Somatostatin Regulator Preparations

Abstract

A spray-dried solid dispersion comprising (a) 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically acceptable polymer, wherein the API is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer. A tablet comprising the spray-dried solid dispersion and one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, and one or more glidants. The tablet is for use in treating acromegaly or neuroendocrine tumors, or both, in humans by oral administration.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 076,024, filed September 9, 2020, which is incorporated herein by reference in its entirety.

[0002] Described herein are pharmaceutical compositions and medicaments that include somatostatin modulators, methods of making such pharmaceutical compositions and medicaments, and methods of using such pharmaceutical compositions and medicaments to treat conditions, diseases, or disorders that would benefit from modulating somatostatin activity. [Background technology]

[0003] Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation through interaction with G protein-coupled somatostatin receptors and inhibition of the release of multiple secondary hormones. Six subtypes of somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5) have been identified, which are encoded by five different somatostatin receptor genes. Modulation of specific subtypes of somatostatin receptors or combinations thereof is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity. Summary of the Invention

[0004] In one aspect, provided herein is a spray-dried solid dispersion, the spray-dried solid dispersion comprising: (a) 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof; and (b) a pharmaceutically acceptable polymer, wherein the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer has a high glass transition temperature (Tg). In some embodiments, the pharmaceutically acceptable polymer comprises a polymer of cellulose, vinyl alcohol, vinyl acetate, propylene glycol, pyrrolidone, vinylpyrrolidone, oxyethylene, oxypropylene, methacrylic acid, methyl methacrylate, ethylene glycol, ethylene glycol glyceride, ethylene oxide, propylene oxide, 2-ethyl-2-oxazoline, maleic acid, methyl vinyl ether, vinyl caprolactam, or combinations thereof, optionally functionalized with any combination of alkyl ethers, alkyl esters, phthalate esters.

[0005] In some embodiments, the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), copolymers of methacrylic acid and methyl methacrylate, polyethylene glycol glycerides composed of mono-, di-, and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropyl cellulose, copolymers of ethylene oxide and propylene oxide blocks, poly(2-ethyl-2-oxazoline), poly(maleic acid / methyl vinyl ether), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide / propylene oxide tetrafunctional block copolymer, d-alpha tocopheryl polyethylene glycol 1000 succinate, or combinations thereof. In some embodiments, the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA). In some embodiments, the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate grade M (HPMCAS-M). In some embodiments, the pharmaceutically acceptable polymer is polyvinylpyrrolidone polyvinyl acetate copolymer in a 6:4 ratio (PVP / VA64).

[0006] In some embodiments, the weight ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof to the pharmaceutically acceptable polymer is about 1:10 to about 10: 1. In some embodiments, the weight ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof to the pharmaceutically acceptable polymer is about 1:1 to about 1:10. In some embodiments, the weight ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof to the pharmaceutically acceptable polymer is about 1:4 to about 1:6. In some embodiments, the weight ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof to the pharmaceutically acceptable polymer is about 1:1.5 to about 1:6.

[0007] In some embodiments, the spray-dried solid dispersion comprises at least about 5% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least about 10% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least about 15% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof.

[0008] In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent. In some embodiments, the non-aqueous solvent is selected from the group consisting of tert-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, and mixtures thereof. In some embodiments, the non-aqueous solvent is selected from the group consisting of methanol, acetone, and mixtures thereof. In some embodiments, the non-aqueous solvent is methanol.

[0009] In some embodiments, the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof is substantially amorphous.

[0010] In some embodiments, the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof is 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof.

[0011] In another aspect, provided herein is a tablet comprising a spray-dried solid dispersion as described herein and one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants, and optionally one or more film coatings.

[0012] In another aspect, provided herein is a tablet comprising 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, and one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants, and optionally one or more film coating agents. In some embodiments, the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer is a spray-dried solid dispersion as described herein. In some embodiments, the one or more pharmaceutically acceptable ingredients include microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the one or more pharmaceutically acceptable ingredients include microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, colloidal silicon dioxide, and magnesium stearate.

[0013] In some embodiments, the tablet contains about 2% to about 20% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof. In some embodiments, the tablet contains about 2% to about 15% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof. In some embodiments, the tablet contains about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof. In some embodiments, the tablet contains about 10% to about 30% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer. In some embodiments, the tablet contains about 20% to about 35% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer.

[0014] In some embodiments, the tablet comprises about 2% to about 10% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in about 10% to about 30% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer; about 40% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, and one or more glidants; and optionally, less than about 5% by weight of one or more film coating agents.

[0015] In some embodiments, the tablet comprises about 2% to about 10% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in about 10% to about 35% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer; about 40% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, and one or more glidants; and optionally, less than about 5% by weight of one or more film coating agents.

[0016] In some embodiments, the tablet comprises about 20% to about 40% by weight of a spray-dried dispersion of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegration aids, one or more lubricants, and one or more glidants; and optionally, less than about 5% by weight of one or more film coating agents.

[0017] In some embodiments, the spray-dried dispersion has a ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) of about 15 / 85 to about 35 / 65.

[0018] In some embodiments, the tablet comprises about 20% to about 35% by weight spray-dried dispersion of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, wherein the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof and the hydroxypropyl methylcellulose acetate are dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer. The spray-dried dispersion comprises a polymer matrix of polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) in a ratio of about 15 / 85 to about 35 / 65, about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, silicon dioxide, and magnesium stearate, and optionally less than about 5% by weight of one or more film coating agents.

[0019] In some embodiments, the tablet is a spray-dried dispersion of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, The spray-dried dispersion comprises a ratio of about 15 / 85 or about 35 / 65 of [5-difluoro-phenyl-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA), and about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegration aids, one or more lubricants, and one or more glidants, and optionally about 5% by weight of one or more film coating agents.

[0020] In some embodiments, the tablet comprises about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, wherein the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof is dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer. The spray-dried dispersion comprises a ratio of about 15 / 85 or about 35 / 65 of hydroxy-benzonitrile monohydrochloride or a solvate thereof to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA), about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, silicon dioxide, and magnesium stearate, and optionally less than about 5% by weight of one or more film coating agents.

[0021] In some embodiments, the tablet contains about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 60 mg, or about 80 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof. In some embodiments, the tablet contains about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof.

[0022] In some embodiments, the tablet contains about 10 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof. In some embodiments, the tablet contains about 20 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof. In some embodiments, the tablet contains about 30 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof. In some embodiments, the tablet contains about 40 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof. In some embodiments, the tablet contains about 50 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof. In some embodiments, the tablet contains about 60 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof.

[0023] In one aspect, described herein is a method of treating acromegaly or neuroendocrine tumors, or both, in a human, the method comprising orally administering to a human having acromegaly or a neuroendocrine tumor any one of the spray-dried dispersion tablets described herein.

[0024] In some embodiments, the tablet is administered once daily. In some embodiments, the tablet is administered at least 30 minutes before a meal. In some embodiments, the tablet is administered at least 60 minutes before a meal. In some embodiments, the tablet is administered in an empty stomach with a glass of water at least 30 minutes before a meal. In some embodiments, the bioavailability of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof from the tablet is not substantially affected by the co-administration of a proton pump inhibitor, a histamine H2 receptor antagonist, or an antacid.

