Pharmaceutical compositions comprising a sarcaprozate salt and nicotinamide for improving oral bioavailability - Patent Application 20070233633

Abstract

In accordance with the present disclosure, pharmaceutical formulations have been discovered that enhance the oral bioavailability of biologically active compounds, including macrocyclic compounds.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 320,976, filed March 17, 2022, which is incorporated by reference in its entirety herein.

[0002] The present disclosure provides pharmaceutical compositions that enhance the oral bioavailability of biologically active compounds. Also disclosed are pharmaceutical compositions that contain macrocyclic compounds that bind to PD-L1 and are capable of inhibiting PD-L1 interactions with PD-1 and CD80. [Background technology]

[0003] Although there is an increasing trend in drug discovery favoring larger molecules such as miramolecules, poor oral bioavailability remains a barrier to more widespread use. Oral administration of large hydrophilic molecules is challenging due to pH and gastric / intestinal enzyme interactions and the low membrane permeability of the intestinal epithelium resulting in minimal passive or carrier-mediated transcellular permeation across the phospholipid bilayer, as well as limited 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] Recently, several cyclic peptides that block PD-L1 interaction with either PD-1 or CD80 have been reported (see, for example, U.S. Patent No. 5,399,433; U.S. Patent No. 5,399,446; U.S. Patent No. 5,399,451; and U.S. Patent No. 5,399,463). Such compounds are useful for enhancing, stimulating, and / or increasing immune responses 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 delivery by injection, as is the case with other larger molecules, but developing oral formulations of such molecules has proven challenging. Thus, there is a need for oral formulations that provide improved bioavailability of large biologically active molecules, such as macrocyclic peptides. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Pat. No. 9,308,263 [Patent Document 2] U.S. Patent No. 9,850,283 [Patent Document 3] U.S. Pat. No. 9,879,046 [Patent Document 4] U.S. Pat. No. 9,856,292 Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides a pharmaceutical composition comprising a biologically active compound, a sarcaprozate salt, and nicotinamide. In certain embodiments, the sarcaprozate salt is sarcaprozate sodium (SNAC).

[0007] In some embodiments, the composition further comprises one or more protease inhibitors. In some embodiments, the one or more protease inhibitors comprise one or more trypsin inhibitors. In some embodiments, the one or more trypsin inhibitors are isolated from bovine pancreas, raw chicken egg white, soybean, or lima bean. In some embodiments, the one or more protease inhibitors are selected from soybean trypsin inhibitor, aprotinin, lima bean trypsin inhibitor, ovomucoid trypsin inhibitor, and combinations thereof.

[0008] In some embodiments, the biologically active compound comprises a cyclic peptide. In some embodiments, the cyclic peptide comprises 5-30 amino acids. In some embodiments, the cyclic peptide comprises 5-20 amino acids. In some embodiments, the cyclic peptide comprises 12-16 amino acids. In some embodiments, the cyclic peptide comprises a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, A is, [ka] Selected from; During the ceremony, [ka] represents the point of attachment to the carbonyl group, and [ka] represents the point of attachment to the nitrogen atom; n is 0, 1, or 2; m is 1 or 2; m' is 0 or 1; z is 0, 1 or 2; w is 1 or 2; p is 0, 1, or 2; R 14 and R 15is independently selected from hydrogen and methyl; R x is selected from hydrogen, amino, hydroxy, and methyl; R v is hydrogen, methyl, or a natural amino acid side chain; R z is hydrogen and -C(O)NHR 16 Selected from; R 16 is hydrogen, -CHR 17 C(O)NH2, -CHR 17 C(O)NHCHR 17 C(O)NH2, -CH2C(O)NHCH(R 17 )C(O)NHCH(R 17a )C(O)NH2;-CH2C(O)NHCH(R 17 )COH; and -(C(R 17a )2)2-X'-R 30 Selected from; Each R 17 is hydrogen, -CH3, -CH2OH, and -(CH2) w -Triazolyl-XR 35 are independently selected from; R 35 is selected from -CO2H and CH3; Each R 17a are independently selected from hydrogen and -CH2CO2H; X' is a chain of 8 to 46 atoms, the atoms being selected from carbon and oxygen, and the chain may contain 1, 2, or 3 C(O)NH groups incorporated therein; and the chain may be optionally substituted with 1 or 2 groups independently selected from -CO2H, -C(O)NH2, -CH2C(O)NH2, and -CH2CO2H; R 30 -COH, -C(O)NR w R x and -CH3, wherein R w and R w’ are independently selected from hydrogen and C1-C6 alkyl, with the proviso that when X' are all carbon, R 30 is other than -CH3; X is -(CH2)2CH(CO2H)NHC(O)(CH2) f ; -(CH2CH2O) g and -(CH2CH2O) g CH2CH2NHC(O)CH2CH2CH(CO2H)NHC(O)(CH2) f Selected from; f is 14, 15, or 16; g is 3, 4, 5, 6, 7, 8, 9, 10, or 11; R 13 represents natural amino acids, unnatural amino acids, -(C(R 17a )2)2-X'-R 30 , and -(CH2) w -Triazolyl-XR 35 Selected from; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are independently selected from natural amino acid side chains and unnatural amino acid side chains, or form a ring with a corresponding vicinal R group as described below; R a , R c , R f , R h , R i , R j , R m , and R n are each independently selected from hydrogen and methyl; R b is hydrogen or methyl, or R b and R 2together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R d is hydrogen or methyl, or R d and R 4 can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl; R e is hydrogen or methyl, or R e and R 5 together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R g is hydrogen or methyl, or R g and R 7 can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, benzyl optionally substituted with halo groups, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with methoxy groups, quinolinyloxy optionally substituted with halo groups, and tetrazolyl; and the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; and Rk is hydrogen or methyl, or R k and R 11 are, together with the atoms attached thereto, selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; and R L is methyl or R L and R 12 together with the atoms to which they are attached form a ring selected from azetidine and pyrrolidine, where each ring is optionally substituted with 1 to 4 independently selected from amino, cyano, methyl, halo, and hydroxy.

[0009] In some embodiments, R c , R f , R h , R i , R m , and R n is hydrogen; R b is methyl or R b and R 2 together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R g is hydrogen or methyl, or R g and R 7can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, benzyl optionally substituted with halo groups, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with methoxy groups, quinolinyloxy optionally substituted with halo groups, and tetrazolyl; and the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; and R L is methyl or R L and R 12 together with the atoms to which they are attached form a ring selected from azetidine and pyrrolidine, where each ring is optionally substituted with 1 to 4 independently selected from amino, cyano, methyl, halo, and hydroxy.

[0010] In some embodiments, R 16 is -CH2C(O)NHCH(R 17 )COH or -(C(R 17a )2)2-X'-R 30 and R 17 is -(CH2) w -Triazolyl-XR 35 It is.

[0011] In some embodiments, the cyclic peptide comprises a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments, the bioactive compound is present in an amount of about 0.1% (w / w) to about 50% (w / w). In some embodiments, the bioactive compound is present in an amount of about 1% (w / w) to about 45% (w / w). In some embodiments, the bioactive compound is present in an amount of about 2% (w / w) to about 40% (w / w). In some embodiments, the biologically active compound is about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), about 50% (w / w), about 51% (w / w), about 52% (w / w), (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), or about 45% (w / w).

[0013] In some embodiments, the sulcaprozate salt is present in an amount of about 30% (w / w) to about 95% (w / w). In some embodiments, the sulcaprozate salt is present in an amount of about 50% (w / w) to about 90% (w / w). In some embodiments, the sulcaprozate salt is present in an amount of about 60% (w / w) to about 85% (w / w). In some embodiments, the sulcaprozate salt is present in an amount of about 60% (w / w) to about 80% (w / w).

[0014] In some embodiments, the biologically active compound and the sarcaprozate salt are present in a w / w ratio of about 0.02 to about 1.5. In some embodiments, the biologically active compound and the sarcaprozate salt are present in a w / w ratio of about 0.03 to about 1.4. In some embodiments, the biologically active compound and the sarcaprozate salt are present in a w / w ratio of about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.10, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, about 1.0, about 1.05, about 1.1, about 1.15, about 1.2, about 1.25, about 1.3, about 1.35, about 1.4, about 1.45, or about 1.5.

[0015] In some embodiments, nicotinamide is present in an amount of about 5% (w / w) to about 60% (w / w). In some embodiments, nicotinamide is present in an amount of about 10% (w / w) to about 50% (w / w). In some embodiments, nicotinamide is present in an amount of about 15% (w / w) to about 40% (w / w). In some embodiments, nicotinamide is present in an amount of about 20% (w / w) to about 30% (w / w).

[0016] In some embodiments, the one or more protease inhibitors are present in an amount of about 0.1% (w / w) to about 50% (w / w), about 0.5% (w / w) to about 40% (w / w), about 0.75% (w / w) to about 30% (w / w), about 1% (w / w) to about 25% (w / w), or about 5% (w / w) to about 20% (w / w).

[0017] In some aspects, the present disclosure provides: (a) cyclic peptide; (b) sarcaprozate sodium in a concentration of about 45% (w / w) to about 80% (w / w); and (c) Nicotinamide at a concentration of about 15% (w / w) to about 30% (w / w) The present invention provides a pharmaceutical composition comprising:

[0018] In some aspects, the present disclosure provides: (a) cyclic peptide; (b) sarcaprozate sodium in a concentration of about 45% (w / w) to about 80% (w / w); (c) nicotinamide at a concentration of about 15% (w / w) to about 30% (w / w); and (d) a protease inhibitor at a concentration of about 1% (w / w) and about 20% (w / w) The present invention provides a pharmaceutical composition comprising:

[0019] In some embodiments, the cyclic peptide comprises a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, A is, [ka] Selected from; During the ceremony, [ka] represents the point of attachment to the carbonyl group, and [ka] represents the point of attachment to the nitrogen atom; n is 0, 1, or 2; m is 1 or 2; m' is 0 or 1; z is 0, 1 or 2; w is 1 or 2; p is 0, 1, or 2; R 14 and R 15 is independently selected from hydrogen and methyl; R x is selected from hydrogen, amino, hydroxy, and methyl; R v is hydrogen, methyl, or a natural amino acid side chain; Rz is hydrogen and -C(O)NHR 16 Selected from; R 16 is hydrogen, -CHR 17 C(O)NH2, -CHR 17 C(O)NHCHR 17 C(O)NH2, -CH2C(O)NHCH(R 17 )C(O)NHCH(R 17a )C(O)NH2;-CH2C(O)NHCH(R 17 )COH; and -(C(R 17a )2)2-X'-R 30 Selected from; Each R 17 is hydrogen, -CH3, -CH2OH, and -(CH2) w -Triazolyl-XR 35 are independently selected from; R 35 is selected from -CO2H and CH3; Each R 17a are independently selected from hydrogen and -CH2CO2H; X' is a chain of 8 to 46 atoms, the atoms being selected from carbon and oxygen, and the chain may contain 1, 2, or 3 C(O)NH groups incorporated therein; and the chain may be optionally substituted with 1 or 2 groups independently selected from -CO2H, -C(O)NH2, -CH2C(O)NH2, and -CH2CO2H; R 30 -COH, -C(O)NR w R x and -CH3, wherein R w and R w’ are independently selected from hydrogen and C1-C6 alkyl, with the proviso that when X' are all carbon, R 30 is other than -CH3; X is -(CH2)2CH(CO2H)NHC(O)(CH2) f ; -(CH2CH2O) g and -(CH2CH2O) gCH2CH2NHC(O)CH2CH2CH(CO2H)NHC(O)(CH2) f Selected from; f is 14, 15, or 16; g is 3, 4, 5, 6, 7, 8, 9, 10, or 11; R 13 represents natural amino acids, unnatural amino acids, -(C(R 17a )2)2-X'-R 30 , and -(CH2) w -Triazolyl-XR 35 Selected from; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are independently selected from natural amino acid side chains and unnatural amino acid side chains, or form a ring with a corresponding vicinal R group as described below; R a , R c , R f , R h , R i , R j , R m , and R n are each independently selected from hydrogen and methyl; R b is hydrogen or methyl, or R b and R 2 together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R d is hydrogen or methyl, or R d and R 4can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl; R e is hydrogen or methyl, or R e and R 5 together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R g is hydrogen or methyl, or R g and R 7 can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, benzyl optionally substituted with halo groups, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with methoxy groups, quinolinyloxy optionally substituted with halo groups, and tetrazolyl; and the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; and R k is hydrogen or methyl, or R k and R 11 are, together with the atoms attached thereto, selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; and RL is methyl or R L and R 12 together with the atoms to which they are attached form a ring selected from azetidine and pyrrolidine, where each ring is optionally substituted with 1 to 4 independently selected from amino, cyano, methyl, halo, and hydroxy.

[0020] In some embodiments, R c , R f , R h , R i , R m , and R n is hydrogen; R b is methyl or R b and R 2 together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R g is hydrogen or methyl, or R g and R 7 can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, benzyl optionally substituted with halo groups, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with methoxy groups, quinolinyloxy optionally substituted with halo groups, and tetrazolyl; and the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; and R L is methyl or R L and R12 together with the atoms to which they are attached form a ring selected from azetidine and pyrrolidine, where each ring is optionally substituted with 1 to 4 independently selected from amino, cyano, methyl, halo, and hydroxy.

[0021] In some embodiments, R 16 is -CH2C(O)NHCH(R 17 )COH or -(C(R 17a )2)2-X'-R 30 and R 17 is -(CH2) w -Triazolyl-XR 35 It is.

[0022] In some embodiments, the cyclic peptide comprises a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0023] In some embodiments, the cyclic peptide is present in an amount of about 1% (w / w) to about 40% (w / w).

[0024] In some aspects, the disclosure provides a kit or article of manufacture comprising (i) a pharmaceutical composition of any one of the above aspects; and (ii) instructions for use.

[0025] In some embodiments, the present disclosure provides a method for improving the oral bioavailability of a bioactive compound in a subject in need thereof, comprising formulating the bioactive compound with a sarcaprozate salt and nicotinamide. In some embodiments of the method, the formulated bioactive compound exhibits improved oral bioavailability compared to the bioactive compound without the sarcaprozate salt and nicotinamide. In some embodiments of the method, the oral bioavailability is improved by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least 700%, or at least 800%. In some embodiments of the method, the sarcaprozate salt is sarcaprozate sodium.

[0026] In some embodiments of the method, the biologically active compound is a cyclic peptide. In some embodiments of the method, the cyclic peptide comprises 5-30 amino acids. In some embodiments, the cyclic peptide comprises 5-20 amino acids. In some embodiments of the method, the cyclic peptide comprises 12-16 amino acids. In some embodiments of the method, the cyclic peptide comprises a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, A is, [ka] Selected from; During the ceremony, [ka] represents the point of attachment to the carbonyl group, and [ka] represents the point of attachment to the nitrogen atom; n is 0, 1, or 2; m is 1 or 2; m' is 0 or 1; z is 0, 1 or 2; w is 1 or 2; p is 0, 1, or 2; R 14 and R 15 is independently selected from hydrogen and methyl; R x is selected from hydrogen, amino, hydroxy, and methyl; R v is hydrogen, methyl, or a natural amino acid side chain; R z is hydrogen and -C(O)NHR 16 Selected from; R 16 is hydrogen, -CHR 17 C(O)NH2, -CHR 17 C(O)NHCHR 17 C(O)NH2, -CH2C(O)NHCH(R 17 )C(O)NHCH(R 17a )C(O)NH2;-CH2C(O)NHCH(R 17 )COH; and -(C(R 17a )2)2-X'-R 30 Selected from; Each R 17 is hydrogen, -CH3, -CH2OH, and -(CH2) w -Triazolyl-XR 35 are independently selected from; R 35 is selected from -CO2H and CH3; Each R 17a are independently selected from hydrogen and -CH2CO2H; X' is a chain of 8 to 46 atoms, the atoms being selected from carbon and oxygen, and the chain may contain 1, 2, or 3 C(O)NH groups incorporated therein; and the chain may be optionally substituted with 1 or 2 groups independently selected from -CO2H, -C(O)NH2, -CH2C(O)NH2, and -CH2CO2H; R 30 -COH, -C(O)NR w R x and -CH3, wherein R w and R w’ are independently selected from hydrogen and C1-C6 alkyl, with the proviso that when X' are all carbon, R 30 is other than -CH3; X is -(CH2)2CH(CO2H)NHC(O)(CH2) f ; -(CH2CH2O) g and -(CH2CH2O) g CH2CH2NHC(O)CH2CH2CH(CO2H)NHC(O)(CH2) f Selected from; f is 14, 15, or 16; g is 3, 4, 5, 6, 7, 8, 9, 10, or 11; R 13 represents natural amino acids, unnatural amino acids, -(C(R 17a )2)2-X'-R 30 , and -(CH2) w -Triazolyl-XR 35 Selected from; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12are independently selected from natural amino acid side chains and unnatural amino acid side chains, or form a ring with a corresponding vicinal R group as described below; R a , R c , R f , R h , R i , R j , R m , and R n are each independently selected from hydrogen and methyl; R b is hydrogen or methyl, or R b and R 2 together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R d is hydrogen or methyl, or R d and R 4 can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl; R e is hydrogen or methyl, or R e and R 5 together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R g is hydrogen or methyl, or R g and R 7can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, benzyl optionally substituted with halo groups, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with methoxy groups, quinolinyloxy optionally substituted with halo groups, and tetrazolyl; and the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; and R k is hydrogen or methyl, or R k and R 11 are, together with the atoms attached thereto, selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; and R L is methyl or R L and R 12 together with the atoms to which they are attached form a ring selected from azetidine and pyrrolidine, where each ring is optionally substituted with 1 to 4 independently selected from amino, cyano, methyl, halo, and hydroxy.

[0027] In some embodiments of the method, R c , R f , R h , R i , R m , and R n is hydrogen; R b is methyl or R b and R 2together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R g is hydrogen or methyl, or R g and R 7 can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, benzyl optionally substituted with halo groups, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with methoxy groups, quinolinyloxy optionally substituted with halo groups, and tetrazolyl; and the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; and R L is methyl or R L and R 12 together with the atoms to which they are attached form a ring selected from azetidine and pyrrolidine, where each ring is optionally substituted with 1 to 4 independently selected from amino, cyano, methyl, halo, and hydroxy.

[0028] In some embodiments of the method, R 16 is -CH2C(O)NHCH(R 17 )COH or -(C(R 17a )2)2-X'-R 30 and R 17 is -(CH2) w -Triazolyl-XR 35 It is.

[0029] In some embodiments of the method, the cyclic peptide is a compound of formula (II) [ka] or a pharma- ceutically acceptable salt thereof.

[0030] In some embodiments, the present disclosure provides a compound of formula (II) [ka] or a pharma- ceutically acceptable salt thereof; and sarcaprozate sodium and nicotinamide, which provide an oral bioavailability of >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%. A composition comprising:

[0031] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutical acceptable salt thereof to >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%, comprising formulating a biologically active compound with a sarcaprozate salt and nicotinamide.

[0032] In some aspects, the disclosure provides a method of inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or kit of any of the above aspects. In some aspects of the method, 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 tract cancer, and breast cancer, and hematological malignancies.

[0033] In some aspects, the present disclosure provides a method of enhancing, stimulating, and / or increasing an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or kit of any of the above aspects.

[0034] In some aspects, the present disclosure provides a method of treating septic shock in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or kit of any of the above aspects.

[0035] In some aspects, the disclosure provides a method of blocking PD-L1 interaction with PD-1 and / or CD80 in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition or kit of any of the above aspects.

[0036] In some embodiments of the method, the formulation is administered orally. In some embodiments of the method, the formulation is administered intravenously. In some embodiments of the method, the formulation is administered intraduodenally.

[0037] In some embodiments, the present disclosure provides a compound of formula (II): [ka] comprising orally administering the compound together with sarcaprozate sodium and nicotinamide, wherein the oral bioavailability of the compound is >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%.

[0038] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof; The present invention provides an orally admistered composition comprising sarcaprozate sodium and nicotinamide, wherein the oral bioavailability of the compound of formula (II) is >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%.

[0039] In some embodiments, the present disclosure provides a compound of formula (II): [ka] orally administering the compound together with sarcaprozate sodium and nicotinamide, wherein the oral bioavailability of the compound is >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%.

[0040] In some embodiments, the present disclosure provides a method of orally adminstering a peptide, comprising administering to a subject a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof; The present invention provides a method comprising orally administering sarcaprozate sodium and nicotinamide, wherein the oral bioavailability of the compound is >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%. [Brief description of the drawings]

[0041] [Figure 1] 1 shows gastric and intenstinal absorption of formulations A and B in rats. [Diagram 2] FIG. 1 shows the pharmacokinetic profiles in dogs of tablet formulations of Compound (II) containing different amounts of sodium sarcaprozate (SNAC) compared to tablet formulations of Compound (II) containing SNAC and a protease inhibitor (PI). [Diagram 3] FIG. 1 shows the pharmacokinetic profiles in dogs of tablet formulations containing different amounts of Compound (II). [Figure 4]FIG. 1 shows the pharmacokinetic profiles in dogs of formulated tablets containing high or low amounts of Compound (II). [Figure 5A] Shown are concentrations of Compound (II) in individual dogs dosed with formulations prepared using a higher tableting weight (700 lb compression force). [Figure 5B] 1 shows individual dog pharmacokinetic profiles of tablet formulations of Compound (II) prepared using a lower compression weight (500 lb compression force). [Figure 6] 1 shows the exposure of Compound (II) in dogs administered 50 mg and 100 mg doses of Compound (II). [Figure 7] 1 shows the exposure of Compound (II) in cynomolgus monkeys administered a 12 mg dose of Compound (II). [Figure 8] 1 shows the exposure of Compound (II) in dogs administered a 70 mg dose of Compound (II). [Figure 9] 1 shows the exposure of Compound (II) in dogs administered a 50 mg dose of Compound (II). [Figure 10] 1 shows the exposure of Compound (II) in dogs administered a 100 mg dose of Compound (II). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] The present disclosure relates to a pharmaceutical composition comprising a biologically active compound; a sarcaprozate salt (such as sarcaprozate sodium); nicotinamide; and optionally one or more protease inhibitors. The composition can improve the bioavailability of the biologically active compound.

[0043] I. Definition In order that this description may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout this detailed description.

[0044] Unless otherwise specified, any atom with unsatisfied valences is assumed to have enough hydrogen atoms to satisfy the valences.

[0045] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. Thus, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein. It is further noted that the claims may be drafted to exclude any optional element. As such, this description is intended to serve as a premise for the use of such exclusive terminology, such as "solely" or "only," in connection with the recitation of claim elements or the use of negative limitations.

[0046] The term "or" is a logical or (i.e., and / or) and does not indicate an exclusive or unless expressly indicated, such as with the terms "either," "unless," "or," and words of similar effect.

[0047] Furthermore, "and / or" as used herein should be construed as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" when used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (single) and "B" (single). Similarly, the term "and / or" when used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: 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 (single); B (single); and C (single).

[0048] Units, prefixes, and symbols are expressed in the form accepted by the International System of Units (SI). Numeric ranges are inclusive of the numbers that define the range. When a range of values ​​is described, it is to be understood that each intervening integer value and each fraction between the upper and lower limits of the range described is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range may be independently included or excluded from the range, and each range in which either one, neither, or both of the limits are included is also encompassed within the scope of the disclosure. Thus, ranges described herein are understood to be shorthand for all values ​​within the range, including the endpoints described. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0049] When a value is explicitly stated, it should be understood that values ​​that are approximately the same quantity or amount as the stated value are also within the scope of this disclosure. When a combination is disclosed, each subcombination of the elements of the combination is also specifically disclosed and is within the scope of this disclosure. Conversely, when different elements or groups of elements are disclosed separately, their combinations are also disclosed. When multiple options are disclosed for any element of a disclosure, examples of each option of the disclosure, either individually or in any combination with other options, are also disclosed hereby; two or more elements of a disclosure may have such an exclusion, and all combinations of elements with such exclusion are disclosed hereby.

[0050] Those of skill in the art will recognize that amino acids include compounds represented by the following general structure: [ka] where R and R' are as discussed herein. Unless otherwise indicated, the term "amino acid" as used herein, alone or as part of another group, includes, without limitation, an amino group and a carboxyl group linked to the same carbon, referred to as the "α" carbon, where R and / or R' can be natural or unnatural side chains, including hydrogen. The "S" absolute configuration at the "α" carbon is commonly 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.

[0051] Unless specifically specified, the amino acids described herein may be of D- or L-stereochemistry and may be substituted as described elsewhere in this disclosure. When stereochemistry is not specified, it should be understood that the disclosure encompasses all stereochemical isomeric forms, or mixtures thereof, that produce the desired activity. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials that possess chiral centers, or by preparation of a mixture of enantiomeric products and subsequent separation, such as by conversion to a diastereomeric mixture followed by subsequent separation or recrystallization, chromatographic methods, or direct enantiomer separation on a chiral chromatographic column. Starting compounds of a particular stereochemistry may either be commercially available or may be made and resolved by techniques known in the art.

[0052] The terms "natural amino acid side chain" and "naturally occurring amino acid side chain," as used herein, refer to the side chain of any of the naturally occurring amino acids that are normally in the S-configuration (i.e., L-amino acids) (i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine,-histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine).

[0053] The terms "unnatural amino acid side chain" and "non-naturally occurring amino acid side chain", as used herein, refer to the side chain of any naturally occurring amino acid that is normally in the R configuration (i.e., a D-amino acid), or C2-C7 alkenyl, C1-C3 alkoxy C1-C3 alkyl, C1-C6 alkoxycarbonyl C1-C3 alkyl, C1-C7 alkyl, C1-C3 alkylsulfanyl C1-C3 alkyl, amido C1-C3 alkyl, amino C1-C3 alkyl, azaindolyl C1-C3 alkyl, benzothiazolyl C1-C3 alkyl, benzothienyl C1-C3 alkyl, benzyloxy C1-C3 alkyl, carboxy C1-C3 alkyl, C3-C 14 cycloalkyl C1-C3 alkyl, diphenylmethyl, furanyl C1-C3 alkyl, imidazolyl C1-C3 alkyl, naphthyl C1-C3 alkyl, pyridinyl C1-C3 alkyl, thiazolyl C1-C3 alkyl, thienyl C1-C3 alkyl; biphenyl C1-C3 alkyl, wherein biphenyl is optionally substituted with a methyl group; heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from C1-C4 alkoxy, C1-C4 alkyl, C1-C3 alkylsulfonylamino, amido, amino, aminoC1-C3 alkyl, aminosulfonyl, carboxy, cyano, halo, haloC1-C3 alkyl, hydroxy, -NC(NH2)2, nitro, and -OP(O)(OH)2; indolyl C1-C3 alkyl, wherein the indolyl moiety is optionally substituted with one group selected from C1-C3 alkoxycarbonyl C1-C3 alkyl, C1-C3 alkyl, carboxy C1-C3 alkyl, halo, hydroxy, and phenyl, wherein the phenyl is optionally further substituted with one, two, or three groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, and halo; NR x R y (C1-C7 alkyl) (wherein R x and R yis hydrogen, C2-C4 alkenyloxycarbonyl, C1-C3 alkyl, C1-C3 alkylcarbonyl, C3-C 14 Independently selected from cycloalkylcarbonyl, furanylcarbonyl, and phenylcarbonyl. When the alkyl linker contains more than one carbon, additional NR x R y (It may also have a group). NR t R u Carbonyl C1-C3 alkyl (wherein R t and R u are independently selected from hydrogen, C1-C3 alkyl, and triphenylmethyl; phenyl optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from C1-C4 alkoxy, C1-C4 alkyl, C1-C3 alkylsulfonylamino, amido, amino, aminoC1-C3 alkyl, aminosulfonyl, carboxy, cyano, halo, haloC1-C3 alkyl, hydroxy, -NC(NH2)2, nitro, and -OP(O)(OH)2; phenyl C1-C3 alkyl, wherein the phenyl moiety is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from C1-C4 alkoxy, C1-C4 alkyl, C1-C3 alkylsulfonylamino, amido, amino, amino C1-C3 alkyl, aminosulfonyl, carboxy, cyano, halo, halo C1-C3 alkyl, hydroxy, -NC(NH2)2, nitro, and -OP(O)(OH)2; and phenoxy C1-C3 alkyl (wherein the phenyl is optionally substituted with a C1-C3 alkyl group) " refers to groups other than naturally occurring amino acid side chains in the R or S configuration (i.e., D- or L-amino acids, respectively) selected from:

[0054] The term "C2-C4 alkenyl," as used herein, refers to a straight or branched chain group of 2 to 4 carbon atoms containing at least one carbon-carbon double bond.

[0055] The term "C2-C7 alkenyl," as used herein, refers to a straight or branched chain group of 2 to 7 carbon atoms containing at least one carbon-carbon double bond.

[0056] The term "C2-C4 alkenyloxy," as used herein, refers to a C2-C4 alkenyl group attached to the parent molecular moiety through an oxygen atom.

[0057] The term "C2-C4 alkenyloxycarbonyl," as used herein, refers to a C2-C4 alkenyloxy group attached to the parent molecular moiety through a carbonyl group.

[0058] The term "C1-C3 alkoxy," as used herein, refers to a C1-C3 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0059] The term "C1-C4 alkoxy," as used herein, refers to a C1-C4 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0060] The term "C1-C6 alkoxy," as used herein, refers to a C1-C6 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0061] Term “C1~C 13 "Alkoxy," as used herein, refers to a C-C alkyl group attached to the parent molecular moiety through an oxygen atom. 13 Refers to an alkyl group.

[0062] The term "C1-C3 alkoxy C1-C3 alkyl," as used herein, refers to a C1-C3 alkoxy group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0063] Term “C1~C 13 "Alkoxycarbonyl," as used herein, refers to a C-C alkyl group attached to the parent molecular moiety through a carbonyl group. 13 Refers to an alkoxy group.

[0064] The term "C1-C3 alkoxycarbonyl C1-C3 alkyl," as used herein, refers to a C1-C3 alkoxycarbonyl group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0065] The term "C1-C6 alkoxycarbonyl C1-C3 alkyl," as used herein, refers to a C1-C6 alkoxycarbonyl group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0066] The term "C1-C3 alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 3 carbon atoms.

[0067] The term "C1-C4 alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 4 carbon atoms.

[0068] The term "C1-C6 alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 6 carbon atoms.

[0069] The term "C1-C7 alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 7 carbon atoms.

[0070] Term “C1~C 13 "Alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 13 carbon atoms.

[0071] The term “C4~C 13 "Alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 4 to 13 carbon atoms.

[0072] The term "C1-C3 alkylcarbonyl," as used herein, refers to a C1-C3 alkyl group attached to the parent molecular moiety through a carbonyl group.

[0073] Term “C1~C 13 "Alkylcarbonyl," as used herein, refers to a C-C alkyl group attached to the parent molecular moiety through a carbonyl group. 13 Refers to an alkyl group.

[0074] The term “C4~C 13 "Alkylcarbonyl," as used herein, refers to a C-C alkyl group attached to the parent molecular moiety through a carbonyl group. 13 Refers to an alkyl group.

[0075] The term "C1-C3 alkylsulfanyl," as used herein, refers to a C1-C3 alkyl group attached to the parent molecular moiety through a sulfur atom.

[0076] Term “C1~C 13 "Alkylsulfanyl," as used herein, refers to a C-C alkyl group attached to the parent molecular moiety through a sulfur atom. 13 Refers to an alkyl group.

[0077] The term "C1-C3 alkylsulfanyl C1-C3 alkyl," as used herein, refers to a C1-C3 alkylsulfanyl group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0078] Term “C1~C 13 "Alkylsulfanylcarbonyl," as used herein, refers to a C-C alkyl group attached to the parent molecular moiety through a carbonyl group. 13 It refers to an alkylsulfanyl group.

[0079] The term "C1-C3 alkylsulfonyl," as used herein, refers to a C1-C3 alkyl group attached to the parent molecular moiety through a sulfonyl group.

[0080] The term "C1-C3 alkylsulfonylamino," as used herein, refers to a C1-C3 alkylsulfonyl group attached to the parent molecular moiety through an amino group.

[0081] The term "amide" as used herein refers to -C(O)NH2.

[0082] The term "amido C1-C3 alkyl," as used herein, refers to an amido group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0083] The term "amino" as used herein refers to --NH.sub.2.

[0084] The term "amino C1-C3 alkyl," as used herein, refers to an amino group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0085] The term "aminosulfonyl," as used herein, refers to an amino group attached to the parent molecular moiety through a sulfonyl group.

[0086] The term "azaindolyl C1-C3 alkyl" as used herein refers to an azaindolyl group that is attached to a parent molecule through a C1-C3 alkyl group. The azaindolyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0087] The term "benzothiazolyl C1-C3 alkyl" as used herein refers to a benzothiazolyl group attached to a parent molecule through a C1-C3 alkyl group. The benzothiazolyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0088] The term "benzothienyl C1-C3 alkyl" as used herein refers to a benzothienyl group attached to a parent molecule through a C1-C3 alkyl group. The benzothienyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0089] The term "benzyl," as used herein, refers to a phenyl group attached to the parent molecular moiety through a CH2 group.

[0090] The term "benzyloxy," as used herein, refers to a benzyl group attached to the parent molecular moiety through an oxygen atom.

[0091] The term "benzyloxy C1-C3 alkyl," as used herein, refers to a benzyloxy group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0092] The term "biphenyl C1-C3 alkyl," as used herein, refers to a biphenyl group attached to the parent molecular moiety through a C1-C3 alkyl group. The biphenyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0093] The term "carbonyl" as used herein refers to -C(O)-.

[0094] The term "carboxy" as used herein refers to -CO2H.

[0095] The term "carboxy C1-C3 alkyl," as used herein, refers to a carboxy group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0096] The term "cyano" as used herein refers to --CN.

[0097] The term “C3~C 14 "Cycloalkyl" as used herein refers to a saturated monocyclic or bicyclic hydrocarbon ring system having 3 to 14 carbon atoms and 0 heteroatoms. Bicyclic rings may be fused, spirocyclic, or bridged rings. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, octahydropentalene, and bicyclo[3.1.1]heptyl.

[0098] The term “C3~C 14"Cycloalkyl C1-C3 alkyl," as used herein, refers to a C3-C alkyl group attached to the parent molecular moiety through a C1-C3 alkyl group. 14 It refers to a cycloalkyl group.

[0099] The term “C3~C 14 "Cycloalkylcarbonyl," as used herein, refers to a C-C alkyl group attached to the parent molecular moiety through a carbonyl group. 14 It refers to a cycloalkyl group.

[0100] The term "diphenylmethyl," as used herein, refers to (Ph)2CH--, where each Ph is a phenyl ring.

[0101] The term "furanyl C1-C3 alkyl," as used herein, refers to a furanyl group attached to the parent molecular moiety through a C1-C3 alkyl group. The furanyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0102] The term "furanylcarbonyl," as used herein, refers to a furanyl group attached to the parent molecular moiety through a carbonyl group.

[0103] The terms “halo” and “halogen” as used herein refer to F, Cl, Br, or I.

[0104] The term "Halo C1~C 13 "Alkoxy," as used herein, refers to a haloC-C alkyl group attached to the parent molecular moiety through an oxygen atom. 13 Refers to an alkyl group.

[0105] The term "Halo C1~C 13 "Alkoxycarbonyl," as used herein, refers to a haloC1-C4 alkyl group attached to the parent molecular moiety through a carbonyl group. 13 Refers to an alkoxy group.

[0106] The term "halo C1-C3 alkyl," as used herein, refers to a C1-C3 alkyl group substituted with one, two, or three halogen atoms.

[0107] The term "Halo C1~C 13 "Alkyl" as used herein refers to a C1-C substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 halogen atoms. 13 Refers to an alkyl group.

[0108] The term "Halo C1~C 13 "Alkylcarbonyl," as used herein, refers to a haloC1-C4 alkyl group attached to the parent molecular moiety through a carbonyl group. 13 Refers to alkyl.

[0109] The term "heterocyclyl" as used herein refers to a 5-, 6-, or 7-membered ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Five-membered rings have 0-2 double bonds and 6- and 7-membered rings have 0-3 double bonds. The term "heterocyclyl" also includes bicyclic groups in which the heterocyclyl ring is fused to a 4- to 6-membered aromatic or non-aromatic carbocyclic ring or to another monocyclic heterocyclyl group. The heterocyclyl groups of the present disclosure are attached to the parent molecular moiety through a carbon atom in the group. Examples of heterocyclyl groups include, but are not limited to, benzothienyl, furyl, imidazolyl, indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, thiazolyl, thienyl, and thiomorpholinyl.

[0110] The term "hydroxy" as used herein refers to --OH.

[0111] The term "imidazolyl C1-C3 alkyl," as used herein, refers to an imidazolyl group attached to the parent molecular moiety through a C1-C3 alkyl group. The imidazolyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0112] The term "indolyl C1-C3 alkyl," as used herein, refers to an indolyl group attached to the parent molecular moiety through a C1-C3 alkyl group. The indolyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0113] The term "isoquinolinyloxy," as used herein, refers to an isoquinoline group attached to the parent molecular moiety through an oxygen atom. The isoquinoline group can be attached to the oxygen atom through any substitutable carbon atom in the group.

[0114] The term "naphthyl C1-C3 alkyl," as used herein, refers to a naphthyl group attached to the parent molecular moiety through a C1-C3 alkyl group. The naphthyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0115] The term "nitro" as used herein refers to --NO.

[0116] The term “NR x R y " as used herein, refers to two groups, R x and R y Refers to. R x and R y is hydrogen, C2-C4 alkenyloxycarbonyl, C1-C3 alkylcarbonyl, C3-C 14 It is independently selected from cycloalkylcarbonyl, furanylcarbonyl, and phenylcarbonyl.

[0117] The term “NR x R y"(C1-C7) alkyl," as used herein, refers to an NR that is attached to the parent molecular moiety through a C1-C7 alkyl group. x R y Refers to the base.

[0118] The term “NR t R u " as used herein, refers to two groups, R t and R u Refers to. R t and R u are independently selected from hydrogen, C1-C3 alkyl, and triphenylmethyl.

[0119] The term “NR t R u "Carbonyl," as used herein, refers to an NR that is attached to the parent molecular moiety through a carbonyl group. t R u Refers to the base.

[0120] The term “NR t R u "Carbonyl C1-C3 alkyl," as used herein, refers to an NR 2 -C3 alkyl group that is attached to the parent molecular moiety through a C1-C3 alkyl group. t R u Refers to the carbonyl group.

[0121] The term "phenoxy," as used herein, refers to a phenyl group attached to the parent molecular moiety through an oxygen atom.

[0122] The term "phenoxy C1-C3 alkyl," as used herein, refers to a phenoxy group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0123] The term "phenyl C1-C3 alkyl," as used herein, refers to a phenyl group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0124] The term "phenylcarbonyl," as used herein, refers to a phenyl group attached to the parent molecular moiety through a carbonyl group.

[0125] The term "pyridinyl C1-C3 alkyl," as used herein, refers to a pyridinyl group attached to the parent molecular moiety through a C1-C3 alkyl group. The pyridinyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0126] The term "quinolinyloxy," as used herein, refers to a quinoline group attached to the parent molecular moiety through an oxygen atom. The quinoline group can be attached to the oxygen atom through any substitutable carbon atom in the group.

[0127] The term "sulfanyl" as used herein refers to --S--.

[0128] The term "sulfonyl" as used herein refers to -SO2-.

[0129] The term "thiazolyl C1-C3 alkyl," as used herein, refers to a thiazolyl group attached to the parent molecular moiety through a C1-C3 alkyl group. The thiazolyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0130] The term "thienyl C1-C3 alkyl," as used herein, refers to a thienyl group attached to the parent molecular moiety through a C1-C3 alkyl group. The thienyl group can be attached to the alkyl moiety through any substitutable atom in the group.

[0131] The term "triphenylmethyl," as used herein, refers to -C(Ph)3, where each Ph is a phenyl group.

[0132] As used herein, the phrase "or a pharma- ceutically acceptable salt thereof" refers to at least one compound, or at least one salt of a compound, or a combination thereof. For example, "a compound of formula (I) or a pharma- ceutically acceptable salt thereof" includes, but is not limited to, a compound of formula (I), two compounds of formula (I), a pharma- ceutically acceptable salt of a compound of formula (I), one or more pharma- ceutically acceptable salts of a compound of formula (I) and a compound of formula (I), and two or more pharma- ceutically acceptable salts of a compound of formula (I).

[0133] The term "treating" refers to (iii) inhibiting a disease, disorder, or condition, i.e., arresting its development; and (iv) alleviating a disease, disorder, or condition, i.e., causing regression of the disease, disorder, and / or condition and / or symptoms associated with the disease, disorder, and / or condition.

[0134] II. Pharmaceutical Compositions In some embodiments, the present disclosure provides a composition comprising a cyclic peptide. The term "composition" as used herein is intended to encompass a product comprising the specified components in the specified amounts, as well as any product that is obtained directly or indirectly from the combination of the specified components in the specified amounts. Such terms relating to pharmaceutical compositions are intended to encompass a product comprising one or more active components and one or more inactive components that constitute the carrier, as well as any product that is obtained directly or indirectly from the combination, complexation or aggregation of any two or more of the components, or from the dissociation of one or more of the components, or from other types of reaction or interaction of one or more of the components. Thus, the pharmaceutical composition of the present invention encompasses any composition made by mixing a compound of the present invention with a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" it is meant that the carrier, diluent or excipient is compatible with the other components of the formulation and is not deleterious to the recipient thereof.

[0135] In some embodiments, the compositions of the present disclosure are suitable for oral administration. These compositions can include solid, semi-solid, gel matrix or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal administration, lingual administration, and sublingual administration. Suitable oral dosage forms can include, without limitation, tablets, minitablets, capsules, pills, troches, lozenges, pastilles, sachets, pellets, medicated 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 present disclosure suitable for oral administration are in the form of tablets or capsules. In some embodiments, the compounds of the present disclosure can be formulated as tablets. In some embodiments, the tablets can be encapsulated into capsules for administration.

[0136] The tablets of the present disclosure may be in the form of compressed tablets, molded tablets, chewable tablets, fast-dissolving tablets, multi-layer compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets that are coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalates. Film coatings can impart the same general characteristics as sugar coatings. Multilayer compressed tablets are compressed tablets made by more than one compression cycle, including multilayer tablets, and compression-coated or dry-coated tablets.

[0137] In some embodiments, the compounds of the present disclosure may be in the form of tablets. In some embodiments, the compounds of the present disclosure may be in the form of compressed tablets. In some embodiments, the compounds of the present disclosure may be in the form of enteric coated tablets.

[0138] In some embodiments, the compositions of the present disclosure can be prepared by dry granulation of the compounds of the present disclosure with one or more pharma- ceutically acceptable carriers, vehicles, and / or excipients. In some embodiments, the compositions of the present disclosure can be prepared by wet granulation.

[0139] In some embodiments, the compositions of the present disclosure may be in the form of soft or hard capsules, which may be made of gelatin, methylcellulose, starch, and / or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), may contain two sections, one sliding over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SEC) are soft, globular shells, such as gelatin shells, plasticized by adding glycerin, sorbitol, or similar polyols. In some embodiments, tsoft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those as described herein, including but not limited to methyl and propyl parabens, 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. Capsules can also be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0140] Coloring and flavoring agents can be used in any of the above dosage forms. Additionally, flavoring and sweetening agents can be particularly useful in the formation of chewable tablets and lozenges.

[0141] In certain aspects, the compositions of the present disclosure may be formulated as immediate or modified release dosage forms, including delayed-, extended-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0142] The compositions of the present disclosure may contain other active ingredients that do not confer therapeutic or prophylactic effectiveness on the composition and / or may contain substances that enhance or supplement the effectiveness of the composition.

[0143] The compositions described herein are typically part of a mixture with suitable pharmaceutical diluents, excipients, and / or carriers (collectively referred to herein as pharmaceutical carriers) that are appropriately selected based on the intended administration form and are consistent with conventional pharmaceutical practice.For example, for oral administration in the form of tablets or capsules, the active drug components can be combined with oral non-toxic, pharma-ceutically acceptable inert carriers.In addition, if desired or necessary, suitable binders, lubricants, surfactants, disintegrants, flow agents, flavoring agents, and coloring agents can also be incorporated into the mixture. Examples of such additives include, but are not limited to, lactose, sucrose, dextrose, dextrates, glucose, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methylcellulose, microcellulose, crosslinked cellulose, such as croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, and sodium starch glycolate. Crosslinked polymers such as bridge starch, crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clays, gums, silica, silicon dioxide, talc, pregelatinized starch, corn starch, magnesium aluminum silicate, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, ethylene oxide copolymers, propylene oxide, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, stearic acid, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, zinc stearate, waxes, talc, and the like, as well as combinations thereof.In some embodiments, the compositions described herein include microcrystalline cellulose, mannitol, croscarmellose sodium, silicon dioxide, magnesium stearate, or a combination thereof.

[0144] In some embodiments, the composition comprises from about 1% (w / w) to about 6% (w / w) of one or more fillers. In some embodiments, the term "filler" refers to an inert substance used to bulk up or make an active ingredient 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 comprises from about 1% (w / w) wt% to 5% (w / w) of one or more fillers. In some embodiments, the composition comprises from about 1%, about 2%, about 3%, about 4%, about 5%, or about 6% (w / w) of one or more fillers.

[0145] In some embodiments, the one or more fillers include microcrystalline cellulose. In some embodiments, the composition comprises about 1% (w / w) to about 6% (w / w) microcrystalline cellulose. In some embodiments, the composition comprises about 1% (w / w) wt% to 5% (w / w) microcrystalline cellulose. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, or about 6% (w / w) microcrystalline cellulose.

[0146] In some embodiments, the composition comprises about 1% (w / w) to about 6% (w / w) of one or more disintegrants. In some embodiments, the term "disintegrant" refers to an agent added to a formulation, particularly a tablet, to facilitate the breakup of the tablet into small pieces in an aqueous environment. Examples of disintegrants include, but are not limited to, croscarmellose sodium, crospovidone, cornstarch, pregelatinized starch, and sodium starch glycolate. In some embodiments, the composition comprises about 1% (w / w) wt% to 5% (w / w) of one or more disintegrants. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, or about 6% (w / w) of one or more disintegrants.

[0147] In some embodiments, the one or more disintegrants include croscarmellose sodium. In some embodiments, the composition comprises about 1% (w / w) to about 6% (w / w) croscarmellose sodium. In some embodiments, the composition comprises about 1% (w / w) wt% to 5% (w / w) croscarmellose sodium. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, or about 6% (w / w) croscarmellose sodium.

[0148] In some embodiments, the composition comprises about 1% (w / w) to about 6% (w / w) silicon dioxide. In some embodiments, the composition comprises about 1% (w / w) to about 5% (w / w) silicon dioxide. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, or about 6% (w / w) silicon dioxide.

[0149] In some embodiments, the composition comprises from about 1% (w / w) to about 6% (w / w) of one or more flow agents. In some embodiments, the term "flow agent" refers to an agent used to increase powder flowability. Examples of flow agents include, but are not limited to, talc, magnesium stearate and other stearates, stearyl fumarate, stearic acid, and silica. In some embodiments, the composition comprises from about 1% (w / w) to about 5% (w / w) of one or more flow agents. In some embodiments, the composition comprises from about 1%, about 2%, about 4%, about 4%, about 5%, or about 6% (w / w) of one or more flow agents.

[0150] In some embodiments, the one or more flow agents include magnesium stearate. In some embodiments, the composition comprises about 1% (w / w) to about 6% (w / w) magnesium stearate. In some embodiments, the composition comprises about 1% (w / w) to about 5% (w / w) magnesium stearate. In some embodiments, the composition comprises about 1%, about 2%, about 4%, about 4%, about 5%, or about 6% (w / w) magnesium stearate.

[0151] In still other embodiments, standard coating procedures, such as those described in Remingon's Pharmaceutical Sciences, 20th Edition (2000), can be used to provide a film coating around the formulations of the compounds described herein.

[0152] A dosage form (pharmaceutical composition) suitable for administration may contain about 1 milligram to about 300 milligrams of active ingredient per dosage unit. In such pharmaceutical compositions, the active ingredient will usually be present in an amount of about 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 about 10 to about 240 milligrams of active ingredient per dosage unit. In some embodiments, a dosage form 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 per dosage unit.

[0153] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a bioactive compound, a sarcaprozate salt, and nicotinamide. In some embodiments, the disclosure provides a pharmaceutical composition comprising a barrier that prevents drug release in an acidic environment, such as in gastric fluid. The bioactive compound may be any compound that exerts a direct physiological effect on an organism. In certain embodiments, the bioactive compound is one whose bioavailability is enhanced when administered as a pharmaceutical composition described herein. In certain embodiments, the bioactive compound is one whose oral bioavailability is enhanced when administered as a pharmaceutical composition described herein. In certain embodiments, the bioactive compound comprises a cyclic peptide. In certain embodiments, the cyclic peptide may comprise 5-30 amino acids. In some embodiments, the cyclic peptide may comprise 5-20 amino acids. In some embodiments, the cyclic peptide may comprise 12-16 amino acids. In certain embodiments, the cyclic peptide backbone may comprise 2-20 amino acids. In certain embodiments, the cyclic peptide backbone may comprise 4-18 amino acids. In certain embodiments, the cyclic peptide backbone may comprise 6-16 amino acids. In certain embodiments, the cyclic peptide backbone may comprise 8 to 14 amino acids. In certain embodiments, the cyclic peptide backbone may comprise 10 to 14 amino acids. In certain embodiments, the cyclic peptide backbone may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids.

[0154] In certain embodiments, the cyclic peptide comprises a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, A is, [ka] Selected from; During the ceremony, [ka] represents the point of attachment to the carbonyl group, and [ka] represents the point of attachment to the nitrogen atom; n is 0, 1, or 2; m is 1 or 2; m' is 0 or 1; z is 0, 1 or 2; w is 1 or 2; p is 0, 1, or 2; R 14 and R 15 is independently selected from hydrogen and methyl; R x is selected from hydrogen, amino, hydroxy, and methyl; R v is hydrogen, methyl, or a natural amino acid side chain; R z is hydrogen and -C(O)NHR 16 Selected from; R 16 is hydrogen, -CHR 17 C(O)NH2, -CHR 17 C(O)NHCHR 17 C(O)NH2, -CH2C(O)NHCH(R 17 )C(O)NHCH(R 17a )C(O)NH2;-CH2C(O)NHCH(R 17 )COH; and -(C(R 17a )2)2-X'-R 30 Selected from; Each R 17 is hydrogen, -CH3, -CH2OH, and -(CH2) w -Triazolyl-XR 35 are independently selected from; R 35 is selected from -CO2H and CH3; Each R 17a are independently selected from hydrogen and -CH2CO2H; X' is a chain of 8 to 46 atoms, the atoms being selected from carbon and oxygen, and the chain may contain 1, 2, or 3 C(O)NH groups incorporated therein; and the chain may be optionally substituted with 1 or 2 groups independently selected from -CO2H, -C(O)NH2, -CH2C(O)NH2, and -CH2CO2H; R 30 -COH, -C(O)NR w R x and -CH3, wherein R w and R w’ are independently selected from hydrogen and C1-C6 alkyl, with the proviso that when X' are all carbon, R 30 is other than -CH3; X is -(CH2)2CH(CO2H)NHC(O)(CH2) f ; -(CH2CH2O) g and -(CH2CH2O) g CH2CH2NHC(O)CH2CH2CH(CO2H)NHC(O)(CH2) f Selected from; f is 14, 15, or 16; g is 3, 4, 5, 6, 7, 8, 9, 10, or 11; R 13 represents natural amino acids, unnatural amino acids, -(C(R 17a )2)2-X'-R 30 , and -(CH2) w -Triazolyl-XR 35 Selected from; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12are independently selected from natural amino acid side chains and unnatural amino acid side chains, or form a ring with a corresponding vicinal R group as described below; R a , R c , R f , R h , R i , R j , R m , and R n are each independently selected from hydrogen and methyl; R b is hydrogen or methyl, or R b and R 2 together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R d is hydrogen or methyl, or R d and R 4 can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl; R e is hydrogen or methyl, or R e and R 5 together with the atoms to which they are attached form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R g is hydrogen or methyl, or R g and R 7can be taken together with the atoms to which they are attached to form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring is optionally substituted with 1 to 4 groups independently selected from amino, benzyl optionally substituted with halo groups, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with methoxy groups, quinolinyloxy optionally substituted with halo groups, and tetrazolyl; and the pyrrolidine and piperidine rings can be optionally fused to a cyclohexyl, phenyl, or indole group; R k is hydrogen or methyl, or R k and R 11 are, together with the atoms attached thereto, selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; and R L is methyl or R L and R 12 may include, together with the atoms to which they are attached, form a ring selected from azetidine and pyrrolidine, where each ring is optionally substituted with 1 to 4 independently selected from amino, cyano, methyl, halo, and hydroxy.

[0155] Certain compounds of the present disclosure may exist in a variety of different stable conformational forms, which may be separable. For example, torsional asymmetry resulting from restricted rotation around an asymmetric single bond due to steric hindrance or ring strain may allow for the separation of different conformers. The present disclosure includes each conformational isomer of these compounds and mixtures thereof.

[0156] Certain compounds of the present disclosure can exist as tautomers, which are compounds that are created by the phenomenon that the protons of a molecule shift to different atoms in the molecule.The term "tautomer" also refers to one of two or more structural isomers that exist in equilibrium and can be easily converted from one isomer to another.All tautomers of the compounds described herein are included within the scope of the present disclosure.

[0157] In certain embodiments, the cyclic peptide is a compound of formula (I), 16 is -CH2C(O)NHCH(R 17 )COH or -(C(R 17a )2)2-X'-R 30 and R 17 is -(CH2) w -Triazolyl-XR 35 (wherein

[0158] In certain aspects, the cyclic peptide is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0159] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described herein, using appropriate isotopically labeled reagents instead of the non-labeled reagents originally used. Such compounds may have a variety of potential uses, for example, as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

[0160] The pharmaceutical compounds of the present disclosure may include one or more pharma- ceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see, for example, Berge, SM et al., J.Pharm.Sci., 66:1-19 (1977)). Salts can be obtained during the final isolation and purification of the compounds described herein, or can be obtained separately by reacting a free base functional group of the compound with a suitable acid, or by reacting an acidic group of the compound with a suitable base. Acid addition salts include those derived from non-toxic inorganic acids, such as acetic acid, succinic acid, fumaric acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, and the like, and those derived from non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium, and the like, as well as those derived from non-toxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like.

[0161] In certain embodiments, the bioactive compound is present in an amount of about 0.1% (w / w) to about 50% (w / w). In certain embodiments, the bioactive compound is present in an amount of about 0.25% (w / w) to about 50% (w / w). In certain embodiments, the bioactive compound is present in an amount of about 0.5% (w / w) to about 50% (w / w). In certain embodiments, the bioactive compound is present in an amount of about 0.75% (w / w) to about 50% (w / w). In some embodiments, the bioactive compound is present in an amount of about 1% (w / w) to about 50% (w / w). In some embodiments, the bioactive compound is present in an amount of about 1% (w / w) to about 45% (w / w). In some embodiments, the bioactive compound is present in an amount of about 2% (w / w) to about 40% (w / w). In some embodiments, the bioactive compound is present in an amount of about 3% (w / w) to about 30% (w / w). In some embodiments, the biologically active compound is present in an amount of about 4% (w / w) to about 20% (w / w). In some embodiments, the biologically active compound is present in an amount of about 5% (w / w) to about 10% (w / w). In some embodiments, the biologically active compound is about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), about 50% (w / w), about 51% (w / w), about 52% (w / w), (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), or about 45% (w / w).

[0162] The pharmaceutical compositions described herein may include a sarcaprozate salt. In certain embodiments, the salt may be sodium, potassium, magnesium, calcium, or tromethamine / tris(hydroxymethyl)aminomethane. In some embodiments, the salt may be sodium.

[0163] In certain embodiments, the sulcaprozate salt is present in an amount of about 30% (w / w) to about 95% (w / w). In some embodiments, the sulcaprozate salt is present in an amount of about 50% (w / w) to about 90% (w / w). In some embodiments, the sulcaprozate salt is present in an amount of about 60% (w / w) to about 85% (w / w). In some embodiments, the sulcaprozate salt is present in an amount of about 60% (w / w) to about 80% (w / w). In some embodiments, the sulcaprozate salt is about 10% (w / w), about 12% (w / w), about 14% (w / w), about 16% (w / w), about 18% (w / w), about 20% (w / w), about 22% (w / w), about 24% (w / w), about 26% (w / w), about 28% (w / w), about 30% (w / w), about 32% (w / w), about 34% (w / w), about 36% (w / w), about 38% (w / w), about 40% (w / w), about 42% (w / w), about 44% (w / w), about 46% (w / w), about 48% (w / w), about 50% (w / w), about 52% (w / w), about 54% (w / w), about 56% (w / w), about 58% (w / w), about 60% (w / w), about 62% (w / w), about 64% (w / w), about 66% (w / w), about 68% (w / w), about 70% (w / w), about 72% (w / w), about 74% (w / w), about 76% (w / w), about 78% (w / w), about 80% (w / w), about 82% (w / w), about 84% (w / w), about 86% (w / w), about 88% (w / w), about 90% (w / w), about 92% (w / w), about 94% (w / w), or about 96% (w / w).

[0164] In certain embodiments, the biologically active compound and the sarcaprozate salt are present in a w / w ratio of about 0.01 to about 2. In certain embodiments, the biologically active compound and the sarcaprozate salt are present in a w / w ratio of about 0.02 to about 1.5. In some embodiments, the biologically active compound and the sarcaprozate salt are present in a w / w ratio of about 0.03 to about 1.4. In some embodiments, the biologically active compound and the sarcaprozate salt are present in a w / w ratio of about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.10, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, about 1.0, about 1.05, about 1.1, about 1.15, about 1.2, about 1.25, about 1.3, about 1.35, about 1.4, about 1.45, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 w / w ratio.

[0165] In certain embodiments, the pharmaceutical compositions described herein may include nicotinamide. In certain embodiments, nicotinamide may be present in an amount of about 1% (w / w) to about 70% (w / w). In certain embodiments, nicotinamide may be present in an amount of about 3% (w / w) to about 65% (w / w). In certain embodiments, nicotinamide may be present in an amount of about 5% (w / w) to about 60% (w / w). In certain embodiments, nicotinamide may be present in an amount of about 10% (w / w) to about 50% (w / w). In certain embodiments, nicotinamide may be present in an amount of about 15% (w / w) to about 40% (w / w). In certain embodiments, nicotinamide may be present in an amount of about 20% (w / w) to about 30% (w / w). In certain embodiments, nicotinamide is present in an amount of about 1% (w / w), about 3% (w / w), about 5% (w / w), about 7% (w / w), about 9% (w / w), about 11% (w / w), about 13% (w / w), about 15% (w / w), about 17% (w / w), about 19% (w / w), about 21% (w / w), about 23% (w / w), about 25% (w / w), about 27% (w / w), about 29% (w / w), about 31% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w), about 59% (w / w), about 60% (w / w), about 61% (w / w), about 62% (w / w), about 63% (w / w), about 64% (w / w), about 65% (w / w), about 66% (w / w), about 67% (w / w), about 68% (w / w), about It may be present in an amount of 7% (w / w), 39% (w / w), about 41% (w / w), about 43% (w / w), about 45% (w / w), about 47% (w / w), about 49% (w / w), about 51% (w / w), about 53% (w / w), about 55% (w / w), about 57% (w / w), about 59% (w / w), about 61% (w / w), about 63% (w / w), about 65% (w / w), about 67% (w / w), about 69% (w / w), or about 70% (w / w).

[0166] In certain embodiments, the pharmaceutical composition may include one or more protease inhibitors. In some embodiments, the one or more protease inhibitors include one or more trypsin inhibitors. In some embodiments, the one or more trypsin inhibitors can be isolated from bovine pancreas, raw chicken egg white, soybean, or lima bean. In some embodiments, the one or more protease inhibitors can be selected from soybean trypsin inhibitor, aprotinin, lima bean trypsin inhibitor, ovomucoid trypsin inhibitor, and combinations thereof.

[0167] In some embodiments, the one or more protease inhibitors may be present in an amount of about 0.1% (w / w) to about 50% (w / w). In some embodiments, the one or more protease inhibitors may be present in an amount of about 0.5% (w / w) to about 40% (w / w). In some embodiments, the one or more protease inhibitors may be present in an amount of about 0.75% (w / w) to about 30% (w / w). In some embodiments, the one or more protease inhibitors may be present in an amount of about 1% (w / w) to about 25% (w / w). In some embodiments, the one or more protease inhibitors may be present in an amount of about 5% (w / w) to about 20% (w / w). In some embodiments, the one or more protease inhibitors may be present in an amount of about 0.5% (w / w) to about 4 ... and more) protease inhibitors are about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), 0.8% (w / w), about 0.9% (w / w), about 1.0% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w), about 17% (w / w), about 18% (w / w), about 19% (w / w), about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% ( In some embodiments, the soluble soluble soluble material may be present in an amount of about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), or about 50% (w / w).

[0168] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a cyclic peptide at a concentration of about 0.1% (w / w) to about 50% (w / w); a sarcaprozate salt at a concentration of about 30% (w / w) to about 95% (w / w); and a nicotinamide at a concentration of about 5% (w / w) to about 60% (w / w). In some aspcts, the sarcaprozate salt can be sarcaprozate sodium. In some embodiments, the biologically active compound can be a cyclic peptide. In some aspcets, the cyclic peptide can be a compound of formula (I), or a pharma- ceutical acceptable salt thereof. In some embodiments, the biologically active compound can be a compound of formula (I), or a pharma- ceutical acceptable salt thereof, where R 16 is -CH2C(O)NHCH(R 17 )COH or -(C(R 17a )2)2-X'-R 30 and R 17 is -(CH2) w -Triazolyl-XR 35 In some embodiments, the biologically active compound may be a compound of formula (II), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition may include one or more protease inhibitors at a concentration between about 1% (w / w) and about 20% (w / w).

[0169] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a cyclic peptide at a concentration of about 1% (w / w) to about 45% (w / w); a sarcaprozate salt at a concentration of about 50% (w / w) to about 90% (w / w); and a nicotinamide at a concentration of about 10% (w / w) to about 50% (w / w). In some aspcts, the sarcaprozate salt can be sarcaprozate sodium. In some embodiments, the biologically active compound can be a cyclic peptide. In some aspcets, the cyclic peptide can be a compound of formula (I), or a pharma- ceutical acceptable salt thereof. In some embodiments, the biologically active compound can be a compound of formula (I), or a pharma- ceutical acceptable salt thereof, where R 16 is -CH2C(O)NHCH(R 17 )COH or -(C(R 17a )2)2-X'-R30 and R 17 is -(CH2) w -Triazolyl-XR 35 In some embodiments, the biologically active compound may be a compound of formula (II), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition may include one or more protease inhibitors at a concentration between about 1% (w / w) and about 20% (w / w).

[0170] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a cyclic peptide at a concentration of about 2% (w / w) to about 40% (w / w); a sarcaprozate salt at a concentration of about 60% (w / w) to about 85% (w / w); and a nicotinamide at a concentration of about 15% (w / w) to about 40% (w / w). In some aspcts, the sarcaprozate salt can be sarcaprozate sodium. In some embodiments, the biologically active compound can be a cyclic peptide. In some aspcts, the cyclic peptide can be a compound of formula (I), or a pharma- ceutical acceptable salt thereof. In some embodiments, the biologically active compound can be a compound of formula (I), or a pharma- ceutical acceptable salt thereof, where R 16 is -CH2C(O)NHCH(R 17 )COH or -(C(R 17a )2)2-X'-R 30 and R 17 is -(CH2) w -Triazolyl-XR 35 In some embodiments, the biologically active compound may be a compound of formula (II), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition may include one or more protease inhibitors at a concentration between about 1% (w / w) and about 20% (w / w).

[0171] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a cyclic peptide; a sarcaprozate salt at a concentration of about 45% (w / w) to about 80% (w / w); and a nicotinamide at a concentration of about 15% (w / w) to about 30% (w / w). In some aspcts, the sarcaprozate salt can be sarcaprozate sodium. In some embodiments, the cyclic peptide can be present at a concentration of about 1% (w / w) to about 45% (w / w). In some embodiments, the biologically active compound can be a cyclic peptide. In some aspcets, the cyclic peptide can be a compound of formula (I), or a pharma- ceutical acceptable salt thereof. In some embodiments, the biologically active compound can be a compound of formula (I), or a pharma- ceutical acceptable salt thereof, where R 16 is -CH2C(O)NHCH(R 17 )COH or -(C(R 17a )2)2-X'-R 30 and R 17 is -(CH2) w -Triazolyl-XR 35 In some embodiments, the biologically active compound may be a compound of formula (II), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition may include one or more protease inhibitors at a concentration between about 1% (w / w) and about 20% (w / w).

[0172] In certain embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof; and sarcaprozate sodium and nicotinamide, which provide an oral bioavailability of >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%. A composition comprising:

[0173] Also within the scope of the present disclosure are kits comprising the compositions of the present disclosure and instructions for use. The kits may further comprise additional reagents. The kits typically include labeling and instructions indicating the intended use of the contents of the kit. The term labeling includes any written or recorded material supplied on or with the kit, or which otherwise accompanies the kit.

[0174] III.How to use In some embodiments, the present disclosure provides a method for improving the oral bioavailability of a bioactive compound in a subject in need thereof, comprising formulating the bioactive compound with a sarcaprozate salt and nicotinamide. In some embodiments, the sarcaprozate salt is sarcaprozate sodium (SNAC). In some embodiments, the formulation further comprises one or more protease inhibitors.

[0175] In some embodiments, the disclosure provides pharmaceutical formulations that improve the oral bioavailability of a biologically active compound. In certain embodiments, the oral bioavailability is improved by at least 5%. In some embodiments, the oral bioavailability is improved by at least 10%. In some embodiments, the oral bioavailability is improved by at least 15%. In some embodiments, the oral bioavailability is improved by at least 20%. In some embodiments, the oral bioavailability is improved by at least 25%. In some embodiments, the oral bioavailability is improved by at least 30%. In some embodiments, the oral bioavailability is improved by at least 35%. In some embodiments, the oral bioavailability is improved by at least 40%. In some embodiments, the oral bioavailability is improved by at least 45%. In some embodiments, the oral bioavailability is improved by at least 50%. In some embodiments, the oral bioavailability is improved by at least 55%. In some embodiments, the oral bioavailability is improved by at least 60%. In some embodiments, oral bioavailability is increased by at least 65%. In some embodiments, oral bioavailability is increased by at least 70%. In some embodiments, oral bioavailability is increased by at least 75%. In some embodiments, oral bioavailability is increased by at least 80%. In some embodiments, oral bioavailability is increased by at least 90%. In some embodiments, oral bioavailability is increased by 100%. In some embodiments, oral bioavailability is increased by 125%. In some embodiments, oral bioavailability is increased by 150%. In some embodiments, oral bioavailability is increased by 175%. In some embodiments, oral bioavailability is increased by 200%. In some embodiments, oral bioavailability is increased by 225%. In some embodiments, oral bioavailability is increased by 250%. In some embodiments, oral bioavailability is increased by 275%. In some embodiments, oral bioavailability is increased by 300%.In some embodiments, oral bioavailability is increased by 325%. In some embodiments, oral bioavailability is increased by 350%. In some embodiments, oral bioavailability is increased by 375%. In some embodiments, oral bioavailability is increased by 400%. In some embodiments, oral bioavailability is increased by 425%. In some embodiments, oral bioavailability is increased by 450%. In some embodiments, oral bioavailability is increased by 475%. In some embodiments, oral bioavailability is increased by 500%. In some embodiments, oral bioavailability is increased by 525%. In some embodiments, oral bioavailability is increased by 550%. In some embodiments, oral bioavailability is increased by 575%. In some embodiments, oral bioavailability is increased by 600%. In some embodiments, oral bioavailability is increased by 625%. In some embodiments, oral bioavailability is increased by 650%. In some embodiments, oral bioavailability is increased by 675%. In some embodiments, oral bioavailability is increased by 700%. In some embodiments, oral bioavailability is increased by 725%. In some embodiments, oral bioavailability is increased by 750%. In some embodiments, oral bioavailability is increased by 775%. In some embodiments, oral bioavailability is increased by 800%.

[0176] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutical acceptable salt thereof to >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%, comprising formulating a biologically active compound with a sarcaprozate salt and nicotinamide.

[0177] The administration of the bioactive compounds described herein includes, without limitation, the administration of a therapeutically effective amount of the compound. The term "therapeutically effective amount" as used herein refers, without limitation, to the amount of a compound to treat a condition treatable by administration of a composition comprising the bioactive compound. This amount is sufficient to show a detectable therapeutic effect or an effect that leads to improvement. The effect can include, by way of example and without limitation, the treatment of the conditions listed herein. The exact effective amount for a subject will depend on the subject's size and health, the nature and extent of the condition being treated, the advice of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration. Thus, it is not useful to specify the exact effective amount in advance.

[0178] In another aspect, the present disclosure relates to a method of inhibiting the growth of tumor cells in a subject using a pharmaceutical composition of the present disclosure. In some embodiments, the bioactive compound has the ability to bind to PD-L1, disrupt the interaction between PD-L1 and PD-1, compete with the binding of PD-L1 to an anti-PD-1 monoclonal antibody known to block the interaction with PD-1, enhance CMV-specific T cell IFNγ secretion, and enhance HIV-specific T cell IFNγ secretion. As a result, in some embodiments, the bioactive compounds of the present disclosure are useful for modifying immune responses, treating diseases such as cancer, infectious diseases, and / or septic shock, stimulating a protective autoimmune response, or stimulating an antigen-specific immune response.

[0179] Cancers whose growth can be inhibited using the pharmaceutical compositions of the present disclosure 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, non-squamous non-small cell lung cancer). Other examples of cancers that can be treated using the methods of the present disclosure include bone cancer, hepatocellular carcinoma, pancreatic cancer, skin cancer, squamous cell carcinoma of the head and neck, cutaneous or intraocular malignant melanoma, 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 intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, hematological malignancies (acute myeloid leukemia, chronic ... The cancers that can be treated include chronic or acute leukemias, including myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphomas, tumor angiogenesis, spinal axis tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinomas, squamous cell carcinomas, T-cell lymphomas, environmentally induced cancers, including those induced by asbestos, and combinations of the above cancers. The pharmaceutical compositions described herein may also be useful in treating metastatic cancers.

[0180] The pharmaceutical compositions described herein can enhance, stimulate, and / or increase the immune response of a subject in need thereof. As used herein, the term "immune response" refers to the action of, for example, lymphocytes, antigen-presenting cells, phagocytes, granulocytes, and soluble macromolecules (including macrocyclic peptides, cytokines, and complement) produced by the above cells or liver to selectively damage, destroy, or eliminate from the body 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 aspects, the immune response can be generated by the innate immune system. In certain aspects, the immune response can be generated by the adaptive immune system. In certain embodiments, the immune response can be generated by the innate immune system and the adaptive immune system.

[0181] The pharmaceutical compositions described herein can be delivered in a number of ways, including but not limited to, orally, subcutaneously, intramuscularly, intraduodenally, or intravenously. As used herein, oral administration includes buccal, lingual, and sublingual administration.

[0182] The compositions are formulated in accordance with accepted pharmaceutical practice (Remington's Pharmaceutical Sciences, 23 rd It can be formulated according to the route of administration in accordance with the Pharmaceuticals and Medical Devices Act (Ed. No. 2013 / 0232369).

[0183] Dosage regimens for the compositions described herein will, of course, vary depending on known factors, such as the species, age, sex, health, medical condition, and weight of the recipient, the nature and extent of the condition, types of concurrent treatments, frequency of treatment, the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disease condition.

[0184] As a general guideline, the daily oral dosage of the active ingredient, when used to obtain the indicated effects, will range from about 0.001 to 500 mg / kg body weight, preferably from about 0.01 to 100 mg / kg body weight, and most preferably from about 0.1 to 20 mg / kg / day. For intravenous administration, the daily dosage of the active ingredient, when used to obtain the indicated effects, will range from 0.001 ng to 100.0 ng / kg body weight per minute during a constant rate infusion. Such constant rate intravenous infusions can be administered at a rate of preferably 0.01 ng to 50 ng / kg body weight per minute and most preferably 0.01 ng to 10.0 mg / kg body weight per minute. The compositions described herein may be administered in a single daily dose, or the total daily dosage may be administered in divided doses two, three, or four times daily. In some embodiments, the present disclosure provides pharmaceutical compositions comprising one or more dosage units.

[0185] biological activity Cyclic peptides can be prepared by methods known to those of skill in the art (see, for example, US Pat. Nos. 9,308,236 and 9,856,292). EXAMPLES

[0186] Example 1 - Topical absorption evaluation of SNAC-based formulations The pharmacokinetics of SNAC-based Compound (II) formulations (prepared according to the procedure described in U.S. Pat. No. 9,856,292) were explored using two different formulations as shown in Table 1.

[0187] [Table 1]

[0188] The study was carried out as a two-treatment, two-area parallel study with four rats in each group in fasted anesthetized male Sprague-Dawley rats (rat weight: approximately 300 g).

[0189] For gastric absorption studies, the subject formulations were administered by oral gavage to rats in which the pylorus was ligated to contain the drug in the gastric compartment.

[0190] For duodenal absorption studies, rats were ligated at the proximal pylorus and the subject formulations were injected directly into the duodenum 5 cm past the pylorus ligation (approximately 15 cm from the pylorus), and the distal portion of the segment was ligated to contain the drug in the intestinal segment.

[0191] Samples of the administered solution were withdrawn from the gastric and duodenal segments at 60 minutes to determine residual drug concentrations.

[0192] As shown in Figure 1 and Table 1, the intestinal compartment provided better systemic absorption of Compound (II) compared to the gastric compartment, with the formulations containing high SNAC and nicotinamide exhibiting over 10-fold higher intestinal exposure compared to the low SNAC and no nicotinamide.

[0193] [Table 2]

[0194] Example 2 - Preparation of Compound (II) Enteric Coated Tablets of 2.5 mg Strength for a 20 mg Dose (8 Tablets Total) The composition of the core tablet is shown in Table 3. Compound (II), SNAC, and nicotinamide were combined in a mortar and blended using a pestle. This mixed blend was then added to a glass bottle along with magnesium stearate and the mixture was blended for 5 minutes using a Turbula mixer (46 RPM, 5 minutes). The final mixture was compressed using a 7 / 32 inch standard circular tableting die at a target weight of 70 mg at 400 lb compression force.

[0195] [Table 3]

[0196] The composition of the seal-coated tablets is shown in Table 4. An aqueous suspension of Opadry 03K was prepared at 7.5% solids. The uncoated core 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 2%. Air volume: 40cfm; Spray rate: 5g / min; Atomization air pressure: 10.8psi; Pattern air pressure: 10.8psi; Inlet temperature: 55℃; Outlet temperature: 40℃; Pan speed: 20~25rpm.

[0197] [Table 4]

[0198] The composition of the enteric coated tablets is shown in Table 5. An aqueous suspension of Acryl EZE II was prepared at 10% solids. Compound (II) seal 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%. For the cynomolgus monkey PK study, four coated tablets were added to each No. 00 gray opaque hard gelatin capsule. Each cynomolgus monkey was administered two capsules (eight coated tablets). Air volume: 45cfm; Spray rate: 5g / min; Atomization air pressure: 10.8psi; Pattern air pressure: 10.8psi; Inlet temperature: 55℃; Outlet temperature: 40℃; Pan speed: 20~25rpm.

[0199] [Table 5]

[0200] Example 3 - Determination of oral absorption of prepared Compound (II) formulations in cynomolgus monkeys Fasted male cynomolgus monkeys (n=3) were administered by oral route, followed by gavage and flushing with water to promote gastrointestinal dissolution. Blood samples were collected at designated time points over 72 hours after dose administration to determine the comparative pharmacokinetics between formulations. Due to the long half-life, this was done in a parallel group design in various different cynomolgus monkey populations. As shown in Figure 7 and Tables 6A and 6B, this formulation provided good Compound (II) concentrations over an extended period of time.

[0201] [Table 6]

[0202] [Table 7]

[0203] Example 4 - Preparation of Compound (II) Enteric Coated Tablets of 3.33 mg Strength for a 20 mg Dose (6 Tablets Total) The composition of the core tablet is shown in Table 7. Compound (II), SNAC, and nicotinamide were combined and blended using a Turbula mixer (46 RPM, 10 minutes). Magnesium stearate was added and the mixture was blended for an additional 5 minutes. The final mixture was compressed using a 9 / 32 inch standard circular tableting die at 700 lb compression force to form tablets with a target weight of 139.2 mg.

[0204] [Table 8]

[0205] The composition of the seal-coated tablets is shown in Table 8. An aqueous suspension of Opadry 03K was prepared at 7.5% solids. The uncoated core 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 2%. Air volume: 40-50cfm; Spray rate: 5g / min; Atomization air pressure: 10.8psi; Pattern air pressure: 10.8psi; Inlet temperature: 55℃; Outlet temperature: 37℃; Pan speed: 20-25rpm.

[0206] [Table 9]

[0207] The composition of the enteric coated tablets is shown in Table 9. An aqueous suspension of Acryl EZE II was prepared at 10% solids. Compound (II) seal-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%. For the dog PK study, three enteric coated tablets were encapsulated into size 00 hard gelatin capsules. Each dog was administered two capsules (six enteric coated tablets). Air volume: 40-50cfm; Spray rate: 5g / min; Atomization air pressure: 10.8psi; Pattern air pressure: 10.8psi; Inlet temperature: 55℃; Outlet temperature: 37℃; Pan speed: 20-25rpm.

[0208] [Table 10]

[0209] Example 5 - Preparation of Compound (II) enteric coated tablets (12 tablets total) of 1.67 mg strength for a 20 mg dose containing a protease inhibitor The composition of the core tablet is shown in Table 10. Compound (II), SNAC, nicotinamide, soybean trypsin inhibitor, and aprotinin were combined and blended. Magnesium stearate was added and the mixture was blended using a Turbula mixer (46 RPM, 5 minutes). The final mixture was compressed using a 7 / 32 inch standard circular tableting die at 400 lb compression force to form tablets with a target weight of 78 mg.

[0210] [Table 11]

[0211] The composition of the seal-coated tablets is shown in Table 11. An aqueous suspension of Opadry 03K was prepared at 7.5% solids. The uncoated core 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 2%. Air volume: 50cfm; Spray rate: 5g / min; Atomization air pressure: 10.8psi; Pattern air pressure: 10.8psi; Inlet temperature: 55℃; Outlet temperature: 37℃; Pan speed: 20~25rpm.

[0212] [Table 12]

[0213] The composition of the enteric coated tablets is shown in Table 12. An aqueous suspension of Acryl EZE II was prepared at 10% solids. Compound (II) seal coated tablets (8 g) and 292 g of 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%. For the dog PK study, six coated tablets were encapsulated into size 00 hard gelatin capsules. Each dog was administered two capsules (12 coated tablets). Air volume: 50cfm; Spray rate: 5g / min; Atomization air pressure: 10.8psi; Pattern air pressure: 10.8psi; Inlet temperature: 55℃; Outlet temperature: 37℃; Pan speed: 20~25rpm.

[0214] [Table 13]

[0215] Example 6 - Preparation of 6.67 mg strength Compound (II) enteric coated tablets (3 tablets total) for a 20 g dose with reduced SNAC The composition of the core tablet is shown in Table 13. Compound (II), SNAC, and nicotinamide were combined and blended using a Turbula mixer (46 RPM, 10 minutes). Magnesium stearate was added and the mixture was blended for an additional 5 minutes. The final mixture was compressed using a 9 / 32 inch standard circular tableting die at 600 lb compression force to form tablets with a target weight of 142.7 mg.

[0216] [Table 14]

[0217] The composition of the seal-coated tablets is shown in Table 14. A clear aqueous suspension of Opadry 03K was prepared at 7.5% solids. The uncoated core 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 2%. Air volume: 45cfm; Spray rate: 5g / min; Atomization air pressure: 10.8psi; Pattern air pressure: 10.8psi; Inlet temperature: 55℃; Outlet temperature: 37℃; Pan speed: 20~25rpm.

[0218] [Table 15]

[0219] The composition of the enteric coated tablets is shown in Table 15. An aqueous suspension of Acryl EZE II was prepared at 10% solids. Compound (II) seal 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%. For the dog PK study, three coated tablets were encapsulated into size 00 hard gelatin capsules. Each dog was administered one capsule (three coated tablets). Air volume: 45cfm; Spray rate: 5g / min; Atomization air pressure: 10.8psi; Pattern air pressure: 10.8psi; Inlet temperature: 55℃; Outlet temperature: 37℃; Pan speed: 20~25rpm.

[0220] [Table 16]

[0221] Example 7 - Determination of oral absorption of prepared Compound (II) formulations in dogs Administration was by oral route to fasted male beagle dogs (n=4) pretreated with pentagastrin, followed by gavage and flushing with water to facilitate gastrointestinal dissolution. Blood samples were collected at designated time points over 72 hours after dose administration to determine comparative pharmacokinetics between formulations. Due to the long half-life, this was done in a parallel group design in various different dog populations. As shown in Figure 3 and Tables 16A and 16B, all three formulations provided good concentrations of Compound (II) over an extended period of time.

[0222] [Table 17]

[0223] [Table 18]

[0224] Example 8 - Preparation of Compound (II) Enteric Coated Tablets of 11.67 mg Strength for a 70 mg Dose (6 Tablets Total) The composition of the core tablet is shown in Table 17. Compound (II), SNAC, and nicotinamide were combined and blended using a Turbula mixer (46 RPM, 10 minutes). Magnesium stearate was added and the mixture was blended for an additional 5 minutes. The final mixture was compressed using a 9 / 32 inch standard circular tableting die at 700 lb compression force to form tablets with a target weight of 147.5 mg.

[0225] [Table 19]

[0226] The composition of the seal-coated tablets is shown in Table 18. An aqueous suspension of Opadry 03K was prepared at 7.5% solids. The uncoated core 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 2%. Air volume: 45cfm; spray rate: 5g / min; atomization air pressure: 12.1psi; pattern air pressure: 10.8psi; inlet temperature: 55°C; outlet temperature: 40°C; pan speed: 23rpm.

[0227] [Table 20]

[0228] The composition of the enteric coated tablets is shown in Table 19. An aqueous suspension of Acryl EZE II was prepared at 10% solids. Compound (II) seal 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%. For the dog PK study, three coated tablets were encapsulated into size 00 hard gelatin capsules. Each dog was administered two capsules (six coated tablets). Air volume: 45cfm; spray rate: 5g / min; atomization air pressure: 12.1psi; pattern air pressure: 10.8psi; inlet temperature: 55°C; outlet temperature: 40°C; pan speed: 28rpm.

[0229] [Table 21]

[0230] Example 9 - Preparation of Compound (II) enteric coated tablets of 5.83 mg strength for a 70 mg dose (12 tablets total) The composition of the core tablet is shown in Table 20. Compound (II), SNAC, and nicotinamide were combined and blended using a Turbula mixer (46 RPM, 10 minutes). Magnesium stearate was added and the mixture was blended for an additional 5 minutes. The final mixture was compressed using a 7 / 32 inch standard circular tableting die at 500 lb compression force to form tablets with a target weight of 73.6 mg.

[0231] [Table 22]

[0232] The composition of the seal-coated tablets is shown in Table 21. An aqueous suspension of Opadry 03K was prepared at 7.5% solids. The uncoated core 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 2%. Air volume: 45cfm; spray rate: 5g / min; atomization air pressure: 11.0psi; pattern air pressure: 11.1psi; inlet temperature: 55°C; outlet temperature: 40°C; pan speed: 20rpm.

[0233] [Table 23]

[0234] The composition of the enteric coated tablets is shown in Table 22. An aqueous suspension of Acryl EZE II was prepared at 10% solids. Compound (II) seal 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%. For the dog PK study, three coated tablets were encapsulated into size 00 hard gelatin capsules. Each dog was administered two capsules (12 coated tablets). Air volume: 45cfm; spray rate: 5g / min; atomization air pressure: 12.1psi; pattern air pressure: 12.0psi; inlet temperature: 55°C; outlet temperature: 40°C; pan speed: 25rpm.

[0235] [Table 24]

[0236] Example 10 - Determination of oral absorption of prepared Compound (II) formulations in dogs Administration was by oral route to fasted male beagle dogs (n=4) pretreated with pentagastrin, followed by gavage and flushing with water to facilitate gastrointestinal dissolution. Blood samples were collected at designated time points over 72 hours after dose administration to determine comparative pharmacokinetics between the formulations. Due to the long half-life, this was done in a parallel group design in various different dog populations. As shown in Figure 8 and Table 23, both formulations provided good concentrations of Compound (II) over an extended period of time.

[0237] [Table 25]

[0238] Example 11 - Preparation of Compound (II) Enteric Coated Tablets of 50 mg Strength for a 100 mg Dose (2 Tablets Total) The composition of the core tablet is shown in Table 24. Compound (II), SNAC, nicotinamide, croscarmellose sodium, silicon dioxide, and microcrystalline cellulose were combined and blended using a bin blender for 250 revolutions at 25 RPM. The blended material was passed through a co-mill equipped with a 32R screen and blended again for 250 revolutions at 25 RPM. Magnesium stearate was added to this mixture and blended for an additional 125 revolutions at 25 RPM to form a preblend. This preblend was roller compacted and milled. The milled granules and extragranular croscarmellose sodium were blended for 250 revolutions at 25 RPM. Extragranular magnesium stearate was added and blended for 125 revolutions at 25 RPM to form the final blend. The final blend was compressed using a standard 0.6030 inch x 0.3140 foot (15.3 mm x 8 mm) oval tableting die to form tablets with a target weight of 500 mg and a hardness of 20 SCU.

[0239] [Table 26]

[0240] [Table 27]

[0241] The tablets were coated in a 4L pan LDCS Hi-Coater with two coats. The first layer was seal coated 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-EZE II aqueous suspension (20% w / w solids) to achieve a target weight gain of 7%. Two tablets were administered to each dog (Table 25).

[0242] Example 12 - Preparation of 10 mg strength Compound (II) enteric coated tablets (total of 10 tablets) for a 100 mg dose The final blends from the above examples were compressed to form tablets with a target weight of 100 mg and a target hardness (harness) of 10 SCU using a 7 / 32 inch (5.55 mm) standard circular tableting die.

[0243] [Table 28]

[0244] The tablets were coated in a 4L pan LDCS Hi-Coater with two coats. The first layer was seal coated 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-EZE II aqueous suspension (20% w / w solids) to achieve a target weight gain of 7%. Five enteric coated tablets were encapsulated in size 00 hard gelatin capsules for the dog PK study. Each dog was administered two capsules (10 enteric coated tablets, Table 26).

[0245] Example 13 - Preparation of Compound (II) enteric coated tablets of 2.5 mg strength for a 100 mg dose (40 tablets total) The composition of the core tablet is shown in Table 27. Compound (II), SNAC, nicotinamide, croscarmellose sodium, silicon dioxide, and microcrystalline cellulose were combined and blended using a bin blender for 250 revolutions at 25 RPM. The blended material was passed through a co-mill equipped with a 32R screen and blended again for 250 revolutions at 25 RPM. Magnesium stearate was added to this mixture and blended for an additional 125 revolutions at 25 RPM to form a preblend. This preblend was roller compacted and milled. The milled granules and extragranular croscarmellose sodium were blended for 250 revolutions at 25 RPM. Extragranular magnesium stearate was added and blended for 125 revolutions at 25 RPM to form the final blend. The final blend was compressed using a 1 / 8 inch (3.175 mm) multi-tip (7 tip) standard circular tableting tool to form tablets with a target weight of 25 mg and a target hardness of 5 SCU.

[0246] [Table 29]

[0247] [Table 30]

[0248] The tablets were coated in a 4L pan LDCS Hi-Coater with two coats. The first layer was seal coated 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-EZE II aqueous suspension (20% w / w solids) to achieve a target weight gain of 10%. Twenty coated tablets were encapsulated in size 00 hard gelatin capsules for the dog PK study. Each dog was administered two capsules (40 coated tablets, Table 28).

[0249] Example 14 - Preparation of Compound (II) Enteric Coated Tablets for a 50 mg Dose with 5 x 10 mg Tablets and 5 x Placebo Tablets The composition of the core tablet is shown in Table 29. SNAC, nicotinamide, croscarmellose sodium, silicon dioxide, and microcrystalline cellulose were combined and blended using a mini V-blender at 28 RPM for 10 minutes. The blended materials were passed through a 20 mesh screen and blended again at 28 RPM for 10 minutes. Magnesium stearate was added to this mixture and blended for an additional 5 minutes at 28 RPM to form a preblend. The preblend was compressed using an 11.28 mm round flat mill to form a compact with a target weight of 400 mg and a target solids content of 0.7. The compact was milled using an oscillator equipped with 4 and 1 mm screens. The milled granules and extragranular croscarmellose sodium were blended at 28 RPM for 10 minutes. The extragranular magnesium stearate was added and blended at 28 RPM for 10 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 100 mg and a target hardness of 10 SCU.

[0250] [Table 31]

[0251] [Table 32]

[0252] The tablets were coated in a 4L pan LDCS Hi-Coater with two coats. The first layer was seal coated 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-EZE II aqueous suspension (20% w / w solids) to achieve a target weight gain of 7%. Five enteric coated tablets were encapsulated in size 00 hard gelatin capsules for the dog PK study. Each dog received one active tablet and one matching placebo capsule (Table 30).

[0253] Example 15 - Preparation of Compound (II) Enteric Coated Tablets of 5 mg Strength for a 50 mg Dose (10 Tablets Total) The composition of the core tablet is shown in Table 31. Compound (II), SNAC, nicotinamide, croscarmellose sodium, silicon dioxide, and microcrystalline cellulose were combined and blended using a mini V-blender at 28 RPM for 10 minutes. The blended material was passed through a 20 mesh screen and blended again at 28 RPM for 10 minutes. Magnesium stearate was added to this mixture and blended for an additional 5 minutes at 28 RPM to form a preblend. The preblend was compressed using an 11.28 mm round flat mill to form a compact with a target weight of 400 mg and a target solids content of 0.7. The compact was milled using an oscillator equipped with 4 and 1 mm screens. The milled granules and extragranular croscarmellose sodium were blended at 28 RPM for 10 minutes. The extragranular magnesium stearate was added and blended at 28 RPM for 10 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 100 mg and a target hardness of 10 SCU.

[0254] [Table 33]

[0255] [Table 34]

[0256] The tablets were coated in a 4L pan LDCS Hi-Coater with two coats. The first layer was seal coated 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-EZE II aqueous suspension (20% w / w solids) to achieve a target weight gain of 7%. Five enteric coated tablets were encapsulated in size 00 hard gelatin capsules for the dog PK study. Each dog was administered two capsules (10 enteric coated tablets, Table 32).

[0257] Example 16 - Determination of oral absorption of prepared Compound (II) formulations in dogs Dogs were administered the following formulations: 2 x 50 mg tablets of 10% API (Example 10, 88.6 mg API potency corrected dose) 10x10mg Tablets of 10% API (Example 11, 88.6mg API Potency Corrected Dose) 5 x 10 mg tablets of 10% API (Example 11, 44.3 mg API post-potency correction dose) and 5 placebo tablets of enhancer only. 10 x 5 mg tablets of 5% API (44.3 mg API potency-adjusted dose) 40 x 2.5 mg tablets of 10% API (Example X, 100 mg potency-adjusted dose)

[0258] As shown in Table 33 and Figures 9 and 10, administering 10 x 10 mg tablets to dogs resulted in higher bioavailability compared to administering 2 x 50 mg tablets. Without being bound by theory, this may be the result of a higher amount of permeation enhancer being available due to increased surface area. Interestingly, however, further increasing the number of tablets to 40 tablets (and decreasing the dose by a factor of X per tablet) resulted in lower bioavailability. Without being bound by theory, this may be due to insufficient local concentration of sarcaprozate sodium for permeation enhancement.

[0259] [Table 35]

[0260] Example 17 - Bioavailability of SNAC Formulations Multiple pharmacokinetic dog studies were conducted with 2-4 arms available for scale-up formulation optimization. Two dose levels, 50 mg and 100 mg, were envisaged for the Phase 1 human study. The results are shown in Table 34.

[0261] [Table 36]

[0262] As shown in Table 34, using a placebo tablet as the source of SNAC resulted in significantly lower bioavailability for the fewer API-containing tablets compared to administering only the API tablet. In addition, 50 mg API and 100 mg API resulted in similar bioavailability.

[0263] It is to be understood that the intention is to use the Detailed Description section to interpret the claims, and not the Summary and Abstract sections, which may set forth one or more, but not all, exemplary aspects of the disclosure as contemplated by the inventors, and thus are not intended to limit the scope of the disclosure and the appended claims in any way.

[0264] The present disclosure has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for convenience of description. Alternative boundaries may be defined so long as the specified functions and relationships thereof are appropriately implemented.

[0265] The foregoing description of specific embodiments will thus fully reveal the general nature of the present disclosure, so that others may easily improve such specific embodiments and / or adapt various applications by applying knowledge within the skill of the art without undue experimentation and without departing from the general concept of the present disclosure. Such adaptations and improvements are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance provided herein. It is to be understood that the phraseology or terminology used herein is for the purpose of description, not limitation, and thus the terminology or terminology used herein should be interpreted in light of the teaching and guidance by those skilled in the art.

[0266] The breadth and scope of the present disclosure should not be limited by any of the exemplary embodiments described above, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. A pharmaceutical composition comprising a bioactive compound, salcaprozate salt, and nicotinamide.

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

3. The pharmaceutical composition according to claim 1 or 2, further comprising one or more protease inhibitors.

4. The pharmaceutical composition according to claim 3, wherein the one or more protease inhibitors comprise one or more trypsin inhibitors.

5. The pharmaceutical composition according to claim 4, wherein one or more trypsin inhibitors are isolated from bovine pancreas, chicken egg white, soybean, or lima bean.

6. The pharmaceutical composition according to claim 3, wherein the one or more protease inhibitors are selected from soybean trypsin inhibitors, aprotinin, lima metrypsin inhibitors, ovomucoid trypsin inhibitors, and combinations thereof.

7. The pharmaceutical composition according to claim 1 or 2, wherein the bioactive compound comprises a cyclic peptide.

8. The pharmaceutical composition according to claim 7, wherein the cyclic peptide comprises 5 to 30 amino acids.

9. The pharmaceutical composition according to claim 7, wherein the cyclic peptide comprises 12 to 16 amino acids.

10. The cyclic peptide is defined by formula (I): 【Chemistry 1】 The compound or its pharmaceutically acceptable salt (In the formula, A is, 【Chemistry 2】 Selected from; During the ceremony, 【Transformation 3】 represents the point of bonding to the carbonyl group, and 【Chemistry 4】 This represents a bond point to the nitrogen atom; n is 0, 1, or 2; m is either 1 or 2; m' is either 0 or 1; z is 0, 1, or 2; w is either 1 or 2; p is 0, 1, or 2; R １４ and R １５ is independently selected from hydrogen and methyl; R ｘ is selected from hydrogen, amino, hydroxy, and methyl; R ｖ These are hydrogen, methyl, or natural amino acid side chains; R ｚ is hydrogen and -C(O)NHR １６ Selected from; R １６ is selected from hydrogen, -CHR １７ C(O)NH ２ -, -CHR １７ C(O)NHCHR １７ C(O)NH ２ -, -CH ２ C(O)NHCH(R １７ )C(O)NHCH(R １７ａ )C(O)NH ２ ; -CH ２ C(O)NHCH(R １７ )CO ２ H; and -(C(R １７ａ ) ２ ) ２ -X'-R ３０ ; and is selected from Each R １７ is hydrogen, -CH ３ ien-CH ２ OH, and -(CH ２ ) ｗ -Triazolyl-X-R ３５ Selected independently from; R ３５ is, -CO ２ H and CH ３ Selected from; Each R １７ａ It is hydrogen and -CH ２ CO ２ Selected independently from H; X' is a chain of 8 to 46 atoms, the atoms selected from carbon and oxygen, and the chain may contain 1, 2, or 3 C(O)NH groups incorporated therein; and the chain is -CO ２ H, -C(O)NH ２ ien-CH ２ C(O)NH ２ , and -CH ２ CO ２ H may be optionally replaced by one or two elements independently selected; R ３０ is, -CO ２ H, -C(O)NR ｗ R ｘ , and -CH ３ Selected from, in the formula, R ｗ and R ｗ’ is hydrogen and C １ ~C ６ R is independently selected from alkyl groups, provided that X' is all carbon. ３０ ha-CH ３ Other than; X is, -(CH) ２ ) ２ CH(CO) ２ H)NHC(O)(CH ２ ) ｆ ; -(CH) ２ CH ２ O) ｇ ; and - (CH ２ CH ２ O) ｇ CH ２ CH ２ NHC(O)CH ２ CH ２ CH(CO) ２ H)NHC(O)(CH ２ ) ｆ Selected from; f is 14, 15, or 16; g is 3, 4, 5, 6, 7, 8, 9, 10, or 11; R １３ These are natural amino acids, unnatural amino acids, -(C(R) １７ａ ) ２ ) ２ -X'-R ３０ , and - (CH ２ ) ｗ -Triazolyl-X-R ３５ Selected from; R １ 、R ２ 、R ３ 、R ４ 、R ５ 、R ６ 、R ７ 、R ８ 、R ９ 、R １０ 、R １１ 、and R １２ is independently selected from natural amino acid side chains and unnatural amino acid side chains or forms a ring with the corresponding vicinal R groups as described below; R ａ 、 R ｃ 、 R ｆ 、 R ｈ 、 R ｉ 、 R ｊ 、 R ｍ 、 and R ｎ are each independently selected from hydrogen and methyl; R ｂ is either hydrogen or methyl, or R ｂ and R ２ Together with the atoms bonded to them, these form rings selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring may be optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R ｄ is either hydrogen or methyl, or R ｄ and R ４ These, together with the atoms bonded to them, can form rings selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring may be optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl; R ｅ is either hydrogen or methyl, or R ｅ and R ５ Together with the atoms bonded to them, these form rings selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring may be optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; R ｇ is either hydrogen or methyl, or R ｇ and R ７ Together with the atoms bonded to them, these can form rings selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring may be optionally substituted with 1 to 4 groups independently selected from amino, benzyl, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, methoxy, isoquinolinyloxy, quinolinyloxy, and tetrazolyl, which may be optionally substituted with a halo group; and the pyrrolidine and piperidine rings may be optionally condensed with a cyclohexyl, phenyl, or indole group; and R ｋ is either hydrogen or methyl, or R ｋ and R １１ together with the atoms bonded to them, are selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring may be optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; and R Ｌ is methyl, or R Ｌ and R １２ The pharmaceutical composition according to claim 7, wherein the atoms bonded thereto, together with the atoms, form a ring selected from azetidine and pyrrolidine, where each ring may be optionally substituted with 1 to 4 atoms independently selected from amino, cyano, methyl, halo, and hydroxyl.

11. The cyclic peptide is a compound of formula (II): 【Transformation 5】 The pharmaceutical composition according to claim 10, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 1 or 2, wherein the bioactive compound is present in an amount of about 0.1% (w / w) to about 50% (w / w).

13. The pharmaceutical composition according to claim 1 or 2, wherein the salcaprozate salt is present in an amount of about 30% (w / w) to about 95% (w / w).

14. The pharmaceutical composition according to claim 1 or 2, wherein the bioactive compound and the salcaprozate salt are present in a w / w ratio of about 0.02 to about 1.

5.

15. The pharmaceutical composition according to claim 1 or 2, wherein the nicotinamide is present in an amount of about 5% (w / w) to about 60% (w / w).

16. (a) Cyclic peptides; (b) Salcaprozate sodium in concentrations of approximately 45% (w / w) to approximately 80% (w / w); and (c) Nicotinamide at a concentration of approximately 15% (w / w) to approximately 30% (w / w) A pharmaceutical composition containing the following:

17. (a) Cyclic peptides; (b) Salcaprozate sodium at concentrations of approximately 45% (w / w) to approximately 80% (w / w); (c) Nicotinamide in concentrations of approximately 15% (w / w) to approximately 30% (w / w); and (d) Protease inhibitors at concentrations of approximately 1% (w / w) and approximately 20% (w / w) A pharmaceutical composition containing the following:

18. The cyclic peptide is a compound of formula (II): 【Transformation 6】 The pharmaceutical composition according to claim 16 or 17, or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to claim 18, wherein the cyclic peptide is present in an amount of about 1% (w / w) to about 40% (w / w).

20. A method for improving the oral bioavailability of a target bioactive compound that requires improved oral bioavailability, comprising formulating the bioactive compound together with a salcaprozate salt and nicotinamide.

21. The method according to claim 20, wherein the formulated bioactive compound exhibits improved oral bioavailability compared to the bioactive compound that does not contain salcaprozate salt and nicotinamide.

22. The method according to claim 20 or 21, wherein the salcaprozate salt is salcaprozate sodium.

23. The method according to claim 20 or 21, wherein the bioactive compound is a cyclic peptide.

24. The cyclic peptide is a compound of formula (II): 【Transformation 7】 The method according to claim 23, or a pharmaceutically acceptable salt thereof.

25. Compound of formula (II): 【Transformation 8】 or a pharmaceutically acceptable salt thereof; A composition comprising sodium salcaprozate and nicotinamide, wherein the sodium salcaprozate and nicotinamide provide oral bioavailability of >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%.

26. Compound of formula (II): 【Chemistry 9】 Or an oral composition comprising a pharmaceutically acceptable salt thereof, sodium salcaprozate, and nicotinamide, wherein the oral bioavailability of the compound of formula (II) is >0.3%, >0.4%, >0.5%, >0.6%, >0.7%, >0.8%, >0.9%, >1.0%, >1.1%, >1.2%, >1.3%, >1.4%, >1.5%, >1.6%, >1.7%, >1.8%, >1.9%, >2.0%, >2.1%, >2.2%, >2.3%, >2.4%, or >2.5%.

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