Pharmaceutical composition for improving oral bioavailability

Abstract

According to the present disclosure, pharmaceutical formulations that improve the oral bioavailability of cyclic peptides have been found.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 490,929, filed March 17, 2023, and U.S. Provisional Application No. 63 / 498,207, filed April 25, 2023, both of which are incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure provides pharmaceutical compositions for improving the oral bioavailability of cyclic peptides. Also disclosed are pharmaceutical compositions comprising macrocyclic compounds that bind to PD-L1 and are capable of inhibiting the interaction of PD-L1 with PD-1 and CD80. Background Technology

[0003] Despite the growing trend in drug discovery favoring larger molecules, such as milla molecules, poor oral bioavailability remains a barrier to wider use. Oral administration of large hydrophilic molecules is challenging due to pH and gastric / small intestinal enzyme interactions, as well as low intestinal epithelial membrane permeability resulting from minimal passive or carrier-mediated transcellular penetration in the phospholipid bilayer and restricted bypass transport via tightly connected cells. Other variables, such as plasma half-life and therapeutic index, also influence the feasibility of oral delivery of milla molecules.

[0004] In recent years, several cyclic peptides that block the interaction between PD-L1 and PD-1 or CD80 have been reported (see, for example, U.S. Patent Nos. 9,308,263; 9,850,283; 9,879,046; and 9,856,292). Such compounds can be used to enhance, stimulate, and / or increase immune responses in patients and can be used to treat conditions such as septic shock and cancer. While oral delivery of these molecules would offer many advantages over injection delivery (as in the case of other large-sized molecules), developing oral formulations of such molecules has proven challenging. Therefore, there is a need for oral formulations that provide improved bioavailability of larger, bioactive molecules such as cyclic peptides. Summary of the Invention

[0005] This disclosure provides pharmaceutical compositions for improving the oral bioavailability of cyclic peptides.

[0006] In a first aspect, this disclosure provides a pharmaceutical composition comprising: a cyclic peptide; and a decanoate. In some aspects, the decanoate is sodium decanoate. In some aspects, the cyclic peptide is a compound (I) having the following formula: Or its pharmaceutically acceptable salt.

[0007] In some aspects, the cyclic peptide is present in an amount of about 0.1 wt% to about 20 wt%. In some aspects, the cyclic peptide is present in an amount of about 0.5 wt% to about 10 wt%. In some aspects, the cyclic peptide is present in an amount of about 6.0 wt% to about 9.50 wt%. In some aspects, the cyclic peptide is present in an amount of about 0.8 wt% to about 5.0 wt%.

[0008] In some aspects, decanoate is sodium decanoate. In some aspects, sodium decanoate is present in an amount of about 15 wt% to about 70 wt%. In some aspects, sodium decanoate is present in an amount of about 20 wt% to about 55 wt%. In some aspects, sodium decanoate is present in an amount of about 20 wt% to about 30 wt%. In some aspects, sodium decanoate is present in an amount of about 27 wt% to about 28 wt%.

[0009] In some respects, the composition is intended for oral administration. In other respects, the composition comprises capsules, tablets, sachets, or pouches.

[0010] In some respects, this disclosure provides a pharmaceutical composition comprising: a. Compound (I) having the following formula: Or its pharmaceutically acceptable salt; b. Approximately 27.5 wt% sodium decanoate; c. Approximately 37 wt% to approximately 43 wt% of microcrystalline cellulose; d. Mannitol, approximately 18 wt% to approximately 22 wt%; e. Approximately 4 wt% of croscarmellose sodium; f. Approximately 2 wt% silicon dioxide; and g. Approximately 2 wt% magnesium stearate.

[0011] In some aspects, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.8%. In some aspects, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 1.7%. In some aspects, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 3.3%. In some aspects, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 6.7%. In some aspects, compound (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 8.3%.

[0012] In some respects, the composition is intended for oral administration. In other respects, the composition comprises capsules, tablets, sachets, or pouches.

[0013] In some respects, the pharmaceutical composition contains sodium decanoate, wherein the sodium decanoate is crystalline.

[0014] In some aspects, this disclosure provides a method for improving the bioavailability of a cyclic peptide in a subject of need, the method comprising formulating the cyclic peptide with sodium decanoate. In some aspects, 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 aspects, the cyclic peptide is a compound (I) having the following formula: Or its pharmaceutically acceptable salt. In some respects, sodium decanoate is crystalline.

[0015] In some aspects, this disclosure provides a method for inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need, said method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein. In some aspects, 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, head and neck squamous cell carcinoma, esophageal cancer, gastrointestinal cancer, breast cancer, and hematologic malignancies.

[0016] In some respects, this disclosure provides a method for enhancing, stimulating, and / or increasing an immune response in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein. Attached Figure Description

[0017] Figure 1 The plasma concentrations of compound (I) over time in cynomolgus monkeys administered 12 mg of compound (I) formulated as described in Example 1 are shown.

[0018] Figure 2 The plasma concentrations of compound (I) over time in dogs treated with 20 mg of compound (I) formulated as described in Example 3 are shown.

[0019] Figure 3 The plasma concentrations of compound (I) over time in dogs treated with 100 mg of compound (I) formulated as described in Examples 5A and 5B are shown.

[0020] Figure 4 The plasma concentrations of compound (I) over time in dogs treated with 100 mg of compound (I) formulated as described in Examples 5B, 5C and 5D are shown. Detailed Implementation

[0021] This disclosure relates to a pharmaceutical composition comprising a cyclic peptide and a decanoate (such as sodium decanoate). The composition can improve the bioavailability of the cyclic peptide. I. Definition

[0022] To facilitate understanding of this specification, certain terms are defined first. Further definitions are provided throughout the detailed implementation.

[0023] Unless otherwise stated, it is assumed that any atom with an unsatisfied valence has hydrogen atoms that are sufficient to satisfy the valence.

[0024] Unless the context otherwise indicates, the singular forms “a / an” and “the” include a plural reference. Thus, the terms “a / an,” “a or more / a,” and “at least one / a” are used interchangeably herein. It should further be noted that claims can be drafted to exclude any optional elements. Thus, this statement is intended to serve as a basis for using exclusive terms such as “solely,” “only,” etc., or for using negative limiting terms in relation to the recitation of the claim elements.

[0025] The term “or” is a logical participle (i.e., and / or) and does not indicate an exclusive participle unless explicitly indicated by terms such as “either,” “unless,” “alternatively,” and similar terms.

[0026] Furthermore, the term “and / or” as used herein should be considered as a specific disclosure of each of the two specified features or components being, or not being, with the other. Therefore, the term “and / or” as used herein in phrases 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 phrases such as “A, B, and / or C” is intended to cover each of the following: 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).

[0027] Units, prefixes, and symbols are represented in their International System of Units (SI) accepted form. A numerical range includes the numerical value that defines the range. In the case of listing a series of values, it should be understood that each intermediate integer value between the upper and lower limits of the listed range, each fraction thereof, and each subrange between such values ​​is also specifically disclosed. The upper and lower limits of any range may be independently included in or excluded from the range, and each range that includes either limit, excludes neither limit, or includes both limits is also covered in this disclosure. Therefore, the ranges listed herein should be understood as abbreviations of all values ​​within the range, including the listed endpoints. For example, the range 1 to 10 should be understood as including any number, combination of numbers, or subranges consisting of groups of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0028] Where values ​​are explicitly listed, it should be understood that values ​​of approximately the same quantity or amount are also within the scope of this disclosure. Where combinations are disclosed, each sub-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 any element disclosed is disclosed to have multiple alternatives, instances in which each of those alternatives is excluded individually or in any combination with other alternatives are also hereby disclosed; more than one element may have such exclusions, and all combinations of elements with such exclusions are hereby disclosed.

[0029] Those skilled in the art will recognize that amino acids include compounds represented by the following general structures: R and R′ are as discussed herein. Unless otherwise stated, 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 attached to the same carbon (referred to as the "α" carbon), wherein R and / or R′ can be natural or non-natural side chains, including hydrogen. The absolute "S" configuration at the "α" carbon is generally referred to as the "L" or "natural" configuration. In the case where both the "R" and "R′" (') substituents are equal to hydrogen, the amino acid is glycine and is not chiral.

[0030] Unless otherwise specified, the amino acids described herein may be D- or L-stereochemical and may be substituted as described elsewhere in this disclosure. It should be understood that, when no stereochemistry is specified, this disclosure covers all stereochemical isomers, or mixtures thereof, that produce the desired activity. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing a chiral center, or by preparing a mixture of enantiomers followed by separation, such as by converting to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on a chiral chromatographic column. Starting compounds for a particular stereochemistry are commercially available or can be prepared and resolved using techniques known in the art.

[0031] As used herein, the phrase “or a pharmaceutically acceptable salt thereof” means 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), compound (I) and one or more pharmaceutically acceptable salts of compound (I), and pharmaceutically acceptable salts of two or more compounds (I).

[0032] The term “treatment” refers to the suppression of a disease, disorder, or symptom, i.e., the prevention of its development; and (iii) the relief of a disease, disorder, or symptom, i.e., the reduction of symptoms associated with the disease, disorder, and / or symptom. II. Pharmaceutical Composition

[0033] In some aspects, this disclosure provides compositions comprising cyclic peptides. As used herein, the term "composition" is intended to cover products comprising a specified amount of a specified ingredient, and any product resulting directly or indirectly from a combination of a specified amount of the specified ingredient. This term, relating to pharmaceutical compositions, is intended to cover products comprising one or more active ingredients and one or more inert ingredients constituting a carrier, and any product resulting directly or indirectly from a combination, complexation, or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or negligible ingredients. Therefore, pharmaceutical compositions of the present invention cover any composition prepared by mixing the compounds of the present invention with a pharmaceutically acceptable carrier. With regard to "pharmaceutically acceptable carrier," it means that the carrier, diluent, or excipient is compatible with the other components of the formulation and is harmless to its recipient.

[0034] In some aspects, the compositions disclosed herein are suitable for oral administration. These compositions may comprise solid, semi-solid, gel-based, or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, small tablets, bilayer tablets, capsules, pills, trochs, lozenges, pastils, sachets, pellets, pharmaceutical 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 aspects, the compositions disclosed herein suitable for oral administration are in the form of tablets or capsules. In some aspects, the compounds disclosed herein may be formulated as tablets. In some aspects, tablets may be encapsulated in capsules for administration.

[0035] The tablets disclosed herein may be in the form of compressed tablets, formulation tablets, chewable sugar tablets, fast-dissolving tablets, multiple-compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and in protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings can impart the same general characteristics as sugar coatings. Multi-compression tablets are compressed tablets prepared through more than one compression cycle, including multilayer tablets and compressed coated tablets or dry-compressed coated tablets.

[0036] In some aspects, the compounds disclosed herein may be in the form of tablets. In some aspects, the compounds disclosed herein may be in the form of compressed tablets. In some aspects, the compounds disclosed herein may be in the form of enteric-coated tablets.

[0037] In some aspects, the compositions disclosed herein can be prepared by dry granulation of the disclosed compounds with one or more pharmaceutically acceptable carriers, mediators, and / or excipients. In some aspects, the compositions disclosed herein can be prepared by wet granulation.

[0038] In some aspects, the compositions disclosed herein may be in the form of soft capsules or hard capsules, which may be made from gelatin, methylcellulose, starch, and / or calcium alginate. Hard gelatin capsules (also known as dry-filled capsules (DFC)) may comprise two parts, one sliding over the other to completely encapsulate the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells (such as gelatin shells) that are plasticized by the addition of glycerol, sorbitol, or similar polyols. In some aspects, the soft gelatin shell may contain preservatives to prevent microbial growth. Suitable preservatives include, but are not limited to, those described herein, including methylparaben and propylparaben, sorbic acid, and combinations thereof. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated in 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. As known to those skilled in the art, capsules may also be coated to alter or maintain the solubility of the active ingredient.

[0039] Colorants and flavoring agents can be used in all of the above dosage forms. Furthermore, flavoring agents and sweeteners are particularly useful in the formation of chewable tablets and sugar tablets.

[0040] In some respects, the compositions disclosed herein can be formulated as immediate-release or modulated-release formulations, including delayed-release, extended-release, pulsatile-release, controlled-release, targeted-release, and programmed-release forms.

[0041] The compositions disclosed herein may contain another active ingredient that does not impair the therapeutic or preventative efficacy of the composition and / or may contain substances that enhance or complement the efficacy of the composition.

[0042] The compositions described herein are typically part of a blend with a suitable pharmaceutical diluent, excipient, and / or carrier (collectively referred to herein as a pharmaceutical carrier) appropriately selected relative to the intended form of administration, and are consistent with conventional pharmaceutical practice. For example, for oral administration in tablet or capsule form, the active pharmaceutical component may be combined with an orally administered, non-toxic, pharmaceutically acceptable inert carrier. Furthermore, suitable binders, lubricants, surfactants, disintegrants, glidants, flavorings, and colorants may also be incorporated into the blend when desired or necessary. Examples of these types of additives include, but are not limited to, cholesterol, capryloyl hexanoyl polyethylene glycol-8 glyceride / capryloyl hexanoyl polyoxyethylene-8 glyceride, calcium phosphate, calcium sulfate, natural starch, pregelatinized starch, sodium starch glycolate, methylcellulose, microcrystalline cellulose, croscarmellose, sodium croscarmellose, sodium croscarmellose, croscarmellose, cross-linked croscarmellose, cross-linked starch (such as sodium carboxymethyl starch), cross-linked polymers (such as croscarmellose, croscarmellose), alginate. Sodium, clay, gum, silica, silicon dioxide, talc, starch, magnesium aluminum silicate, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, stearic acid, calcium hydroxide, talc, corn starch, sodium stearoyl fumarate, stearic acid, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, zinc stearate, wax, talc, etc., and combinations thereof. In some aspects, the compositions described herein comprise cholesterol, octanoyl hexanoyl polyethylene glycol-8 glyceride / octanoyl hexanoyl polyoxyethylene-8 glyceride, silicon dioxide, croscarmellose sodium, and magnesium stearate. In some respects, the compositions described herein comprise microcrystalline cellulose, mannitol, croscarmellose sodium, silicon dioxide, magnesium stearate, or combinations thereof.

[0043] In some aspects, the composition comprises about 15 wt% to about 80 wt% of one or more fillers. In some aspects, the term "filler" refers to an inactive 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 aspects, the composition comprises about 20 wt% to about 75 wt% of one or more fillers. In some aspects, the composition comprises about 25 wt% to about 70 wt% of one or more fillers. In some aspects, the composition comprises about 30 wt% to about 65 wt% of one or more fillers. In some aspects, the composition comprises about 35 wt% to about 60 wt% of one or more fillers. In some aspects, the composition comprises 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%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, and about 47 wt%. About 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, about 55 wt%, about 56 wt%, about 57 wt%, about 58 wt%, about 59 wt%, about 60 wt%, about 61 wt%, about 62 wt%, about 63 wt%, about 64 wt%, about 65 wt%, about 66 wt%, about 67 wt%, about 68 wt%, about 69 wt%, about 70 wt%, about 71 wt%, about 72 wt%, about 73 wt%, about 74 wt%, about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, or about 80 wt% of one or more fillers.

[0044] In some aspects, one or more fillers include microcrystalline cellulose. In some aspects, the composition comprises about 10 wt% to about 50 wt% microcrystalline cellulose. In some aspects, the composition comprises about 15 wt% to about 49 wt% microcrystalline cellulose. In some aspects, the composition comprises about 20 wt% to about 48 wt% microcrystalline cellulose. In some aspects, the composition comprises about 25 wt% to about 47 wt% microcrystalline cellulose. In some aspects, the composition comprises about 30 wt% to about 46 wt% microcrystalline cellulose. In some aspects, the composition comprises about 35 wt% to about 45 wt% microcrystalline cellulose. In some aspects, the composition comprises about 37 wt% to about 43 wt% microcrystalline cellulose. In some aspects, the composition comprises 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%, about Microcrystalline cellulose in the form of 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%.

[0045] In some aspects, one or more fillers include mannitol. In some aspects, the composition contains about 5 wt% to about 30 wt% mannitol. In some aspects, the composition contains about 10 wt% to about 27 wt% mannitol. In some aspects, the composition contains about 15 wt% to about 25 wt% mannitol. In some aspects, the composition contains about 18 wt% to about 22 wt% mannitol. In some aspects, the composition comprises 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.

[0046] In some aspects, the composition comprises about 2 wt% to about 6 wt% of one or more disintegrants. In some aspects, the term "disintegrant" refers to an agent added to a formulation (particularly tablets) to promote the disintegration of the tablets into smaller fragments in an aqueous environment. Examples of disintegrants include, but are not limited to, sodium croscarmellose, crospovidone, and sodium carboxymethyl starch. In some aspects, the composition comprises about 3 wt% to about 5 wt% of one or more disintegrants. In some aspects, the composition comprises about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, or about 6 wt% of one or more disintegrants.

[0047] In some aspects, one or more disintegrants include croscarmellose sodium. In some aspects, the composition comprises about 2 wt% to about 6 wt% of croscarmellose sodium. In some aspects, the composition comprises about 3 wt% to about 5 wt% of croscarmellose sodium. In some aspects, the composition comprises about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, or about 6 wt% of croscarmellose sodium.

[0048] In some aspects, the composition comprises silica, talc, calcium silicate, or mixtures thereof. In some aspects, the composition comprises about 1 wt% to about 4 wt% silica. In some aspects, the composition comprises about 1 wt% to about 3 wt% silica. In some aspects, the composition comprises about 1 wt%, about 2 wt%, about 3 wt%, or about 4 wt% silica.

[0049] In some aspects, the composition comprises about 1 wt% to about 4 wt% of one or more flow aids. In some aspects, the term "flow aid" refers to an agent used to increase the flow of powder. Examples of flow aids include, but are not limited to, talc, calcium stearate, sodium stearate, stearic acid, stearoyl fumarate, magnesium stearate, and silica. In some aspects, the composition comprises about 1 wt% to about 3 wt% of one or more flow aids. In some aspects, the composition comprises about 1 wt%, about 2 wt%, about 3 wt%, or about 4 wt% of one or more flow aids.

[0050] In some aspects, the composition comprises about 1 wt% to about 4 wt% magnesium stearate. In some aspects, the composition comprises about 1 wt% to about 3 wt% magnesium stearate. In some aspects, the composition comprises about 1 wt%, about 2 wt%, about 3 wt%, or about 4 wt% magnesium stearate.

[0051] In other respects, standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 23rd edition (2020), can be used to provide film coatings around formulations of the compounds described herein.

[0052] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 300 mg of active ingredient / dose unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.5% to 95% by weight based on the total weight of the composition. In some aspects, dosage forms suitable for administration may contain from about 10 to about 240 mg of active ingredient / dose unit. In some aspects, dosage forms suitable for administration may contain about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, or about 240 mg of active ingredient / dose unit.

[0053] In some aspects, this disclosure provides pharmaceutical compositions comprising the cyclic peptide described herein, a pharmaceutically acceptable salt thereof, a decanoate thereof, and at least one pharmaceutically acceptable carrier. In other aspects, this disclosure provides pharmaceutical compositions comprising the cyclic peptide as described herein, a pharmaceutically acceptable salt thereof, sodium decanoate, and at least one pharmaceutically acceptable carrier.

[0054] This disclosure provides pharmaceutical compositions comprising a cyclic peptide and a decanoate. In some aspects, the salt is sodium decanoate, potassium decanoate, lithium decanoate, or magnesium decanoate. In some aspects, the salt is sodium decanoate. In some aspects, the cyclic peptide backbone may contain 2 to 20 amino acids. In some aspects, the cyclic peptide backbone may contain 4 to 18 amino acids. In some aspects, the cyclic peptide backbone may contain 6 to 16 amino acids. In some aspects, the cyclic peptide backbone may contain 8 to 14 amino acids. In some aspects, the cyclic peptide backbone may contain 10 to 14 amino acids. In some aspects, the cyclic peptide backbone may contain 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids.

[0055] In some respects, cyclic peptides can include compounds (I) having the following formula: Or its pharmaceutically acceptable salt.

[0056] This disclosure is intended to include all isotopes of atoms present in the compounds of this invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example but without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14C. The isotopically labeled compounds disclosed herein can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described herein, employing a suitable isotopically labeled reagent instead of an otherwise employed unlabeled reagent. Such compounds can have a variety of potential uses, such as as standards and reagents in determining biological activity. With stable isotopes, such compounds can have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0057] The pharmaceutical compounds disclosed herein may include one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” is a salt that retains the desired biological activity of the parent compound without conferring 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 solely 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. Acid addition salts include those derived from non-toxic inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, etc.) and those derived from non-toxic organic acids (such as aliphatic monocarboxylic acids and aliphatic dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, aromatic acids, aliphatic and aromatic sulfonic acids, etc.). Alkali addition salts include those derived from alkaline earth metals (such as sodium, potassium, magnesium, calcium, etc.) and those derived from non-toxic organic amines (such as N,N′-dibenzylethylenediamine, N-methylglucosamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, etc.).

[0058] In some aspects, the cyclic peptide comprises about 0.1 wt% to about 25 wt% of the pharmaceutical composition. In some aspects, the cyclic peptide comprises about 0.1 wt% to about 20 wt% of the pharmaceutical composition. In some aspects, the cyclic peptide comprises about 0.5 wt% to about 10 wt% of the pharmaceutical composition. In some aspects, the cyclic peptide comprises about 0.8 wt% to about 5 wt% of the pharmaceutical composition. In some aspects, the cyclic peptide comprises about 6.0 wt% to about 9.5 wt% of the pharmaceutical composition. In some aspects, the cyclic peptides constitute about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.0 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 4.0 wt%, about 4.5 wt%, about 5.0 wt%, and about 5.5 wt% of the composition. Approximately 6.0 wt%, approximately 6.5 wt%, 6.6 wt%, 6.7 wt%, 6.8 wt%, 6.9 wt%, approximately 7.0 wt%, approximately 7.5 wt%, approximately 8.0 wt%, approximately 8.1 wt%, approximately 8.2 wt%, approximately 8.3 wt%, approximately 8.4 wt%, approximately 8.5 wt%, approximately 9.0 wt%, approximately 9.5 wt%, approximately 10.0 wt%, approximately 11.0 wt%, approximately 12.0 wt%, approximately 13.0 wt%, approximately 14.0 wt%, approximately 15.0 wt%, approximately 16.0 wt%, approximately 17.0 wt%, approximately 18.0 wt%, approximately 19.0 wt%, approximately 20.0 wt%.

[0059] The pharmaceutical compositions described herein comprise sodium decanoate. In some aspects, sodium decanoate comprises about 10 wt% to about 80 wt% of the composition. In some aspects, sodium decanoate comprises about 15 wt% to about 70 wt% of the composition. In some aspects, sodium decanoate comprises about 20 wt% to about 60 wt% of the composition. In some aspects, sodium decanoate comprises about 20 wt% to about 55 wt% of the composition. In some aspects, sodium decanoate comprises about 20 wt% to about 30 wt% of the composition. In some aspects, sodium decanoate comprises about 27 wt% to about 28 wt% of the composition. In some respects, sodium decanoate comprises 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%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt% of the composition. wt%, about 45wt%, about 46wt%, about 47wt%, about 48wt%, about 49wt%, about 50wt%, about 51wt%, about 52wt%, about 53wt%, about 54wt%, about 55wt%, about 56wt%, about 57wt%, about 58wt%, about 59wt%, about 60wt%, about 61wt%, about 62wt%, about 63wt%, about 64wt%, about 65wt%, about 66wt%, about 67wt%, about 68wt%, about 69wt%, about 70wt%, about 71wt%, about 72wt%, about 73wt%, about 74wt%, about 75wt%, about 76wt%, about 77wt%, about 78wt%, about 79wt%, or about 80wt%.

[0060] In some respects, sodium decanoate is amorphous, produced by spray drying or another suitable process. In other respects, sodium decanoate is crystalline. Without being bound by any particular theory, crystalline sodium decanoate can, in some cases, provide improved physical properties compared to spray-dried sodium decanoate, such as favorable flowability or less adhesion.

[0061] In some aspects, this 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 silica, and about 1 wt% to about 4 wt% of magnesium stearate. In some aspects, the cyclic peptide is compound (I).

[0062] In some aspects, this 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 silica, and about 1 wt% to about 3 wt% of magnesium stearate. In some aspects, the cyclic peptide is compound (I).

[0063] In some aspects, this 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 silica, and about 2 wt% of magnesium stearate. In some aspects, the cyclic peptide is compound (I).

[0064] In some aspects, this 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 silica, and about 2 wt% of magnesium stearate. In some aspects, the cyclic peptide is compound (I).

[0065] In some aspects, this 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 silica, and about 2 wt% of magnesium stearate. In some aspects, the cyclic peptide is compound (I).

[0066] In some aspects, this 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 silica, and about 2 wt% of magnesium stearate. In some aspects, the cyclic peptide is compound (I).

[0067] In some aspects, this 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 silica, and about 2 wt% of magnesium stearate. In some aspects, the cyclic peptide is compound (I).

[0068] Also within the scope of this disclosure are kits containing the compositions disclosed herein and instructions for use. Kits may further contain additional reagents. Kits typically include labels and instructions for use indicating the intended use of the kit contents. Terminology labels include any written or recorded material provided on or with the kit, or otherwise accompanying the kit. III. Instructions for Use

[0069] This disclosure provides pharmaceutical formulations that improve the bioavailability of cyclic peptides. In some aspects, 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%.

[0070] The administration of the cyclic peptides described herein includes, but is not limited to, the administration of therapeutically effective amounts of the compound. As used herein, the term "therapeuticly effective amount" refers to, but is not limited to, the amount of the cyclic peptide used to treat a condition that can be treated by administration of a composition comprising the compound. This amount is sufficient to demonstrate a detectable therapeutic or ameliorative effect. Effects may include, for example, but not limited to, treatment of the conditions listed herein. The precise effective amount used on a subject will depend on the subject's size and health condition, the nature and extent of the condition being treated, the advice of the treating physician, and the choice of the therapy or combination of therapies used for administration. Therefore, specifying an exact effective amount in advance is not helpful.

[0071] In another aspect, this disclosure relates to a method of inhibiting the growth of tumor cells in a subject using the pharmaceutical composition disclosed herein. In some aspects, the cyclic peptide is capable of binding to PD-L1, disrupting the interaction between PD-L1 and PD-1, competing with anti-PD-1 monoclonal antibodies known to block the interaction with PD-1 for binding to PD-L1, enhancing CMV-specific T cell IFNγ secretion, and enhancing HIV-specific T cell IFNγ secretion. Therefore, in some aspects, the cyclic peptide disclosed herein can be used to alter immune responses, treat diseases such as cancer, infectious diseases, and / or septic shock, stimulate protective autoimmune responses, or stimulate antigen-specific immune responses.

[0072] Cancers whose growth can be inhibited by the pharmaceutical compositions disclosed herein include, but are not limited to, cancers that typically respond to immunotherapy. Representative examples include melanoma (e.g., metastatic malignant 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 non-small cell lung cancer and non-squamous non-small cell lung cancer). Examples of other cancers that can be treated using the methods disclosed herein include bone cancer, hepatocellular carcinoma, pancreatic cancer, skin cancer, squamous cell carcinoma of the head and neck, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, 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 bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, and hematologic malignancies (such as chronic or...). Acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal pelvis cancer, vegetations of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal cord axon tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environment-induced cancers (including those induced by asbestos), and combinations of said cancers. The pharmaceutical compositions described herein may also be used to treat metastatic cancers.

[0073] The pharmaceutical compositions described herein can enhance, stimulate, and / or increase immune responses in subjects in need. As used herein, the term "immune response" refers to the behavior of, for example, lymphocytes, antigen-presenting cells, phagocytes, granulocytes, and soluble macromolecules (including macrocyclic peptides, cytokines, and complement) produced by these cells or the liver, resulting in selective damage, destruction, or elimination therefrom of invading pathogens, pathogen-infected cells or tissues, cancer cells, or (in the case of autoimmune or pathological inflammation) normal human cells or tissues. In some aspects, immune responses may be generated by the innate immune system. In some aspects, immune responses may be generated by the adaptive immune system. In some embodiments, immune responses may be generated by both the innate and adaptive immune systems.

[0074] The pharmaceutical compositions described herein, with some modifications, can be delivered by a variety of methods, including but not limited to oral, subcutaneous, intramuscular, duodenal, or intravenous administration. The compositions can be formulated according to the route of administration based on acceptable pharmaceutical practice (Fingl et al., The Pharmacological Basis of Therapeutics, Chapter 1, p. 1 (1975); Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co. Easton, PA (1990)).

[0075] Of course, the dosage regimens of the compositions described herein will vary depending on known factors such as the recipient's species, age, sex, health condition, medical condition, and weight; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of medicine required to prevent, combat, or halt the progression of a disease state.

[0076] As a general guideline, when used for the indicated effects, the daily oral dose of the active ingredient will be in the range of about 0.001 to 500 mg / kg body weight, preferably between about 0.01 and 100 mg / kg body weight / day, and most preferably between about 0.1 and 20 mg / kg / day. Intravenously, when used for the indicated effects, during a constant-rate infusion, the daily dose of the active ingredient will be in the range of 0.001 ng to 100.0 ng / min / kg body weight. Such a constant intravenous infusion can preferably be administered at a rate of 0.01 ng to 50 ng / min / kg body weight, and most preferably at a rate of 0.01 ng to 10.0 mg / min / kg body weight. The compositions described herein can be administered as a single daily dose, or the total daily dose can be administered in divided doses twice, three, or four times daily. Bioactivity

[0077] Compound (I) (prepared according to the procedure described in U.S. Patent No. 9,856,292). Example 1 Preparation of 1 mg strength compound (I) enteric-coated tablets for 12 mg doses (total 12 mg) Tablets)

[0078] The composition of the uncoated chip formulation is shown in Table 1. Cholesterol was weighed and dissolved in Labrasol ALF in a glass vial. Sodium decanoate and silica were combined in a mortar and mixed using a pestle. The solution containing cholesterol dissolved in Labrasol ALF was added to the blend of sodium decanoate and silica. The vial containing the solution was rinsed with 1 g of ethanol, and the rinse solution was added to the blend. In another vial, compound (I) was dissolved in 8 g of ethanol and added to the blend. The vial containing the solution was rinsed with 1 g of ethanol, and the rinse solution was added to the blend. The blend containing all formulation components was mixed in a mortar and pestle until the blend was visually homogeneous. The mixture was placed on an aluminum tray and dried overnight in a vacuum oven at 50°C. The dried particles were then placed in a mortar and gently ground and passed through a 30-mesh sieve. The sieved granules were then added to a glass vial along with croscarmellose sodium, and the mixture was blended for 10 minutes using a Turbula mixer (32 RPM, 10 minutes). Magnesium stearate was then added to the glass vial, and the final mixture was blended for 5 minutes using a Turbula mixer (32 RPM, 5 minutes). The powder blend was then compressed using a 7 / 32” (5.55 mm) round standard concave tool at a compression force of 400 lb to form tablets with a target weight of 70 mg. Table 1: Composition of Uncoated Chip Formulation *Amount of compound (I) after correcting for potency using 89% of the assay "original" value. **Adjust the amount of silica to compensate for valence correction. ***Ethanol is removed during the drying step.

[0079] The composition of the sealed-coated tablets is shown in Table 2. An aqueous suspension of Opadry03K with a solid content of 7.5% was prepared. Uncoated tablets and placebo tablets were placed in a Vector 0.5-L coating pan. The tablets were pan-coated to achieve a target weight gain of 2%. Table 2: Composition of Sealed Coated Tablets Element % (w / w) Uncoated chip tablets and placebo tablets* 98.04 Opadry 03K19229 1.96 total 100.00 *Add placebo tablets to achieve the appropriate batch size for the coating process.

[0080] The composition of the enteric-coated tablets is shown in Table 3. An aqueous suspension of Acryl EZE II with a 10% solids content was prepared. Sealed-coated tablets and placebo tablets were added to a Vector 0.5-L coating pan. The tablets were pan-coated to achieve a target weight gain of 7%. Six enteric-coated tablets were encapsulated in #00 hard gelatin capsules for a cynomolgus monkey PK study. Each cynomolgus monkey was administered two capsules (12 enteric-coated tablets). Table 3: Composition of enteric coating Element % (w / w) Sealed coated tablets and placebo tablets* 93.46 Acryl-EZE II 493Z180022White 6.54 total 100.00 *Add placebo tablets to achieve the appropriate batch size for the coating process. Example 2 Determination of oral absorption of the prepared compound (I) formulation in cynomolgus monkeys

[0081] The drug was administered orally to fasted male cynomolgus macaques (n=3), followed by flushing with water via tube feeding to promote gastrointestinal dissolution. Blood samples were collected at predetermined times within 72 hours post-administration to measure comparative pharmacokinetic studies between formulations. Due to the long half-life, these studies were conducted in parallel groups across different cynomolgus macaque populations. Mean exposure was [data missing]. Figure 1 As shown in Figure 4 and Table 4, the error bars indicate the standard deviation. Both Figure 4 and Table 4 show that the formulation provided good plasma concentrations of compound (I) over the extended time period. Table 4: Pharmacokinetic profile of the prepared tablets Example 3 20 mg doses of compound (I) with a strength of 2 mg were prepared using 660 mg sodium decanoate. (Total 10 tablets)

[0082] The composition of the uncoated 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 vial and blended using a turular mix (32 RPM, 5 min). Magnesium stearate was added to the same vial and gently mixed using a spatula. The powder mixture was then blended using a turular mix (32 RPM, 5 min). The powder blend was compressed using a 7 / 32-inch (5.55 mm) round standard concave tool at a compression force of 300 lb to form tablets with a target weight of 70 mg. Table 5: Composition of Uncoated Chip Agents Element % (w / w) Dosage (mg) Compound (I)* 2.89 20** Sodium decanoate 95.51 660 magnesium stearate 1.59 11 total** 100 691 *Based on 89% determination of the amount of "as is" adjusted compound (I). **Adjust the total dose after efficacy correction.

[0083] The composition of the sealed-coated tablets is shown in Table 6. An aqueous suspension of Opadry03K with a solid content of 7.5% was prepared. Uncoated tablets and placebo tablets were placed in a Vector 0.5-L coating pan. The tablets were pan-coated to achieve a target weight gain of 2%. Table 6: Composition of Sealed Coated Tablets Element % (w / w) Uncoated chip tablets and placebo tablets* 98.04 Opadry 03K19229 Transparent 1.96 total 100.00 *Add placebo tablets to achieve the appropriate batch size for the coating process.

[0084] The composition of the enteric-coated tablets is shown in Table 7. An aqueous suspension of Acryl-EZE II with a 10% solids content was prepared. Compound (I)-sealed coated tablets and placebo tablets were added to a Vector 0.5-L coating pan. The tablets were pan-coated to achieve a target weight gain of 7%. Five enteric-coated tablets were encapsulated in #0 hard gelatin capsules for a canine PK study. Two capsules (10 enteric-coated tablets) were administered to each dog. Table 7: Composition of Enteric-Coated Tablets Element % (w / w) Sealed coated tablets and placebo tablets* 93.58 Acryl-EZE II 493Z180022White 6.52 total 100.00 *Add placebo tablets to achieve the appropriate batch size for the coating process. Example 4 Dog pK study

[0085] Compound (I) was administered as a single 20 mg dose (2 x 10 mg capsules) to fasted dogs (4) pretreated with pentagastrin. Blood samples were collected over a 72-hour period. Figure 2 The average exposure is shown. Error bars describe the standard deviation. As shown in the figure and Table 8, dogs had consistent plasma concentrations of compound (I) over the 72-hour period. Table 8: Pharmacokinetic profile of the prepared tablets Example 5 Effects of sodium decanoate content and tablet quantity on the performance of compound (I) formulation in dogs

[0086] 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 dose of 100 mg; and (2) the number of tablets administered to achieve the selected dose of 100 mg. Example 5A 100 mg doses of compound (I) with a strength of 2.083 mg were prepared using sodium decanoate (total of 48 tablets).

[0087] The composition of the uncoated chip agent is shown in Table 9. Compound (I), sodium decanoate, microcrystalline cellulose, mannitol, croscarmellose sodium, and silica were added to a glass vial and blended at 25 RPM for 10 minutes using a turbo mixer. The blended powder was then passed through a 20-mesh sieve and blended again at 25 RPM for 10 minutes. Magnesium stearate was added to the mixture and blended again at 25 RPM for 3 minutes to form a pre-blend. Table 9: Formulation Composition of Uncoated Chip Formulations *Based on 88.6% determination of the amount of "original" adjusting compound (I) **Regulate microcrystalline cellulose to compensate for potency correction.

[0088] The premix was compressed using a 3 / 4-inch (19.05 mm) round flat-face tool to form a compact with a target weight of 1,000 mg and a target solids fraction of 0.6–0.7. The compact was added to a mortar and pestle apparatus and gently ground with 10 compacts at a time. The ground material was passed through a 10-mesh sieve, and the remaining material was pressed through the sieve. The resulting granules were passed through an 18-mesh sieve, and the remaining material was pressed through the sieve. The sieved granules and the exocrosslinked sodium carboxymethyl cellulose were added to a glass bottle and blended at 25 RPM for 10 minutes. Exocrosslinked magnesium stearate was added and blended at 25 RPM for 3 minutes to form the final blend.

[0089] The final blend was compressed using a 1 / 8-inch (3.175 mm) round standard concave multi-punch (7-punch) tool to form tablets with a target weight of 25 mg and a target tensile strength of 1.5-2 MPa.

[0090] The tablets were coated with two layers in a 0.5-L pan LDCS Hi-Coater. The first layer was sealed with Opadry 03K aqueous suspension (10% w / w solids) to achieve a target weight gain of 2%. The second layer was enteric-coated with Acryl-EZEII aqueous suspension (20% w / w solids) to achieve a target weight gain of 10%. Twenty-four enteric-coated tablets were encapsulated in #00 hard gelatin capsules for canine PK studies. Each dog was administered two capsules (48 enteric-coated tablets). Example 5B 100 mg doses of compound (I) with a strength of 2.083 mg were prepared using sodium decanoate (660 mg). Enteric-coated tablets (total 48 tablets) were prepared. Table 10: Formulation Composition of Uncoated Chip Formulations *Amount of compound (I) after correcting for potency with 88.6% of the determination "as is". **Regulate microcrystalline cellulose and mannitol to compensate for potency correction. ***Based on total batch size. Water is removed during the drying step.

[0091] The composition of the uncoated granules is shown in Table 10. All granule components were added to a 250 mL MiPro granulator bowl and mixed for 3 minutes at an impeller speed of 1300 RPM and a shredder speed of 300 RPM. While maintaining the impeller and shredder speeds, water was added at a rate of 0.5 mL / min. After the water addition was complete, the granular blend was mixed again for 3 minutes at the same impeller and shredder speeds. The resulting granules were then passed through an 8-mesh sieve and placed in an aluminum tray. The tray was then placed in a convection oven at 40°C for 1 hour. The dried granules were then passed through a co-mill equipped with a 45R sieve.

[0092] The milled granules and the exfoliated cross-linked sodium carboxymethyl cellulose were added to a glass vial and blended at 25 RPM for 10 minutes. 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” (3.175 mm) multi-punch (7-punch) round standard concave tool to form tablets with a target weight of 25 mg and a target tensile strength of 1.5–2 MPa.

[0093] The tablets were coated with two layers in a 0.5-L pan LDCS Hi-Coater. The first layer was sealed with Opadry 03K aqueous suspension (10% w / w solids) to achieve a target weight gain of 2%. The second layer was enteric-coated with Acryl-EZEII aqueous suspension (20% w / w solids) to achieve a target weight gain of 10%. Twenty-four enteric-coated tablets were encapsulated in #00 hard gelatin capsules for canine PK studies. Each dog was administered two capsules (48 enteric-coated tablets). Example 5C 10 mg of compound (I) with a strength of 10 mg was prepared using 660 mg of sodium decanoate. Enteric-coated tablets (total of 10 tablets) were prepared.

[0094] The composition of the uncoated chip agent is shown in Table 11. Compound (I), sodium decanoate, microcrystalline cellulose, mannitol, croscarmellose sodium, and silica were added to a glass vial and blended at 25 RPM for 10 minutes using a turbo mixer. The blend was then passed through a 20-mesh sieve and blended again at 25 RPM for 10 minutes. Magnesium stearate was added to the mixture and blended again at 25 RPM for 3 minutes to form a pre-blend. Table 11: Formulation Composition of Uncoated Chip Formulations *Based on 86.6% determination of the amount of "original" adjusting compound (I) **Regulate microcrystalline cellulose to compensate for potency correction.

[0095] The premix was compressed using an 11.28 mm circular flat-face tool to form a compact with a target weight of 400 mg and a target solids fraction of 0.6–0.7%. The compact was milled using a vibrator equipped with 4 mm and 1 mm sieves. The sieved particles and extra-granular cross-linked sodium carboxymethyl cellulose were added to a glass vial 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” (5.55 mm) circular standard concave tool to form tablets with a target weight of 120 mg and a target tensile strength of 1.5–2 MPa.

[0096] The tablets were coated with two layers in a 0.5-L pan LDCS Hi-Coater. The first layer was sealed with Opadry 03K aqueous suspension (10% w / w solids) to achieve a target weight gain of 2%. The second layer was enteric-coated with Acryl-EZEII aqueous suspension (20% w / w solids) to achieve a target weight gain of 7%. Five enteric-coated tablets were encapsulated in #00 hard gelatin capsules for canine PK studies. Each dog was administered two capsules (10 enteric-coated tablets). Example 5D 100 mg dose of 50 mg strength compound (I) enteric-coated tablets were prepared using 660 mg sodium decanoate (total of 2 tablets).

[0097] The final blend from Example 5C was compressed using a 15.3 mm x 8 mm elliptical standard concave tool to form tablets with a target weight of 600 mg and a target tensile strength of 1.5–2 MPa. The tablets were coated with two layers in a 0.5–L pan LDCS Hi-Coater. The first layer was sealed with an aqueous suspension of Opadry O3K (10% w / w solids) to achieve a 2% target weight gain. The second layer was enteric-coated with an aqueous suspension of Acryl-EZEII (20% w / w solids) to achieve a 7% target weight gain. Two enteric-coated tablets were administered to each dog. Example 5E Dog pK study

[0098] Different formulations of compound (I) were administered as a single 100 mg dose to fasted dogs (4) pretreated with pentagastrin. Blood samples were collected over a 72-hour period. Figure 3 and 4 The average exposure is shown. Error bars describe the standard deviation. As shown in Figure 12 and Table 12, dogs had consistent plasma concentrations of compound (I) over the 72-hour time period.

[0099] like Figure 3 As shown, a high decanoate level (660 mg) is required to enhance API penetration. Reducing the amount of sodium decanoate decreases PK exposure (at 330 mg sodium decanoate). Figure 4 As shown, for the 660 mg sodium decanoate formulation, reducing the number of tablets from 48 or 10 to 2 resulted in improved PK exposure. Table 12 summarizes all PK data for all formulations tested in Example 5. Table 12: Pharmacokinetic profile of the prepared tablets Example 6 Proposed formulation for first-in-human (FIH) studies

[0100] The proposed formulations for first-in-human (FIH) administration are shown in Table 13 below. Table 13: Predicted Human Preparations

[0101] It should be understood that the Detailed Description section, rather than the Summary and Abstract section, is intended to be used to interpret the claims. The Summary and Abstract section may set forth one or more, but not all, exemplary aspects of this disclosure as the inventors(s) have contemplated, and therefore is not intended to limit this disclosure and the appended claims in any way.

[0102] This disclosure has been described above using functional building blocks that illustrate the implementation of specified functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries can be defined as long as the specified functions and their relationships are properly executed.

[0103] The foregoing description of the specific aspects so fully reveals the general nature of this disclosure that others can readily modify and / or adapt such specific aspects for various applications by applying knowledge within the scope of the art, without excessive experimentation and without departing from the general concepts of this disclosure. Therefore, based on the teachings and guidance presented herein, such modifications and adaptations are intended to be within the meaning and scope of equivalent solutions to the disclosed aspects. It should be understood that the wording or terminology herein is for descriptive rather than limiting purposes, and that the terminology or terminology in this specification should be interpreted by those skilled in the art based on the teachings and guidance.

[0104] The breadth and scope of this disclosure should not be limited by any of the foregoing exemplary aspects, but should be defined solely by the following claims and their equivalents.

Claims

1. A pharmaceutical composition comprising: Cyclic peptides; and Decanoate.

2. The pharmaceutical composition of claim 1, wherein, This decanoate is sodium decanoate.

3. The pharmaceutical composition according to claim 1 or 2, wherein, The cyclic peptide is a compound (I) having the following formula: Or its pharmaceutically acceptable salt.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein, The cyclic peptide is present in amounts from 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 amounts 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 amounts 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 amounts 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 amounts 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 amounts 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. The pharmaceutical composition according to any one of claims 1 to 11, wherein, This composition is for oral administration.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein, The composition includes capsules, tablets, small tablets, or sachets.

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

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

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

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

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

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

20. The pharmaceutical composition according to any one of claims 14 to 19, wherein, This composition is for oral administration.

21. The pharmaceutical composition according to any one of claims 14 to 20, wherein, The composition includes capsules, tablets, small tablets, or sachets.

22. The pharmaceutical composition according to any one of claims 2 to 21, wherein, Sodium decanoate is crystalline.

23. A method for improving the bioavailability of a cyclic peptide in subjects in need, the method comprising formulating the cyclic peptide together with sodium decanoate.

24. The method of claim 23, wherein, 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%.

25. The method of claim 23 or 24, wherein, The cyclic peptide is compound (I): Or its pharmaceutically acceptable salt.

26. The method according to any one of claims 23 to 25, wherein, Sodium decanoate is crystalline.

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

28. The method of claim 26, wherein, The cancers selected include 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, head and neck squamous cell carcinoma, esophageal cancer, gastrointestinal cancer and breast cancer, as well as hematologic malignancies.

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

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