[0025] Other features and advantages of the compositions, compounds, and methods described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. [Brief explanation of the drawings]

[0026] [Figure 1] 1 illustrates the dose proportionality observed in humans administered HMG capsule or SDD tablet formulations of Compound A-HCl. [Figure 2] 1 illustrates the performance of HMG capsule and SDD tablet formulations of Compound A-HCl in dogs with and without pentagastrin pretreatment. DETAILED DESCRIPTION OF THE INVENTION

[0027] Somatostatin (SST), also known as somatotropin release-inhibiting factor (SRIF), was first isolated as a 14-amino acid peptide from ovine hypothalamii (Brazeau et al., Science 179, 77-79, 1973). An N-terminally extended 28-amino acid peptide with similar biological activity to the 14-amino acid somatostatin was subsequently isolated (Pradayrol et al., FEBS Letters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA, 77, 6827-6831, 1980). SST is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SST acts via both endocrine and paracrine pathways to affect its target cells. Many of these effects involve the inhibition of secretion of other hormones, most notably growth hormone (GH). They are produced by a wide variety of cell types in the central nervous system (CNS) and intestine and have multiple functions, including regulating the secretion of growth hormone (GH), insulin, glucagon, and many other hormones that are antiproliferative.

[0028] These pleiotropic actions of somatostatin are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5). The six somatostatin receptor proteins are encoded by five distinct somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16, 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405, 1997). All receptors are members of the class A subgroup of the G protein-coupled receptor (GPCR) superfamily. The SSTR2A receptor is the most widely expressed subtype in human tumors and is the primary receptor that inhibits GH secretion. Unless otherwise specified, the term SSTR2 refers to SSTR2a.

[0029] It is possible to selectively modulate any one of the somatostatin receptor subtypes, or a combination thereof. In some embodiments, selective modulation of any one of the somatostatin receptor subtypes relative to other somatostatin receptor subtypes, or a combination thereof, is useful in various clinical applications. In some embodiments, selective modulation of any one of the somatostatin receptor subtypes relative to other somatostatin receptor subtypes reduces undesirable side effects in various clinical applications.

[0030] For example, modulation of SSTR2 activity mediates inhibition of growth hormone (GH) release from the anterior pituitary gland and glucagon release from the pancreas. SSTR2 is also involved in many other biological functions, including, but not limited to, cell proliferation, nociception, inflammation, and angiogenesis. In some embodiments, selective SSTR2 modulators are used to treat acromegaly, enteric neuroendocrine tumors, pain, neuropathy, nephropathy, and inflammation, as well as retinopathies resulting from abnormal blood vessel growth. In some other embodiments, selective SSTR2 modulators are used to treat, among other conditions, arthritis, pain, cancer, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, Cushing's disease, acute lung injury, acute respiratory distress syndrome, and ophthalmological diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, and Graves' ophthalmology.

[0031] In some embodiments, SSTR3 agonists inhibit insulin secretion. In some embodiments, SSTR4 agonists exhibit anti-inflammatory and anti-nociceptive effects. In some embodiments, SSTR5 agonists inhibit insulin secretion. In addition, SSTR5 is involved in regulating growth hormone release.

[0032] Somatostatin peptides and their receptor subtypes are widely expressed in the brain, and their disruption or reduction in activity may be involved in some psychiatric and neurodegenerative diseases.For example, the concentration of somatostatin in the brain cortex and hippocampus is reduced in schizophrenia, and one of the most consistent neuropathological findings in this patient group is the loss of somatostatin-expressing cortical inhibitory interneurons.Somatostatin is also highly expressed in brain regions associated with seizures, suggesting that it plays an important role in epilepsy.Somatostatin levels are reduced in the hippocampus of Alzheimer's disease and Parkinson's disease patients, suggesting the restoration of its signal transduction as a potential drug target for neurodegeneration.

[0033] In one aspect, the compound 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof is a selective non-peptide SST2-biased agonist suitable for oral administration to a mammal in need of treatment with a somatostatin modulator.

[0034] In some embodiments, the somatostatin receptor modulators described herein are useful across a wide range of therapeutic applications. In some embodiments, the somatostatin receptor modulators described herein are used to treat a variety of diseases or conditions, including, but not limited to, acromegaly, neuroendocrine tumors, retinopathies and other eye disorders, neuropathy, nephropathy, respiratory diseases, cancer, pain, neurodegenerative diseases, inflammatory diseases, and psychiatric and neurodegenerative disorders. In some embodiments, the somatostatin receptor modulators described herein are used to treat acromegaly, neuroendocrine tumors, or both in a mammal. In some embodiments, the somatostatin receptor modulators described herein are used to treat acromegaly in a mammal. In some embodiments, the somatostatin receptor modulators described herein are used to treat neuroendocrine tumors.

[0035] In some embodiments, somatostatin receptor modulators described herein inhibit the secretion of various hormones and nutrients in mammals. In some embodiments, somatostatin receptor modulators described herein are used to suppress certain endocrine secretions, including, but not limited to, GH, insulin, glucagon, and prolactin. Suppression of certain endocrine secretions is useful for treating disorders such as acromegaly, endocrine tumors such as carcinoids, VIPomas, insulinomas, and glucagonomas, or diabetes and diabetes-related pathologies, including retinopathy, neuropathy, and nephropathy. In some embodiments, somatostatin receptor modulators described herein are used to suppress exocrine secretions in the pancreas, stomach, and intestine for the treatment of disorders such as pancreatitis, fistulas, bleeding ulcers, and diarrhea associated with diseases such as AIDS or cholera. Disorders involving the autocrine or paracrine production of nutrients such as IGF-1 (and some endocrine factors) that can be treated by administration of the compounds described herein include cancers of the breast, prostate, and lung (both small cell epidermoid and non-small cell epidermoid), as well as hepatoma, neuroblastoma, colon and pancreatic adenocarcinoma (ductal type), chondrosarcoma, and melanoma, diabetic retinopathy, and atherosclerosis associated with restenosis after vascular graft and angioplasty.

[0036] In some embodiments, somatostatin receptor modulators described herein are used to inhibit mediators of neurogenic inflammation (e.g., substance P or tachykinins) and may be used to treat rheumatoid arthritis; psoriasis; local inflammation such as that associated with photodermatitis, eczema, or other sources of pruritus; inflammatory bowel disease; irritable bowel syndrome; and allergies, including asthma and other respiratory diseases. In some other embodiments, somatostatin receptor modulators described herein function as neuromodulators in the central nervous system and are useful in the treatment of Alzheimer's disease and other forms of dementia, pain, and headaches. In some embodiments, somatostatin receptor modulators described herein provide cytoprotection in disorders involving splanchnic blood flow, including liver cirrhosis and esophageal varices.

[0037] Compound A is a somatostatin modulator useful in the methods of treatment described herein.

[0038] Compound A As used herein, Compound A refers to 3-(4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl)-2-hydroxy-benzonitrile, having the chemical structure shown below.

[0039] [ka]

[0040] Compound A is a selective, non-peptide SST2-biased agonist. In clinical trials, Compound A has demonstrated an estimated bioavailability of about 70% and an observed half-life of about 42 to about 50 hours. In some embodiments, Compound A is used to treat acromegaly, neuroendocrine tumors, or both. In some embodiments, Compound A is used to treat acromegaly. In some embodiments, Compound A is used to treat neuroendocrine tumors.

[0041] In some embodiments, the free base form of Compound A is incorporated into the formulations described herein. In some embodiments, Compound A is incorporated into the formulations described herein as a pharmaceutically acceptable salt. In some embodiments, Compound A is incorporated into the formulations described herein as a pharmaceutically acceptable solvate.

[0042] "Pharmaceutically acceptable," as used herein, refers to a material, such as a carrier or diluent, that does not destroy the biological activity or properties of the compound and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0043] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are useful in solid dosage forms because they are typically more soluble and dissolve more rapidly in gastric and intestinal fluids than non-ionic species. Furthermore, their solubility is often a function of pH, allowing for selective dissolution in one or another part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Also, salt-forming molecules can be in equilibrium in a neutral form, allowing for controlled passage through biological membranes.

[0044] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with an acid. In some embodiments, a compound disclosed herein (i.e., in free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), These include, but are not limited to, gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0045] In some embodiments, Compound A is incorporated into the formulations described herein as a pharmaceutically acceptable salt form selected from Compound A hydrochloride and Compound A methanesulfonate. In some embodiments, the salt form of Compound A is Compound A monohydrochloride. In some embodiments, the salt form of Compound A is Compound A dihydrochloride. In some embodiments, the salt form of Compound A is Compound A monomethanesulfonate. In some embodiments, the salt form of Compound A is Compound A dimethanesulfonate.

[0046] In one embodiment, Compound A monohydrochloride (Compound A-HCl) is incorporated into the pharmaceutical compositions described herein. Compound A monohydrochloride (Compound A-HCl), also known as 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, has the following structure:

[0047] [ka]

[0048] In some embodiments, the salt form of Compound A is amorphous. In some embodiments, Compound A monohydrochloride is amorphous.

[0049] In some embodiments, the salt form of Compound A is crystalline. In some embodiments, Compound A monohydrochloride is crystalline.

[0050] It should be understood that reference to a pharmaceutically acceptable salt includes solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are formed during the crystallization process using a pharmaceutically acceptable solvent, such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated and solvated forms.

[0051] Therapeutic drugs that can be administered to mammals, such as humans, must be prepared according to regulatory guidelines. These government regulatory guidelines are referred to as Good Manufacturing Practices (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvent in the final product. Preferred solvents are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3)" (November 2005).

[0052] Solvents are divided into three classes: Class 1 solvents are toxic and should be avoided; Class 2 solvents are solvents whose use is restricted during the manufacture of therapeutic drugs; and Class 3 solvents are solvents with low toxicity potential and low risk to human health. Data on Class 3 solvents show low toxicity in acute or short-term studies and negative genotoxicity tests.

[0053] Class 1 solvents to avoid include benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0054] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0055] Class 3 solvents, which possess low toxicity, include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0056] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacturing of the APIs. In most cases, the solvents are not completely removed by practical manufacturing techniques. The appropriate selection of solvents for API synthesis can enhance yield or determine properties such as crystalline morphology, purity, and solubility. Therefore, the solvent is an important parameter in the synthesis process.

[0057] In some embodiments, the composition comprising Compound A-HCl comprises a residual amount of an organic solvent. In some embodiments, the composition comprising Compound A-HCl comprises a residual amount of a Class 2 or Class 3 solvent. In some embodiments, the composition comprising Compound A-HCl comprises a residual amount of a solvent selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, methanol, acetone, dimethylformamide, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, and ethanol.

[0058] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0059] The term "modulate," as used herein, means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0060] The term "modulator," as used herein, refers to a molecule that interacts directly or indirectly with a target. The interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0061] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes of administration. Those of skill in the art are familiar with administration techniques that can be used in conjunction with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0062] Terms such as "co-administration," as used herein, are intended to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0063] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated. Results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the quantity of a composition comprising a compound disclosed herein that is required to result in a clinically meaningful reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques such as a dose escalation study.

[0064] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0065] The term "pharmaceutical combination," as used herein, refers to a product resulting from the mixing or combining of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a concomitant drug are both administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a concomitant drug are administered to a patient as separate entities simultaneously, concurrently, or sequentially with no specific intervening time limit, such that such administration results in effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0066] The terms "article of manufacture" and "kit" are used synonymously.

[0067] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other ape and simian species; livestock animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0068] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating symptoms caused by a disease or condition, or arresting the symptoms of a disease or condition prophylactically and / or therapeutically.

[0069] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into preparations used in pharmacy. Appropriate formulation depends on the selected route of administration. Overviews of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosures.

[0070] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be carried out by any method that allows delivery of the compound to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient.

[0071] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, or as a powder or granules.

[0072] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in a dosage suitable for such administration. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty acid, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets for identification or to characterize different combinations of active compound doses.

[0073] Conventional techniques for producing solid oral dosage forms include, but are not limited to, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, or (5) wet granulation. See, e.g., Lachman et al., *The Theory and Practice of Industrial Pharmacy* (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Worcester coating), tangential coating, top spraying, tableting, extrusion, etc.

[0074] It will be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

[0075] Provided herein is a tablet comprising Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises Compound A-HCl or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants, and optionally one or more film coating agents.

[0076] In some embodiments, described herein is a spray-dried solid dispersion comprising: (a) Compound A-HCl or a solvate thereof; and (b) a pharmaceutically acceptable polymer, wherein the Compound A-HCl or a solvate thereof is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer.

[0077] Described herein, in some embodiments, are tablets prepared using the spray-dried solid dispersions described herein.

[0078] Spray-dried solid dispersion (SDD) The amorphous state of most small molecule drugs is thermodynamically unstable and kinetically unstable unless the glass transition temperature (Tg) is sufficiently high. However, the amorphous state can be stabilized by dilution of the drug in an excipient matrix. When amorphous molecules are dispersed in a high-Tg matrix, the low molecular mobility provides a diffusion barrier that inhibits the molecular mobility required for phase separation during storage. Phase separation into drug-rich domains is a precursor to crystal nucleation, ultimately leading to extensive crystallization and loss of the solubility advantage. In some embodiments, pharmaceutically acceptable polymers for use in preparing spray-dried solid dispersions are polymers with high Tg. When the active pharmaceutical ingredient (API) and excipients are thermodynamically immiscible with each other in the solid state, spray-dried dispersions (SDDs) are formulated so that the resulting Tg of the mixture, including absorbed water, is at least 10°C to 20°C greater than typical storage conditions. Additionally, moisture uptake during storage must be considered by choosing either a non-hygroscopic polymer or packaging format, as absorbed water plasticizes the dispersion and lowers the Tg.

[0079] In some embodiments, Compound A-HCl or a solvate thereof in the spray-dried solid dispersions described herein is substantially amorphous.

[0080] In some embodiments, the pharmaceutically acceptable polymer comprises a polymer of cellulose, vinyl alcohol, vinyl acetate, propylene glycol, pyrrolidone, vinylpyrrolidone, oxyethylene, oxypropylene, methacrylic acid, methyl methacrylate, ethylene glycol, ethylene glycol glyceride, ethylene oxide, propylene oxide, 2-ethyl-2-oxazoline, maleic acid, methyl vinyl ether, vinyl caprolactam, or combinations thereof, optionally functionalized with any combination of alkyl ethers, alkyl esters, phthalate esters.

[0081] In some embodiments, the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, cellulose acetate methacrylic acid and methyl methacrylate copolymers, polyethylene glycol glycerides composed of mono-, di-, and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropyl cellulose, copolymers of ethylene oxide and propylene oxide blocks, poly(2-ethyl-2-oxazoline), poly(maleic acid / methyl vinyl ether), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide / propylene oxide tetrafunctional block copolymer, d-alpha tocopheryl polyethylene glycol 1000 succinate, or combinations thereof.

[0082] In some embodiments, the spray-dried dispersion further comprises a dispersion polymer selected from hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (hydroxypropyl methylcellulose acetate succinate; HPMCAS, e.g., HPMCAS-H, HPMCAS-L, or HPMCAS-M), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP / VA), polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof.

[0083] HPMCAS is a cellulosic polymer with four semi-randomly hydroxyl-substituted groups: methoxy, hydroxypropyloxy, acetate, and succinate. The polymer is available in three grades: L, M, and H, based on the weight percent content of acetyl and succinoyl groups in the HPMCAS molecule. Grade L: 5-9 weight percent acetate, 14-18 weight percent succinate, 20-24 weight percent methoxy, and 5-9 weight percent hydroxypropyloxy. Grade M: 7-11 weight percent acetate, 10-14 weight percent succinate, 21-25 weight percent methoxy, and 5-9 weight percent hydroxypropyloxy. Grade H: 10-14 weight percent acetate, 4-8 weight percent succinate, 22-26 weight percent methoxy, and 6-10 weight percent hydroxypropyloxy.

[0084] In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit L100-55, poly(methacrylic acid-co-methyl methacrylate) (PMMAMA, or trade name Eudragit L100), Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55, and Soluplus.

[0085] In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / VA 64 and HPMCAS-M. In some embodiments, the pharmaceutically acceptable polymer is PVP / VA 64. In some embodiments, the pharmaceutically acceptable polymer is HPMCAS-M.

[0086] In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:10 to about 10:1. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:1 to about 1:10. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:3 to about 1:8. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:4 to about 1:7. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:4 to about 1:6. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:5 to about 1:6. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:10. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:9. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:8. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:7. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:6. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:5. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:4. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:3. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:2. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:1.

[0087] In some embodiments, the spray-dried solid dispersion comprises at least 5% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 10% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 15% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 20% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 25% by weight of Compound A-HCl or a solvate thereof. The % amounts are calculated based on the free base, i.e., Compound A.

[0088] In some embodiments, the spray-dried solid dispersion comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 15% Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 35% Compound A-HCl or a solvate thereof. The % amount is calculated based on the free base, i.e., Compound A.

[0089] In some embodiments, the spray-dried solid dispersion comprises about 5% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 6% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 7% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 8% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 9% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 10% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 11% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 12% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 13% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 14% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 15% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 16% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 17% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 18% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 19% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 20% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 21% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 22% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 23% by weight of Compound A-HCl or a solvate thereof.In some embodiments, the spray-dried solid dispersion comprises about 24% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 25% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 25% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 27% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 28% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 29% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 30% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 31% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 32% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 33% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 34% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 35% by weight of Compound A-HCl or a solvate thereof. The % amounts are calculated based on the free base, i.e., Compound A.

[0090] In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent. In some embodiments, the non-aqueous solvent is present in a detectable amount. In some embodiments, the spray-dried solid dispersion is free of a non-aqueous solvent.

[0091] In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent selected from the group consisting of tert-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, and mixtures thereof. In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent selected from the group consisting of methanol, acetone, and mixtures thereof. In some embodiments, the spray-dried solid dispersion further comprises methanol.

[0092] tablet In one aspect, described herein is a tablet comprising Compound A-HCl or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants, and optionally one or more film coatings.

[0093] In some embodiments, Compound A-HCl or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer is a spray-dried solid dispersion described herein.

[0094] In some embodiments, the tablet comprises about 2% to about 20% by weight of Compound A-HCl or a solvate thereof, hi some embodiments, the tablet comprises about 2% to about 15% by weight of Compound A-HCl or a solvate thereof.

[0095] In some embodiments, the tablet comprises about 10% to about 30% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer, hi some embodiments, the tablet comprises about 20% to about 35% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer.

[0096] In some embodiments, the tablet comprises about 2% to about 10% by weight of Compound A-HCl or a solvate thereof dispersed in about 10% to about 30% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer.

[0097] In some embodiments, the tablet comprises about 2% to about 10% by weight of compound A-HCl or a solvate thereof dispersed in about 10% to about 30% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer; about 40% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, and one or more glidants; and optionally, less than about 5% by weight of one or more film coating agents.

[0098] In some embodiments, additional excipients in the tablet, in addition to the spray-dried solid dispersion, include one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants, or any combination thereof. In some embodiments, additional excipients in the tablet, in addition to the spray-dried solid dispersion, include microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate.

[0099] In some embodiments, the tablet comprises one or more fillers / binders / diluents selected from celluloses (such as microcrystalline cellulose, carboxymethylcellulose, ethylcellulose, and methylcellulose), starch, gelatin, sugars (such as sucrose, glucose, dextrose, mannitol, and lactose), natural and synthetic gums (such as acacia, sodium alginate, panwar gum, and ghatti gum), polyvinylpyrrolidinone, polyethylene glycol, waxes, and any combination thereof. In some embodiments, the tablet comprises microcrystalline cellulose and mannitol.

[0100] In some embodiments, one or more fillers / binders / diluents in a tablet described herein comprise about 20% to about 80% by weight of the total tablet weight. In some embodiments, one or more fillers / binders / diluents in a tablet described herein comprise about 40% to about 65% by weight of the total tablet weight. In some embodiments, one or more fillers / binders / diluents in a tablet described herein comprise about 50% to about 65% by weight of the total tablet weight. In some embodiments, one or more fillers / binders / diluents in a tablet described herein comprise about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weight of the total tablet weight. In some embodiments, one or more fillers / binders / diluents in a tablet described herein comprise about 58% by weight of the total tablet weight. In some embodiments, less than 70%, less than 65%, less than 60%, less than 55%, or less than 50% by weight of the total tablet weight comprises one or more fillers / binders / diluents. In some embodiments, less than 60% by weight of the total tablet weight comprises one or more fillers / binders / diluents.

[0101] In some embodiments, the tablet comprises one or more disintegrants selected from croscarmellose sodium, crospovidone, sodium starch glycolate, veegum HV, methylcellulose, agar, bentonite, cellulose, carboxymethylcellulose, and any combination thereof. In some embodiments, the tablet comprises crospovidone.

[0102] In some embodiments, one or more disintegrants in the tablets described herein comprise about 2% to about 30% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein comprise about 5% to about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein comprise about 10% to about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein comprise about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein comprise about 15% by weight of the total tablet weight. In some embodiments, less than 20% by weight of the total tablet weight comprises one or more disintegrants.

[0103] In some embodiments, the tablet comprises one or more lubricants selected from talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, and any combination thereof. In some embodiments, the tablet comprises magnesium stearate.

[0104] In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1% to about 5% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1% to about 2% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1% to about 1% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.5% by weight of the total tablet weight. In some embodiments, less than 2% by weight of the total tablet weight comprises one or more lubricants. In some embodiments, less than 1% by weight of the total tablet weight comprises one or more lubricants.

[0105] In some embodiments, the tablet contains one or more lubricants. A lubricant is a substance added to a powder to improve its flowability. Examples of lubricants include magnesium stearate, colloidal silicon dioxide, starch, and talc. In some embodiments, the tablet contains colloidal silicon dioxide.

[0106] In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1% to about 5% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1% to about 2% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.5% to about 1.5% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1 weight percent, about 0.2 weight percent, about 0.3 weight percent, about 0.4 weight percent, about 0.5 weight percent, about 0.6 weight percent, about 0.7 weight percent, about 0.8 weight percent, about 0.9 weight percent, about 1 weight percent, about 1.1 weight percent, about 1.2 weight percent, about 1.3 weight percent, about 1.4 weight percent, about 1.5 weight percent, about 1.6 weight percent, about 1.7 weight percent, about 1.8 weight percent, about 1.9 weight percent, or about 2 weight percent of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 1 weight percent of the total tablet weight. In some embodiments, less than 2 weight percent of the total tablet weight comprises one or more lubricants. In some embodiments, less than 1.5 weight percent of the total tablet weight comprises one or more lubricants.

[0107] Additional excipients In some embodiments, the tablets described herein contain additional excipients, including but not limited to buffering agents, lubricants, preservatives, and coloring agents. Additional excipients such as bulking agents, tonicity agents, and chelating agents are within the scope of this embodiment.

[0108] Non-limiting examples of buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitate, a mixture of an amino acid and a buffering agent, a mixture of an aluminum glycinate and a buffering agent, a mixture of an acid salt of an amino acid and a buffering agent, and a mixture of an alkali salt of an amino acid and a buffering agent. Additional buffering agents include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0109] In some embodiments, the tablets described herein contain a preservative. Preservatives include antimicrobial agents, antioxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium disulfite, sodium sulfite, parabens (methyl-, ethyl-, butyl-), benzoic acid, potassium sorbate, vanillin, and the like.

[0110] In some embodiments, the tablets described herein contain a coloring agent for identification of the resulting liquid form and / or for aesthetic purposes. Suitable coloring agents include, by way of example, FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide, and mixtures thereof.

[0111] Additional excipients are contemplated in tablet embodiments. These additional excipients are selected based on function and compatibility with the tablet compositions described herein and can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, PA: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975), Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, NY: Marcel Decker 1980), and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entireties.

[0112] In a further embodiment, the tablets described herein are coated tablets, such as enteric coated tablets, sugar coated tablets, or film coated tablets.

[0113] In one embodiment, the individual unit doses also include a film coating that disintegrates upon oral ingestion or upon contact with diluent. In one embodiment, these formulations are manufactured by conventional techniques.

[0114] Compressed tablets are solid dosage forms prepared by compressing the bulk blend formulation described above. In various embodiments, compressed tablets designed to dissolve in the mouth contain one or more flavoring agents. In other embodiments, compressed tablets will contain a film surrounding the final compressed tablet. In some embodiments, the film coating aids in patient compliance (e.g., Opadry® coating or sugar coating). Film coatings, including Opadry®, typically range from about 1% to about 5% of the tablet weight. In other embodiments, compressed tablets contain one or more excipients.

[0115] Provided herein are film-coated tablet forms that include a combination of an active ingredient (e.g., Compound A-HCl) and one or more tableting excipients to form a tablet core and then coat the core. The tablet core is produced using conventional tableting processes, followed by compression and coating.

[0116] An enteric coating is a coating that resists the action of stomach acid but dissolves or disintegrates in the intestine.

[0117] In one embodiment, the oral solid dosage form disclosed herein comprises an enteric coating. The enteric coating comprises one or more of cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, methacrylic acid copolymer, cellulose acetate (and its succinate and phthalate versions), styrene maleic acid copolymer, polymethacrylic acid / acrylic acid copolymer, hydroxyethyl ethylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate tetrahydrophthalate, acrylic resin, and shellac.

[0118] Enteric coatings are applied to tablets, pills, capsules, pellets, beads, granules, particles, etc., to prevent them from dissolving until they reach the small intestine.

[0119] Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.

[0120] Film-coated tablets are compressed tablets 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 phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and press-coated or dry-coated tablets. In some embodiments, tablets are coated with a water-soluble, pH-independent film coating (e.g., Opadry products) that allows for immediate disintegration to release the active ingredient at a high rate.

[0121] Dose in tablets In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 5 mg to about 100 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 5 mg to about 80 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 5 mg to about 60 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 10 mg to about 40 mg.

[0122] In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 10 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 20 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 30 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 40 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 50 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 60 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 70 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 80 mg.

[0123] Dosage and Treatment Regimen In one embodiment, the pharmaceutical compositions disclosed herein are used as medicaments for the treatment of a disease or condition in a mammal that would benefit from modulation of somatostatin activity. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof.

[0124] In certain embodiments, compositions containing Compound A described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0125] In general, however, doses used in adult human treatment are typically in the range of about 10 mg to about 100 mg per day of Compound A. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered consecutively or at appropriate intervals, for example, as two, three, four or more sub-doses per day.

[0126] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments in which the compound is administered once daily. [Example]

[0127] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0128] Example 1: Oral Capsules Representative capsules are listed below in Table 1.

[0129] [Table 1]

[0130] A typical description of the manufacturing process for hot melt granulation capsules follows.

[0131] Step 1: High Shear Wet Granulation: Vitamin E polyethylene glycol succinate (TPGS) is melted. Compound A-HCl, mannitol, microcrystalline cellulose, croscarmellose sodium, and silicon dioxide are charged into a high shear wet granulator and mixed. The melted Vitamin E TPGS is sprayed onto the granulated ingredients.

[0132] Stage 2: Crushing: The wet granulation is milled through a screening mill using an appropriately sized screen.

[0133] Step 3: Blending:Sieve the sodium stearyl fumarate using an appropriate size screen. Charge the milled granulation into a diffusion mixer (tumble) along with the sodium stearyl fumarate and blend.

[0134] Phase 4: Encapsulation: The 10 mg capsules were automatically encapsulated into size 2 gelatin capsules.

[0135] Example 2: Spray-dried solid dispersion Spray-dried solid dispersions were prepared using 15% Compound A-HCl by weight: 15 / 85 Compound A-HCl / HPMCAS-M and 15 / 85 Compound A-HCl / PVP VA64. Production was completed using a Bend Lab Dryer BLD-150 with a drying gas capacity of 150 kg / h. Parameters modified included solution solids loading for the HPMCAS-M SDD formulation to help reduce nozzle bearding, and dryer outlet temperature for the PVP VA64 SDD to eliminate potential variability during clinical manufacturing. The original process parameter screening plan specified using a larger orifice nozzle to produce larger particles, resulting in reduced dryer outlet temperature conditions. However, based on the results of the first spray run, it was determined that the atomization pressure required to achieve the desired solution flow rate was too low to fully atomize the solution with the larger orifice. Because dryer outlet temperature tends to be more variable than solution flow rate, the parameter screen was shifted to focus solely on eliminating the dryer outlet temperature while ensuring complete atomization of the droplets. Variations in the dryer outlet temperature can affect the residual solvent level in the SDD, which can affect physical and chemical stability. All sprays were completed successfully with good yields, demonstrating a robust process space for both formulations.

[0136] 15 / 85 Compound A HPMCAS-M SDD Formulation Manufacturing Details Three sub-batches of 15 / 85 Compound A-HCl / HPMCAS-M SDD were sprayed to explore the manufacturing process space and prepare for clinical trial manufacturing. When the sub-batches were first sprayed at 10 wt% solids, significant nozzle bearing, which appeared to affect the spray plume, was observed after approximately 45 minutes on the solution.

[0137] The solution was diluted to 8 wt% and sub-batches were made over a 1 hour period to ensure reduced bear- ing. After approximately 50 minutes on solution, very little bear- ing was observed in this batch, but this did not appear to affect the atomization plume, so an 8 wt% solids loading was chosen.

[0138] Chilled water at 2 GPM and approximately 7°C was run through the spray dryer lid throughout all spraying to keep the lid cool and prevent sticking and browning. No significant lid buildup or browning was observed throughout production. No cleaning was performed between sprays, and all spraying was completed from one solution with additional solvent added prior to the production of Batches 2A and 2C. The production parameters used for all three sub-batches are outlined in Table 2.

[0139] [Table 2]

[0140] 15 / 85 Compound A-HCl / PVP VA64 SDD Formulation Manufacturing Details A process parameter screening spray and FPN demonstration batch was also completed for the 15 / 85 Compound A-HCl / PVP VA64 SDD formulation. The dryer outlet temperature was modified to eliminate the risk of process parameter variability and prepare for clinical trial manufacturing.

[0141] The process space was limited by the maximum dryer outlet temperature, dryer outlet temperature, and minimum desired solution flow rate. To avoid adhesion or browning of SDD on the spray dryer lid, the maximum inlet temperature was specified at 160°C, and the minimum flow rate was set at 100 g / min to ensure sufficient throughput. The minimum and maximum dryer outlet temperatures were 40°C and 65°C, respectively, to ensure that the particles were sufficiently dried and that the dryer outlet temperature did not exceed the Tg of the wet particles.

[0142] Process parameter screening spraying of the PVP VA64 formulation explored the manufacturing space by varying the dryer outlet temperature, which allowed for investigation of the effect of dryer relative saturation on particle residual solvent content, morphology, density, and stability.

[0143] Cooling water was run at 2 GPM and approximately 7°C throughout all sprays to prevent lid buildup and browning, neither of which was recorded. No nozzle bearding was observed throughout all three runs. All sprays were completed from one solution. Production details for each sub-batch are summarized in Table 3.

[0144] [Table 3]

[0145] SDD characterization Particle characteristics: Particle size distribution and bulk and tap densities were measured for each batch of Compound A-HCl SDD. HPMCAS-M SDD had a larger particle size because the HPMCAS-M solution was more viscous than the PVP VA64 solution, resulting in larger droplets for a given nozzle configuration. Increasing the solids loading in the Lot 2B solution resulted in a larger particle size than Batches 2A and 2C, again due to the higher viscosity of the spray solution. The particle size distributions for all PVP VA-64 batches were similar, as expected.

[0146] The bulk and tapped densities of 2A and 2C are similar, but batch 2B is slightly lower in density, likely due to larger particles. The bulk and tapped densities of all PVPVA-64 batches are similar, indicating that the process is robust with respect to the effect of dryer outlet temperature on powder properties.

[0147] Residual solvent and moisture content: Residual methanol and water in six SDDs were measured using GC and KF, respectively. All SDDs contained residual methanol below the ICH guideline of 0.3 wt% after secondary drying, suggesting adequate drying at 40°C / 15% RH.

[0148] Morphology by SEM: The particle morphology of all six SDDs was evaluated via SEM. Each SDD exhibited typical morphology with no evidence of irregular particles, suggesting adequate atomization for all conditions tested. HPMCAS-M particles were primarily crushed spherical, while the PVP VA64 SDD contained a larger proportion of spherical particles.

[0149] Crystallinity by PXRD: All six SDDs were evaluated for crystallinity using PXRD. All SDDs were amorphous by PXRD, which was evident in the absence of sharp diffraction peaks.

[0150] Thermal Properties by DSC: All six SDDs were characterized by modulated DSC. The results are summarized in Table 4. All SDDs produced were amorphous and homogeneous by DSC, as evidenced by the presence of a single glass transition in the inverse thermal signal. None of the formulations showed signs of crystallization after the Tg, suggesting that Compound A has a low propensity to crystallize at these temperatures for both formulations. Furthermore, both formulations exhibited elevated Tg compared to ambient temperature, suggesting low physical stability risk under dry conditions. The PVP VA64 formulation requires packaging to minimize humidity.

[0151] [Table 4]

[0152] overview Physical stability observations: PVP VA64 SDD appeared to deliquesce upon storage, with crystals observed after 3 months (40°C / 75% RH open). Storage with a desiccant is recommended. HPMCAS-M SDD was physically stable over 6 months at 40°C / 75% RH open.

[0153] Chemical Stability Observations: Potential for acid-catalyzed degradation in the HPMCAS-M formulation relative to stability. Some degradation was observed in the PVP VA64 formulation, but less pronounced than in the HPMCAS-M SDD. The PVPVA SDD requires release due to physical stability concerns.

[0154] 15% by weight Compound A / PVP VA64 was selected as the primary SDD formulation.

[0155] 12-month stability: 15% Compound A-HCl / PVP-VA64 SDD Twelve-month SDD samples were stored with desiccant at 5°C, 25°C / 60% RH, and 40°C / 75% RH. Samples were prepared for water analysis by Karl Fischer titration and analyzed immediately. The remaining samples were vacuum dried overnight to remove residual moisture and preserve the physical state of the SDD for further characterization. The list of analytical tests performed for characterization included appearance, moisture content by Karl Fischer titration, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), thermal characterization by modulated differential scanning calorimetry (mDSC), dissolution performance by microcentrifuge (MCT) test, and assay and related substances by HPLC.

[0156] Conclusions from PXRD analysis on 12-month SDD stability samples: There was no evidence of crystallinity in samples stored for 12 months at each of the stability conditions.

[0157] Conclusions from SEM analysis of 12-month SDD stability samples: No particle fusion was observed across all stability conditions at 12 months. There was no evidence of crystallinity in samples stored at 12 months at each of the stability conditions.

[0158] SEM analysis of 12-month SDD stability samples concludes: No particle fusion is observed across all stability conditions at 12 months. There was no evidence of crystallinity in samples stored at 12 months at each of the stability conditions.

[0159] Conclusions from mDSC analysis of 12-month SDD stability samples: Thermograms obtained from replicate analyses of 12-month SDD samples held at 5°C were not reproducible, and the cause of this result is currently unknown. The 5°C samples were determined to be physically stable by all other characterization techniques. 12-month SDD samples held at 25°C / 60% RH and 40°C / 75% RH exhibited a single, reproducible Tg between 124 and 125°C, supporting the conclusion that SDD is stable after 12 months of storage with desiccant at these conditions.

[0160] Conclusions of the MCT dissolution analysis on the 12-month SDD stability samples: The non-sink dissolution performance of the 12-month stability samples is consistent with the initial (t0) samples stored at -20°C.

[0161] 35 / 65 Compound A-HCl / PVP VA64 SDD Formulation Manufacturing Details A spray-dried solid dispersion was prepared using 35 wt% Compound A-HCl: 35 / 65 Compound A-HCl / PVP VA64 formulation.

[0162] The preparation of SDD was completed using an SD-180 laboratory dryer. Secondary drying was completed using a Binder Convection Dryer. Preparation details are summarized in Table 5.

[0163] The spraying was completed successfully with good yield.

[0164] [Table 5]

[0165] Example 3: Oral Tablets Representative 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg spray-dried dispersion tablets are provided in Tables 6, 7, 8, 9, 10, 11, 12, and 13.

[0166] Typical excipients used to prepare tablets include microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate, and Opadry White 03K184116 (film coating).

[0167] [Table 6]

[0168] [Table 7]

[0169] [Table 8]

[0170] [Table 9]

[0171] [Table 10]

[0172] [Table 11]

[0173] [Table 12]

[0174] [Table 13]

[0175] [Table 14]

[0176] A representative, non-limiting description of the manufacturing process for SDD tablets follows.

[0177] Step 1: Spray drying: Compound A-HCl and copovidone are dissolved in MeOH. The solution is spray dried. The spray-dried dispersion (Compound A-HCl SDD) is collected.

[0178] Stage 2: Roller Compaction: A granulation blend consisting of Compound A-HCl SDD, filler, disintegrant, glidant, and lubricant is blended. In some embodiments, a granulation blend consisting of Compound A-HCl SDD, mannitol, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide is prepared and blended. The intragranular portion of magnesium stearate is passed through a screen and added to the granulation blend. The resulting blend is blended. The granulation blend is loaded into the hopper of a roller compactor and compressed into ribbons. The ribbons are passed through a mesh screen using an in-line vibratory mill to break the ribbons and mill them into granules.

[0179] In some embodiments, the granulated blend comprises about 20% to about 35% (w / w of final tablet weight) Compound A-HCl SDD. In some embodiments, the granulated blend comprises about 21%, 22%, about 28%, 29%, about 33%, or about 34% (w / w of final tablet weight) Compound A-HCl SDD. In some embodiments, the Compound A-HCl SDD comprises 15 / 85 Compound A-HCl / HPMCAS-M, 15 / 85 Compound A-HCl / PVPVA64, or 35 / 65 Compound A-HCl / PVPVA 64 SDD.

[0180] Step 3: Blending: The intragranular material is mixed with extragranular excipients, which include one or more excipients selected from fillers, disintegrants, glidants, and lubricants. The extragranular components include microcrystalline cellulose, crospovidone, and colloidal silicon dioxide. The extragranular lubricant, magnesium stearate, is sieved using an appropriate size screen and then added to the blend and mixed.

[0181] Stage 4: Compression: The final blend is compressed into tablets.

[0182] Step 5: Pan Coating: A film coating suspension of Opadry White 03K18416 is prepared in purified water and the tablets are coated with Opadry White 03K18416 in a perforated coating pan.

[0183] Example 4: Evaluation of formulation performance in dogs Test Design Two conditions* were evaluated in dogs: +Pg pretreatment (mimicking the fasting human stomach, pH 1-2) and -Pg pretreatment (mimicking humans taking PPIs or antacids, pH 3-5). (*: 1-week washout between conditions; Pg = pentagastrin.)

[0184] Compound A-HCl solution N = 4 non-naive dogs. Vehicle: propylene glycol. Condition: -Pg. Compound A-HCl HMG Capsules

[0185] N = 4 non-naive dogs. Conditions: +Pg, -Pg.

[0186] Compound A-HCl spray-dried dispersion tablets: PVPVA N = 2 groups of 6 non-naive male dogs. Conditions: +Pg, -Pg.

[0187] The results of this study are shown in Tables 15 and 16.

[0188] [Table 15]

[0189] As shown in Table 15 and Figure 2, in dogs not pretreated with pentagastrin, the HMG capsule formulation performed poorly, while the spray-dried dispersion tablet performed well. For the HMG capsule formulation, the AUC without pentagastrin was only 11% of the AUC with pentagastrin (98.2 ng*hr / mL compared to 917 ng*hr / mL). In comparison, the AUC for the PVPVA SDD tablet without pentagastrin was 185% and 124%, respectively, of the condition with pentagastrin. These data indicate that the PVPVA SDD tablet formulation is superior in environments with high gastric pH (e.g., those present in subjects taking PPIs or antacids).

[0190] [Table 16]

[0191] Example 5: Phase 1 multi-cohort single-dose study to evaluate the relative bioavailability, performance, and safety of two formulations of Compound A The study was conducted in up to three cohorts, each with a specific primary objective.

[0192] Cohort 1: To characterize the performance of 10 mg tablets prepared by spray-dried dispersion (SDD) of Compound A-HCl salt.

[0193] Cohort 2: To evaluate the relative bioavailability of 10 mg SDD tablets compared to Compound A-HCl hot melt granulation (HMG) formulation, 10 mg capsules. To determine the effect of food administration timing on the pharmacokinetics of a low dose 10 mg SDD tablet.

[0194] Cohort 3: To determine the effect of food administration timing on the pharmacokinetics and dose proportionality of SDD tablets at doses higher than 20 mg. To determine the optimal dosing regimen that provides adequate systemic exposure with a short post-dose fasting period.

[0195] Study Design: A maximum of 36 healthy male and female subjects were enrolled. Cohorts 1 and 2 each consisted of four periods, and Cohort 3 consisted of three periods.

[0196] Cohort 1: SDD tablets were evaluated. Up to 12 healthy male and female subjects were enrolled in each cohort. Cohort 1 consisted of four periods. In Period 1, subjects received a proton pump inhibitor (lansoprazole, 15 mg BID, taken orally at least 30 minutes before meals, once in the morning and once in the evening) for 3 days (starting on Day -3). On Day 4 (Day 1 of the study), fasted subjects received their final dose of lansoprazole (15 mg), followed 60 minutes later by 20 mg of Compound A (two 10 mg SDD tablets). In Period 2, fasted subjects received 20 mg of Compound A (two 10 mg SDD tablets). In Period 3, fasted subjects received 20 mg of Compound A (two 10 mg SDD tablets) with a high-fat, high-calorie meal. In Period 4, fasted subjects will receive 80 mg of Compound A (up to 8 x 10 mg SDD tablets). The actual dose was selected based on pharmacokinetic data from Period 2.

[0197] Period 1: In the evening before dosing (Day -1), subjects received an evening dose of 15 mg lansoprazole, were offered dinner at least 30 minutes after lansoprazole administration, and were then required to fast overnight (≥10 hours) on Day -1. On Day 1, subjects received a morning dose (final dose) of 15 mg lansoprazole, followed at least 60 minutes later by Compound A (2 x 10 mg SDD tablets). After Compound A, subjects continued fasting for 2 hours, after which they were allowed to consume a standard meal.

[0198] Period 2: Subjects were asked to fast overnight (≥10 hours) on Day 7. On Day 8, 20 mg of Compound A (2 x 10 mg SDD tablets) was orally administered. After Compound A, subjects continued fasting for 2 hours, after which they were allowed to consume a standard meal.

[0199] Period 3: Subjects were asked to fast overnight (≥10 hours) on Day 14. On Day 15, subjects were allowed to consume a high-fat, high-calorie meal within 30 minutes. Once the meal was completed, Compound A (2 x 10 mg SDD tablets) was administered (within 30 minutes of the start of the meal). No additional food was provided for at least 4 hours after Compound A administration.

[0200] Subjects were prohibited from engaging in more than 30 minutes of vigorous exercise per day, beginning 3 days prior to day -1 and continuing throughout the study.

[0201] PK and safety assessments, including adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, 12-lead ECG, Holter and telemetry monitoring (Period 4 only), and physical examinations, were performed at scheduled times throughout the study.

[0202] Cohort 2: The cohort consisted of four periods, each of which received a single oral dose of 20 mg Compound A (2 x 10 mg SDD).

[0203] Period 1: Subjects were required to fast overnight (≥10 hours) on Day -1. On Day 1, subjects were given a low-fat meal 2 hours after administration of 20 mg of Compound A (2 x 10 mg HMG capsules, reference formulation).

[0204] Period 2: Subjects were asked to fast overnight (≥10 hours) on Day 7. On Day 8, subjects were given a low-fat meal 2 hours after administration of 20 mg of Compound A (2 x 10 mg SDD tablets, test formulation).

[0205] Period 3: Subjects were asked to fast overnight (≥10 hours) on day 14. On day 15, subjects were given a low-fat meal 1 hour after administration of 20 mg of Compound A (2 x 10 mg SDD tablets).

[0206] Period 4: Subjects were asked to fast overnight (≥10 hours) on day 21. On day 22, subjects were given a low-fat meal 0.5 hours after administration of 20 mg of Compound A (2 x 10 mg SDD tablets).

[0207] The final study visit was Day 29. Subjects were prohibited from engaging in more than 30 minutes of vigorous exercise per day throughout the study, beginning 3 days prior to Day -1. PK and safety assessments, including adverse event (AE) monitoring, clinical tests, vital sign measurements, 12-lead ECG, and physical examinations, were performed at scheduled times throughout the study.

[0208] Cohort 3: The cohort consisted of three periods. In each period, a single dose of SDD (40, 60, or 80 mg) of Compound A was orally administered (four 10 mg SDD tablets, six 10 mg SDD tablets, or eight 10 mg SDD tablets). A washout period of at least 10 days was allowed between each dose of Compound A.

[0209] Period 1: Subjects were asked to fast overnight (≥10 hours) on Day -1. On Day 1, subjects were given a standard meal 1 hour after administration of 40 mg of Compound A (4 x 10 mg SDD tablets).

[0210] Period 2: Subjects were asked to fast overnight (≥10 hours) on Day 10. On Day 11, subjects were given a standard meal 1 or 2 hours after administration of 80 Compound A (8 x 10 mg SDD tablets). The timing of the meal (1 or 2 hours after administration of Compound A) was related to the mean AUC determined in Period 1. 0-24 was influenced by.

[0211] Period 3: Subjects were asked to fast overnight (≥10 hours) on Day 20. On Day 21, subjects received a standard meal 1 or 4 hours after administration of 60 or 80 mg of Compound A (6 x 10 mg SDD tablets or 8 x 10 mg SDD tablets). The amount and timing of the standard meal were determined based on the mean AUC determined in Period 2. 0-24 was influenced by.

[0212] The final study visit was Day 29. Subjects were prohibited from engaging in more than 30 minutes of vigorous exercise per day throughout the study, beginning 3 days prior to Day -1. PK and safety assessments, including adverse event (AE) monitoring, clinical tests, vital sign measurements, 12-lead ECG, and physical examinations, were performed at scheduled times throughout the study.

[0213] Study population: Up to 36 healthy male or female subjects aged 18 to 55 years (inclusive) were enrolled. For Cohort 2 only, male and female subjects aged 18 to 65 years (inclusive) at screening.

[0214] Inclusion criteria Each subject had to meet all of the following inclusion criteria to be enrolled in the study: male and female subjects aged 18 to 55 years (inclusive) at screening; for Cohort 2 only, male and female subjects aged 18 to 65 years (inclusive) at screening; and a body mass index (BMI) of 18 to 30 kg / m. 2 (endpoints inclusive). - Willingness to abstain from strenuous, unaccustomed exercise and sports, defined as more than 30 minutes per day, beginning 3 days before Day 1 and continuing throughout the study. If subjects are heterosexual or bisexual women, they must not be of childbearing potential or agree to use two highly effective or clinically acceptable methods of contraception.

[0215] Exclusion criteria Healthy subjects meeting any of the following criteria were excluded from the study: - Previous treatment with Compound A. - Uncontrolled or active major systemic disease that could jeopardize study participation or interfere with the assessment of study endpoints. - History or presence of malignancy within the past 5 years, except for adequately treated basal or squamous cell carcinoma of the skin. - Active acute or chronic infection. - Use of any investigational drug prior to the first dose of study drug, within the past 60 days or 5 half-lives, whichever is longer. - Use of tobacco and / or nicotine-containing products, recreational drugs, or alcohol within 48 hours prior to admission and agreement to abstain throughout the study. - History of alcohol abuse and / or other drug dependence or active abuse and / or dependence within 1 year prior to screening. - Use of any prescription or over-the-counter (OTC) medication or alternative medication within 14 days prior to Day 1. - Use of caffeine-containing beverages or foods within 48 hours prior to Day 1 and 48 hours prior to each visit day in all subsequent periods. