polyoxyl-8 glyceride, silicon dioxide, croscarmellose sodium, and magnesium stearate. In some embodiments, the compositions described herein include microcrystalline cellulose, mannitol, croscarmellose sodium, silicon dioxide, magnesium stearate, or a combination thereof.

[0041] In some embodiments, the composition contains one or more fillers in an amount of about 15 wt% to about 80 wt%. In some embodiments, the term “filler” refers to an inert substance used to make the active ingredient larger or easier to handle. Examples of fillers include, but are not limited to, lactose, sucrose, microcrystalline cellulose, calcium carbonate, and calcium phosphate. In some embodiments, the composition contains one or more fillers in an amount of about 20 wt% to about 75 wt%. In some embodiments, the composition contains one or more fillers in an amount of about 25 wt% to about 70 wt%. In some embodiments, the composition contains one or more fillers in an amount of about 30 wt% to about 65 wt%. In some embodiments, the composition contains one or more fillers in an amount of about 35 wt% to about 60 wt%. In some embodiments, the composition contains approximately 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, and 47 wt%. It contains one or more fillers in an amount of approximately 48 wt%, approximately 49 wt%, approximately 50 wt%, approximately 51 wt%, approximately 52 wt%, approximately 53 wt%, approximately 54 wt%, approximately 55 wt%, approximately 56 wt%, approximately 57 wt%, approximately 58 wt%, approximately 59 wt%, approximately 60 wt%, approximately 61 wt%, approximately 62 wt%, approximately 63 wt%, approximately 64 wt%, approximately 65 wt%, approximately 66 wt%, approximately 67 wt%, approximately 68 wt%, approximately 69 wt%, approximately 70 wt%, approximately 71 wt%, approximately 72 wt%, approximately 73 wt%, approximately 74 wt%, approximately 75 wt%, approximately 76 wt%, approximately 77 wt%, approximately 78 wt%, approximately 79 wt%, or approximately 80 wt%.

[0042] In some embodiments, one or more fillers contain microcrystalline cellulose. In some embodiments, the composition contains about 10 wt% to about 50 wt% of microcrystalline cellulose. In some embodiments, the composition contains about 15 wt% to about 49 wt% of microcrystalline cellulose. In some embodiments, the composition contains about 20 wt% to about 48 wt% of microcrystalline cellulose. In some embodiments, the composition contains about 25 wt% to about 47 wt% of microcrystalline cellulose. In some embodiments, the composition contains about 30 wt% to about 46 wt% of microcrystalline cellulose. In some embodiments, the composition contains about 35 wt% to about 45 wt% of microcrystalline cellulose. In some embodiments, the composition contains about 37 wt% to about 43 wt% of microcrystalline cellulose. In some embodiments, the composition contains approximately 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, and 30 wt%. Contains approximately wt%, 31wt%, 32wt%, 33wt%, 34wt%, 35wt%, 36wt%, 37wt%, 38wt%, 39wt%, 40wt%, 41wt%, 42wt%, 43wt%, 44wt%, 45wt%, 46wt%, 47wt%, 48wt%, 49wt%, or 50wt% microcrystalline cellulose.

[0043] In some embodiments, one or more fillers contain mannitol. In some embodiments, the composition contains about 5 wt% to about 30 wt% of mannitol. In some embodiments, the composition contains about 10 wt% to about 27 wt% of mannitol. In some embodiments, the composition contains about 15 wt% to about 25 wt% of mannitol. In some embodiments, the composition contains about 18 wt% to about 22 wt% of mannitol. In some embodiments, the composition contains about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt% of mannitol.

[0044] In some embodiments, the composition contains one or more disintegrants in an amount of about 2 wt% to about 6 wt%. In some embodiments, the term “disintegrant” means an agent added to a formulation, more specifically to a tablet, to facilitate the breakdown of the tablet into smaller fragments in an aqueous environment. Examples of disintegrants include, but are not limited to, croscarmellose sodium, crospovidone, and sodium starch glycolate. In some embodiments, the composition contains one or more disintegrants in an amount of about 3 wt% to about 5 wt%. In some embodiments, the composition contains one or more disintegrants in an amount of about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, or about 6 wt%.

[0045] In some embodiments, one or more disintegrants include croscarmellose sodium. In some embodiments, the composition includes about 2 wt% to about 6 wt% of croscarmellose sodium. In some embodiments, the composition includes about 3 wt% to about 5 wt% of croscarmellose sodium. In some embodiments, the composition includes about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, or about 6 wt% of croscarmellose sodium.

[0046] In some embodiments, the composition comprises silicon dioxide, talc, calcium silicate, or a mixture thereof. In some embodiments, the composition comprises about 1 wt% to about 4 wt% silicon dioxide. In some embodiments, the composition comprises about 1 wt% to about 3 wt% silicon dioxide. In some embodiments, the composition comprises about 1 wt%, about 2 wt%, about 3 wt%, or about 4 wt% silicon dioxide.

[0047] In some embodiments, the composition contains one or more fluidizing agents in an amount of about 1 wt% to about 4 wt%. In some embodiments, the term “fluidizing agent” refers to an agent used to increase the flow of powder. Examples of fluidizing agents include, but are not limited to, talc, calcium stearate, sodium stearate, stearic acid, stearyl fumarate, magnesium stearate, and silica. In some embodiments, the composition contains one or more fluidizing agents in an amount of about 1 wt% to about 3 wt%. In some embodiments, the composition contains one or more fluidizing agents in an amount of about 1 wt%, about 2 wt%, about 3 wt%, or about 4 wt%.

[0048] In some embodiments, the composition contains about 1 wt% to about 4 wt% magnesium stearate. In some embodiments, the composition contains about 1 wt% to about 3 wt% magnesium stearate. In some embodiments, the composition contains about 1 wt%, about 2 wt%, about 3 wt%, or about 4 wt% magnesium stearate.

[0049] In yet another embodiment, a film coating can be provided around the formulations of the compounds described herein using a standard coating procedure, such as that described in Remingon's Pharmaceutical Sciences, 23rd Edition (2020).

[0050] A dosage form (pharmaceutical composition) suitable for administration may contain approximately 1 milligram to approximately 300 milligrams of the active ingredient per dose unit. In such pharmaceutical compositions, the active ingredient is typically present in an amount of approximately 0.5 to 95% by weight based on the total weight of the composition. In some embodiments, a dosage form suitable for administration may contain approximately 10 to approximately 240 milligrams of the active ingredient per dose unit. In some embodiments, a dosage form suitable for administration may contain approximately 10, approximately 20, approximately 30, approximately 40, approximately 50, approximately 60, approximately 70, approximately 80, approximately 90, approximately 100, approximately 110, approximately 120, approximately 130, approximately 140, approximately 150, approximately 160, approximately 170, approximately 180, approximately 190, approximately 200, approximately 210, approximately 220, approximately 230, or approximately 240 mg of the active ingredient per dose unit.

[0051] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a cyclic peptide or a pharmaceutically acceptable salt thereof as described herein, a salt of decanoic acid, and at least one pharmaceutically acceptable carrier. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a cyclic peptide or a pharmaceutically acceptable salt thereof as described herein, sodium decanoate, and at least one pharmaceutically acceptable carrier.

[0052] This disclosure provides pharmaceutical compositions comprising a cyclic peptide and a salt of decanoic acid. In some embodiments, the salt is sodium decanoate, potassium decanoate, lithium decanoate, or magnesium decanoate. In some embodiments, the salt is sodium decanoate. In certain embodiments, the cyclic peptide skeleton may contain 2 to 20 amino acids. In certain embodiments, the cyclic peptide skeleton may contain 4 to 18 amino acids. In certain embodiments, the cyclic peptide skeleton may contain 6 to 16 amino acids. In certain embodiments, the cyclic peptide skeleton may contain 8 to 14 amino acids. In certain embodiments, the cyclic peptide skeleton may contain 10 to 14 amino acids. In certain embodiments, the cyclic peptide skeleton may contain 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids.

[0053] In a particular embodiment, the cyclic peptide is given by formula: [ka] It may contain compound (I) having, or a pharmaceutically acceptable salt thereof.

[0054] This disclosure is intended to include all isotopes of the atoms present in the compounds. Isotopes include atoms with the same atomic number but different mass numbers. Common examples, but not limited to, include deuterium and tritium as isotopes of hydrogen, and 13C and 14C as isotopes of carbon. Compounds of this disclosure labeled with isotopes can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described herein, using appropriate isotope-labeled reagents instead of the unlabeled reagents that would normally be used. Such compounds may have various potential uses, for example, as standards and reagents for determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably alter their biological, pharmacological, or pharmacokinetic properties.

[0055] The pharmaceutical compounds of this disclosure may include one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” means a salt that retains the desired biological activity of the parent compound and does not impart any undesirable toxicological effects (see, for example, Remington's Pharmaceutical Sciences, 23rd Edition (2020)). Salts may be obtained during the final isolation and purification of the compounds described herein, or separately by reacting the free basic functional group of the compound with a suitable acid, or by reacting the acidic group of the compound with a suitable base. Examples of acid addition salts include non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorus, as well as those derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, aromatic acids, and aliphatic and aromatic sulfonic acids. Examples of base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, and calcium, as well as non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine.

[0056] In certain embodiments, the cyclic peptide constitutes approximately 0.1 wt% to approximately 25 wt% of the pharmaceutical composition. In some embodiments, the cyclic peptide constitutes approximately 0.1 wt% to approximately 20 wt% of the pharmaceutical composition. In some embodiments, the cyclic peptide constitutes approximately 0.5 wt% to approximately 10 wt% of the pharmaceutical composition. In some embodiments, the cyclic peptide constitutes approximately 0.8 wt% to approximately 5 wt% of the pharmaceutical composition. In some embodiments, the cyclic peptide constitutes approximately 6.0 wt% to approximately 9.5 wt% of the pharmaceutical composition. In some aspects, cyclic peptides make up about 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.0 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, and 5.5 wt% of the composition. It consists of approximately 6.0 wt%, 6.5 wt%, 6.6 wt%, 6.7 wt%, 6.8 wt%, 6.9 wt%, 7.0 wt%, 7.5 wt%, 8.0 wt%, 8.1 wt%, 8.2 wt%, 8.3 wt%, 8.4 wt%, 8.5%, 9.0 wt%, 9.5 wt%, 10.0 wt%, 11.0 wt%, 12.0 wt%, 13.0 wt%, 14.0 wt%, 15.0 wt%, 16.0 wt%, 17.0 wt%, 18.0 wt%, 19.0 wt%, or 20.0 wt%.

[0057] The pharmaceutical compositions described herein contain sodium decanoate. In certain embodiments, sodium decanoate constitutes about 10 wt% to about 80 wt% of the composition. In certain embodiments, sodium decanoate constitutes about 15 wt% to about 70 wt% of the composition. In certain embodiments, sodium decanoate constitutes about 20 wt% to about 60 wt% of the composition. In certain embodiments, sodium decanoate constitutes about 20 wt% to about 55 wt% of the composition. In certain embodiments, sodium decanoate constitutes about 20 wt% to about 30 wt% of the composition. In certain embodiments, sodium decanoate constitutes about 27 wt% to about 28 wt% of the composition. In certain aspects, sodium decanoate is present in the composition at concentrations of approximately 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, and 2 wt%. 5wt%, about 26wt%, about 27wt%, about 28wt%, about 29wt%, about 30wt%, about 31wt%, about 32wt%, about 33wt%, about 34wt %, about 35wt%, about 36wt%, about 37wt%, about 38wt%, about 39wt%, about 40wt%, about 41wt%, about 42wt%, about 43wt%, about 44wt%, about 45wt%, about 46wt%, about 47wt%, about 48wt%, about 49wt%, about 50wt%, about 51wt%, about 52wt%, about 53w t%, approximately 54wt%, approximately 55wt%, approximately 56wt%, approximately 57wt%, approximately 58wt%, approximately 59wt%, approximately 60wt%, approximately 61wt%, approximately 62wt%, It consists of approximately 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, or 80 wt%.

[0058] In some embodiments, sodium decanoate is amorphous and produced by spray drying or another suitable process. In some embodiments, sodium decanoate is crystalline. While not constrained by any particular theory, crystallized sodium decanoate can, in some cases, achieve improved physical properties such as favorable flow or lower viscosity compared to spray-dried sodium decanoate.

[0059] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising about 0.1 wt% to about 25 wt% of a cyclic peptide, about 10 wt% to about 80 wt% of sodium decanoate, about 10 wt% to about 50 wt% of microcrystalline cellulose, about 5 wt% to about 30 wt% of mannitol, about 2 wt% to about 6 wt% of croscarmellose sodium, about 1 wt% to about 4 wt% of silicon dioxide, and about 1 wt% to about 4 wt% of magnesium stearate. In some embodiments, the cyclic peptide is compound (I).

[0060] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising about 0.1 wt% to about 20 wt% of a cyclic peptide, about 15 wt% to about 70 wt% of sodium decanoate, about 15 wt% to about 49 wt% of microcrystalline cellulose, about 10 wt% to about 27 wt% of mannitol, about 3 wt% to about 5 wt% of croscarmellose sodium, about 1 wt% to about 3 wt% of silicon dioxide, and about 1 wt% to about 3 wt% of magnesium stearate. In certain embodiments, the cyclic peptide is compound (I).

[0061] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising about 0.8 wt% of a cyclic peptide, about 27.5 wt% of sodium decanoate, about 42 wt% of microcrystalline cellulose, about 21 wt% of mannitol, about 4 wt% of croscarmellose sodium, about 2 wt% of silicon dioxide, and about 2 wt% of magnesium stearate. In certain embodiments, the cyclic peptide is compound (I).

[0062] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising about 1.7 wt% of a cyclic peptide, about 27.5 wt% of sodium decanoate, about 42 wt% of microcrystalline cellulose, about 21 wt% of mannitol, about 4 wt% of croscarmellose sodium, about 2 wt% of silicon dioxide, and about 2 wt% of magnesium stearate. In certain embodiments, the cyclic peptide is compound (I).

[0063] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising about 3.3 wt% of a cyclic peptide, about 27.5 wt% of sodium decanoate, about 41 wt% of microcrystalline cellulose, about 20 wt% of mannitol, about 4 wt% of croscarmellose sodium, about 2 wt% of silicon dioxide, and about 2 wt% of magnesium stearate. In certain embodiments, the cyclic peptide is compound (I).

[0064] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising about 6.7 wt% of a cyclic peptide, about 27.5 wt% of sodium decanoate, about 38.5 wt% of microcrystalline cellulose, about 19 wt% of mannitol, about 4 wt% of croscarmellose sodium, about 2 wt% of silicon dioxide, and about 2 wt% of magnesium stearate. In certain embodiments, the cyclic peptide is compound (I).

[0065] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising about 8.3 wt% of a cyclic peptide, about 27.5 wt% of sodium decanoate, about 37 wt% of microcrystalline cellulose, about 19 wt% of mannitol, about 4 wt% of croscarmellose sodium, about 2 wt% of silicon dioxide, and about 2 wt% of magnesium stearate. In certain embodiments, the cyclic peptide is compound (I).

[0066] Furthermore, the scope of this disclosure also includes kits comprising the compositions and instructions for use of the disclosed compositions. The kits may further contain additional reagents. The kits typically include labels indicating the intended use of the kit's contents and instructions for use. Terminology labels include any documentation or recorded material on the kit, supplied with the kit, or otherwise accompanying the kit in any way.

[0067] III.How to use This disclosure provides pharmaceutical formulations that improve the bioavailability of cyclic peptides. In certain embodiments, the bioavailability is improved by at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, or at least about 1.0%.

[0068] Administration of cyclic peptides as described herein includes, but is not limited to, the administration of a therapeutically effective dose of the compound. As used herein, “therapeutic dose” means, but is not limited to, the amount of cyclic peptide used to treat a condition treatable by administration of a composition containing the compound. Such a dose is sufficient to produce a detectable therapeutic effect or an effect leading to improvement. Such effects may include, but are not limited to, the treatment of conditions listed herein. The exact effective dose for a subject depends on the size and health status of the subject, the nature and severity of the condition being treated, the recommendations of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective dose in advance.

[0069] In another aspect, the Disclosure relates to a method for inhibiting tumor cell growth in a subject using the pharmaceutical compositions of the Disclosure. In some aspects, the cyclic peptides can bind to PD-L1, disrupt the interaction between PD-L1 and PD-1, compete with the binding of PD-L1 to known anti-PD-1 monoclonal antibodies that block interaction with PD-1, enhance CMV-specific T cell IFNγ secretion, and enhance HIV-specific T cell IFNγ secretion. As a result, in some aspects, the cyclic peptides of the Disclosure are useful for modifying immune responses, treating diseases such as cancer, infectious diseases, and / or septic shock, stimulating protective autoimmune responses, or stimulating antigen-specific immune responses.

[0070] Cancers whose growth can be inhibited using the pharmaceutical compositions of this disclosure include, but are not limited to, cancers that typically respond to immunotherapy. Representative examples include melanoma (e.g., metastatic melanoma), renal cell carcinoma, prostate cancer (including, but not limited to, castration-resistant prostate cancer), breast cancer, colon cancer, and lung cancer (including, but not limited to, squamous cell non-small cell lung cancer and non-squamous cell non-small cell lung cancer). Other cancers that can be treated using the methods of this disclosure include bone cancer, hepatocellular carcinoma, pancreatic cancer, skin cancer, head and neck squamous cell carcinoma, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, gastrointestinal cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, hematological malignancies (acute myeloid leukemia, Examples of cancers include chronic or acute leukemias (such as chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia), pediatric solid tumors, lymphocytic lymphoma, bladder cancer, renal cancer or ureteral cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axial tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermal carcinoma, squamous cell carcinoma, T-cell lymphoma, asbestos-induced cancers, and combinations of the above cancers. Furthermore, the pharmaceutical compositions described herein may also be useful for the treatment of metastatic cancer.

[0071] The pharmaceutical compositions described herein can enhance, stimulate, and / or increase the immune response in subjects requiring enhancement, stimulation, and / or increase of the immune response. As used herein, “immune response” refers to the action of, for example, lymphocytes, antigen-presenting cells, phagocytic cells, granulocytes, and soluble macromolecules (such as macrocyclic peptides, cytokines, and complements) produced by the above cells or the liver, resulting in selective damage, destruction, or elimination from the human body of an invading pathogen, a pathogen-infected cell or tissue, a cancerous cell, or, in the case of autoimmune or pathological inflammation, a normal human cell or tissue. In certain embodiments, the immune response may be generated by the innate immune system. In certain embodiments, the immune response may be generated by the adaptive immune system. In certain embodiments, the immune response may be generated by both the innate and adaptive immune systems.

[0072] The pharmaceutical compositions described herein can be delivered by a number of methods, including, but not limited to, oral, subcutaneous, intramuscular, duodenal, or intravenous, with some modifications. The compositions can be formulated according to a route of administration based on acceptable pharmaceutical practice (Fingl et al., in The Pharmacological Basis of Therapeutics, Chapter 1, p.1 (1975); Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, PA (1990)).

[0073] The dosage regimens for the compositions described herein will naturally vary depending on known factors such as the recipient's species, age, sex, health, medical condition, and weight; the nature and severity of symptoms; the type of treatment performed concurrently; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian may determine and prescribe the effective amount of drug necessary to prevent, counteract, or halt the progression of a disease condition.

[0074] As a general guideline, the daily oral dose of the active ingredient, when used to obtain the desired effect, will be approximately 0.001 to 500 mg / kg body weight per day, preferably approximately 0.01 to 100 mg / kg body weight, and most preferably approximately 0.1 to 20 mg / kg / day. For intravenous administration, the daily dose of the active ingredient, when used to obtain the desired effect, will be approximately 0.001 ng to 100.0 ng / kg body weight per minute during constant-rate infusion. Such constant-rate intravenous infusion can preferably be administered at a rate of 0.01 ng to 50 ng / kg body weight per minute, most preferably 0.01 ng to 10.0 mg / kg body weight per minute. The compositions described herein may be administered as a single daily dose, or the total daily dose may be administered in two, three, or four divided doses per day. [Examples]

[0075] biological activity Compound (I) (prepared according to the procedure described in U.S. Patent No. 9,856,292).

[0076] Example 1 Preparation of 1 mg strength enteric-coated tablets of compound (I) for a 12 mg dose (total of 12 tablets) Table 1 shows the composition of the core tablets. Cholesterol was weighed and dissolved in Labrasol ALF in a glass vial. Sodium decanoate was mixed with silicon dioxide in a mortar and blended using a pestle. The solution containing the dissolved cholesterol in Labrasol ALF was added to the blend of sodium decanoate and silicon dioxide. The vial containing the solution was rinsed with 1 g of ethyl alcohol and the rinse solution was added to the blend. Compound (I) was dissolved in 8 g of ethyl alcohol in a separate vial and added to the blend. The vial containing the solution was rinsed with 1 g of ethyl alcohol and the rinse solution was added to the blend. The blend containing all the formulation components was mixed in a mortar with a pestle until the blend was visually homogeneous. The mixture was placed in an aluminum tray and dried overnight in a vacuum oven at 50°C. The dried granules were then placed in a mortar, gently crushed, and passed through a 30-mesh screen. Next, the screened granules were added to a glass bottle along with croscarmellose sodium, and the mixture was blended for 10 minutes using a Turbula mixer (32 RPM, 10 min). Then, magnesium stearate was added to the glass bottle, and the final mixture was blended for 5 minutes using a Turbula mixer (32 RPM, 5 min). The powder blend was compressed using a standard 7 / 32 inch (5.55 mm) round dies at a compression force of 400 lb to form tablets of a target weight of 70 mg.

[0077] [Table 1]

[0078] The composition of the seal-coated tablets is shown in Table 2. An aqueous suspension of Opadry 03K was prepared with a solid content of 7.5%. The core uncoated tablets and placebo tablets were placed in a Vector 0.5L coating pan. The tablets were pan-coated to achieve a 2% target weight increase.

[0079] [Table 2]

[0080] The composition of the enteric-coated tablets is shown in Table 3. An aqueous suspension of Acryl EZE II was prepared with 10% solids. Seal-coated tablets and placebo tablets were added to a Vector 0.5L coating pan. The tablets were pan-coated to achieve a 7% target weight increase. For the cyno-PK study, six enteric-coated tablets were encapsulated in size #00 hard gelatin capsules. Each cynomolgus monkey was administered two capsules (12 enteric-coated tablets).

[0081] [Table 3]

[0082] Example 2 Determination of oral absorption of compound (I) preparations in cynomolgus monkeys Fasted male cynomolgus monkeys (n=3) were administered the compound orally, followed by a forced gasgage flush to promote dissolution in the gastrointestinal tract. Blood samples were collected at predetermined time points over 72 hours after dose administration, and comparative pharmacokinetics between the formulations were measured. Due to the long half-lives, a parallel-group design was used in different sets of cynomolgus monkeys. The mean exposure is shown in Figure 1, and the error bars represent the standard deviation. As shown in both Figure and Table 4, the formulations achieved good plasma concentrations of compound (I) over long periods.

[0083] [Table 4]

[0084] Example 3 Preparation of 2 mg strength compound (I) enteric-coated tablets for a 20 mg dose (total of 10 tablets) containing 660 mg of sodium decanoate. The composition of the core tablets is shown in Table 5. Compound (I) and sodium decanoate were combined using a mortar and pestle. The powder mixture was transferred to a glass bottle and blended using a Turbular mixture (32 RPM, 5 min). Magnesium stearate was added to the same bottle and gently mixed using a spatula. The powder mixture was blended using a Turbular mixture (32 RPM, 5 min). The powder blend was compressed using a 7 / 32 inch (5.55 mm) standard round dies with a compression force of 300 lb to form tablets with a target weight of 70 mg.

[0085] [Table 5]

[0086] The composition of the seal-coated tablets is shown in Table 6. An aqueous suspension of Opadry 03K was prepared with a solid content of 7.5%. The core uncoated tablets and placebo tablets were placed in a Vector 0.5L coating pan. The tablets were pan-coated to achieve a target weight increase of 2%.

[0087] [Table 6]

[0088] The composition of the enteric-coated tablets is shown in Table 7. An aqueous suspension of Acryl EZE II was prepared with a 10% solids content. Compound (I) seal-coated tablets and placebo tablets were added to a Vector 0.5L coating pan. The tablets were pan-coated to achieve a 7% target weight increase. For the canine PK study, five enteric-coated tablets were encapsulated in size #0 hard gelatin capsules. Each dog was administered two capsules (10 enteric-coated tablets).

[0089] [Table 7]

[0090] Example 4 Canine pK research Fasted dogs (4) pretreated with pentagastriin were administered a single 20 mg dose (2 x 10 mg capsules) of compound (I). Blood samples were collected over 72 hours. Figure 2 shows the mean exposure. The error bars represent the standard deviation. As shown in Figure and Table 8, the plasma concentration of compound (I) remained consistent in the dogs over the 72-hour period.

[0091] [Table 8]

[0092] Example 5 Effect of sodium decanoate amount and number of tablets on the performance of compound (I) formulation in dogs This study was initiated to determine whether oral bioavailability could be affected by (1) changing the amount of sodium decanoate from 330 mg to 660 mg at a 100 mg dose, and (2) the number of tablets administered to achieve a preferred dose of 100 mg.

[0093] Example 5A Preparation of 2.083 mg strength compound (I) enteric-coated tablets for a 100 mg dose (48 tablets total), containing 330 mg of sodium decanoate. The composition of the core tablets is shown in Table 9. Compound (I), sodium decanoate, microcrystalline cellulose, mannitol, croscarmellose sodium, and silicon dioxide were added to a glass bottle and blended using a turbulent mixer at 25 RPM for 10 minutes. The blended powder was passed through a 20-mesh screen and blended again at 25 RPM for 10 minutes. Magnesium stearate was added to the mixture and blended for another 3 minutes at 25 RPM to form a pre-blended product.

[0094] [Table 9]

[0095] The pre-blended material was compressed using a 3 / 4-inch (19.05 mm) round flat die to form a compressed material with a target weight of 1,000 mg and a target solids content of 0.6–0.7. The compressed material was added to a mortar and pestle setup and gently ground by 10 compressions at a time. The ground material was passed through a 10-mesh screen, and the remaining material was also passed through the screen and pressed. The resulting granules were passed through an 18-mesh screen, and the remaining material was also passed through the screen and pressed. The screened granules and extra-granular croscarmellose sodium were added to a glass bottle and blended at 25 RPM for 10 minutes. Extra-granular magnesium stearate was added and blended at 25 RPM for 3 minutes to form the final blend.

[0096] The final blend was compressed using a 1 / 8-inch (3.175 mm) standard circular multi-tip (7-tip) tableting dies to form tablets with a target weight of 25 mg and a target tensile strength of 1.5–2 MPa.

[0097] The tablets were coated in a two-layer coating in a 0.5L pan of LDCS Hi-Coater. The first layer was a seal coating with Opadry 03K aqueous suspension (10% w / w solids) to achieve a 2% target weight increase. The second layer was an enteric coating with Acryl-EZE II aqueous suspension (20% w / w solids) to achieve a 10% target weight increase. For the canine PK study, 24 enteric-coated tablets were encapsulated in size #00 hard gelatin capsules. Each dog was administered two capsules (48 enteric-coated tablets).

[0098] Example 5B Preparation of 2.083 mg strength compound (I) enteric-coated tablets for a 100 mg dose (48 tablets total), containing 660 mg of sodium decanoate.

[0099] [Table 10]

[0100] Table 10 shows the composition of the core tablets. All granule components were added to a 250 mL MiPro granulator bowl and blended for 3 minutes at an impeller speed of 1300 RPM and a chopper speed of 300 RPM. Water was added at a rate of 0.5 mL / min while maintaining the impeller and chopper speeds. After the addition of water was complete, the granulated blend was mixed for another 3 minutes at the same impeller and chopper speeds. The resulting granules were then passed through an 8-mesh screen and placed in an aluminum pan. The pan was then placed in a convection oven at 40°C for 1 hour. The dried granules were then passed through a mill equipped with a 45R screen.

[0101] The crushed granules and extra-granular croscarmellose sodium were added to a glass bottle and blended at 25 RPM for 10 minutes. Extra-granular magnesium stearate was added and blended at 25 RPM for 3 minutes to form the final blend. The final blend was compressed using a 1 / 8-inch (3.175 mm) multi-tip (7-tip) standard round tableting dies to form tablets with a target weight of 25 mg and a target tensile strength of 1.5–2 MPa.

[0102] The tablets were coated in a 0.5L pan of LDCS Hi-Coater with a two-layer coating. The first layer was a seal coating with Opadry 03K aqueous suspension (10% w / w solids) to achieve a 2% target weight increase. The second layer was an enteric coating with Acryl-EZE II aqueous suspension (20% w / w solids) to achieve a 10% target weight increase. For the canine PK study, 24 enteric-coated tablets were encapsulated in size #00 hard gelatin capsules. Each dog was administered two capsules (48 enteric-coated tablets).

[0103] Example 5C Preparation of 10 mg strength compound (I) enteric-coated tablets for a 100 mg dose (total of 10 tablets), containing 660 mg of sodium decanoate. Table 11 shows the composition of the core tablet. Compound (I), sodium decanoate, microcrystalline cellulose, mannitol, croscarmellose sodium, and silicon dioxide were added to a glass bottle and blended using a turbular mixer at 25 RPM for 10 minutes. The blended material was passed through a 20-mesh screen and blended again at 25 RPM for 10 minutes. Magnesium stearate was added to this mixture and blended for another 3 minutes at 25 RPM to form a pre-blended product.

[0104] [Table 11]

[0105] Using an 11.28 mm circular flat die, the pre-blended material was compressed to form a compressed material with a target weight of 400 mg and a target solids content of 0.6–0.7. The compressed material was pulverized using an oscillator equipped with 4 mm and 1 mm screens. The screened granules and extra-granular croscarmellose sodium were added to a glass bottle and blended at 25 RPM for 10 minutes. Extra-granular magnesium stearate was added and blended at 25 RPM for 3 minutes to form the final blend. The final blend was compressed using a 7 / 32 inch (5.55 mm) standard circular tableting die to form tablets with a target weight of 120 mg and a target tensile strength of 1.5–2 MPa.

[0106] The tablets were coated in a two-layer coating in a 0.5L pan of LDCS Hi-Coater. The first layer was a seal coating with Opadry 03K aqueous suspension (10% w / w solids) to achieve a 2% target weight increase. The second layer was an enteric coating with Acryl-EZE II aqueous suspension (20% w / w solids) to achieve a 7% target weight increase. For the canine PK study, five enteric-coated tablets were encapsulated in size #00 hard gelatin capsules. Each dog was administered two capsules (10 enteric-coated tablets).

[0107] Example 5D Preparation of 50 mg strength compound (I) enteric-coated tablets for a 100 mg dose (2 tablets total), containing 660 mg of sodium decanoate. Using a standard 15.3 mm × 8 mm oval diesel, the final blend derived from Example 5C was compressed to form tablets with a target weight of 600 mg and a target tensile strength of 1.5–2 MPa. The tablets were coated in a two-layer coating in a 0.5 L pan LDCS Hi-Coater. The first layer was a seal coating with Opadry 03K aqueous suspension (10% w / w solids) to achieve a 2% increase in target weight. The second layer was an enteric coating with Acryl-EZE II aqueous suspension (20% w / w solids) to achieve a 7% increase in target weight. Each dog was administered two enteric-coated tablets.

[0108] Example 5E Canine pK research Fasted dogs (4) pretreated with pentagastrin were administered a single 100 mg dose of different formulations of compound (I). Blood samples were collected over 72 hours. Figures 3 and 4 show the mean exposure levels. Error bars represent the standard deviation. As shown in Figure and Table 12, the dogs maintained consistent plasma concentrations of compound (I) over the 72-hour period.

[0109] As shown in Figure 3, a high decanoate level (660 mg) was required to enhance API penetration. Reducing the amount of sodium decanoate resulted in decreased PK exposure at 330 mg of sodium decanoate. As shown in Figure 4, for the 660 mg sodium decanoate formulation, reducing the number of tablets from 48 or 10 to 2 improved PK exposure. Table 12 summarizes all PK data for all formulations tested in Example 5.

[0110] [Table 12]

[0111] Example 6 Candidate formulations for First-in-Human (FIH) research The candidate formulations for first-in-human (FIH) administration are shown in Table 13 below.

[0112] [Table 13]

[0113] It should be understood that the section on modes for carrying out the invention, rather than the section on summary and abstract of the invention, is intended to be used to interpret the claims. The section on summary and abstract of the invention may show one or more, but not all, exemplary modes of the disclosure contemplated by the inventors, and is not intended to limit the scope of the disclosure and the appended claims in any way.

[0114] This disclosure has been described above using functional construction blocks that exemplify the implementation of the specified functions and their relationships. The boundaries of these functional construction blocks are arbitrarily defined herein for the convenience of the description. Alternative boundaries may be defined, provided that the specified functions and their relationships are adequately performed.

[0115] The foregoing description of the specified embodiments is intended to fully illustrate the general nature of the disclosure, and others can easily modify and / or adapt such specific embodiments to various uses by applying knowledge within the scope of the art without excessive experimentation and without departing from the general concepts of the disclosure. Therefore, such adaptations and modifications are intended to be included in the meaning and scope of the equivalents of the disclosed embodiments, based on the teachings and guidance presented herein. It should be understood that the style and terminology used herein are for illustrative purposes only, not limitation, so that they can be interpreted by those skilled in the art in light of the teachings and guidance provided herein.

[0116] The breadth and scope of this disclosure should not be limited by any of the exemplary embodiments described above, but should be defined solely by the following claims and equivalents.

Claims

1. Cyclic peptides; and Decanoate A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein the decanoate is sodium decanoate.

3. The aforementioned cyclic peptide has the formula: 【Chemistry 1】 The pharmaceutical composition according to claim 1 or 2, which is a compound (I) having, or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cyclic peptide is present in an amount of about 0.1 wt% to about 20 wt%.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the cyclic peptide is present in an amount of about 0.5 wt% to about 10 wt%.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the cyclic peptide is present in an amount of about 6.0 wt% to about 9.50 wt%.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the cyclic peptide is present in an amount of about 0.8 wt% to about 5.0 wt%.

8. The pharmaceutical composition according to any one of claims 2 to 7, wherein the sodium decanoate is present in an amount of about 15 wt% to about 70 wt%.

9. The pharmaceutical composition according to any one of claims 2 to 8, wherein the sodium decanoate is present in an amount of about 20 wt% to about 55 wt%.

10. The pharmaceutical composition according to any one of claims 2 to 9, wherein the sodium decanoate is present in an amount of about 20 wt% to about 30 wt%.

11. The pharmaceutical composition according to any one of claims 2 to 10, wherein the sodium decanoate is present in an amount of about 27 wt% to about 28 wt%.

12. A pharmaceutical composition according to any one of claims 1 to 11, for oral administration.

13. A pharmaceutical composition according to any one of claims 1 to 12, comprising a capsule, tablet, mini-tablet, or sachet.

14. a. formula: 【Chemistry 2】 Compound (I) having, or a pharmaceutically acceptable salt thereof; b. Approximately 27.5 wt% sodium decanoate; c. Approximately 37 wt% to 43 wt% of microcrystalline cellulose; d. Approximately 18 wt% to 22 wt% mannitol; e. Approximately 4 wt% croscarmellose sodium; f. Approximately 2 wt% silicon dioxide; and g. Approximately 2 wt% magnesium stearate A pharmaceutical composition containing the following:

15. The pharmaceutical composition according to claim 14, wherein compound (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.8%.

16. The pharmaceutical composition according to claim 14, wherein compound (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 1.7%.

17. The pharmaceutical composition according to claim 14, wherein compound (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 3.3%.

18. The pharmaceutical composition according to claim 14, wherein compound (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 6.7%.

19. The pharmaceutical composition according to claim 14, wherein compound (I), or a pharmaceutically acceptable salt thereof, is present in an amount of about 8.3%.

20. A pharmaceutical composition according to any one of claims 14 to 19, for oral administration.

21. A pharmaceutical composition according to any one of claims 14 to 20, comprising a capsule, tablet, mini-tablet, or sachet.

22. The pharmaceutical composition according to any one of claims 2 to 21, wherein the sodium decanoate is crystallized.

23. A method for improving the bioavailability of a cyclic peptide in a subject where improved bioavailability of the cyclic peptide is required, comprising formulation the cyclic peptide together with sodium decanoate.

24. The method according to claim 23, wherein the oral bioavailability is improved by at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, or at least about 1.0%.

25. The cyclic peptide is compound (I): 【Transformation 3】 The method according to claim 23 or 24, or a pharmaceutically acceptable salt thereof.

26. The method according to any one of claims 23 to 25, wherein the sodium decanoate is crystallized.

27. A method for inhibiting the growth, proliferation, or metastasis of cancer cells in a subject requiring inhibition of the growth, proliferation, or metastasis of cancer cells, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described in any one of claims 1 to 22.

28. The method according to claim 26, wherein the cancer is selected from the group consisting of melanoma, renal cell carcinoma, squamous cell non-small cell lung cancer (NSCLC), non-squamous cell NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, squamous cell carcinoma of the head and neck, esophageal cancer, gastrointestinal cancer, breast cancer, and hematological malignancies.

29. A method for enhancing, stimulating, and / or increasing an immune response in a subject requiring enhancement, stimulation, and / or increase of an immune response, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 22.

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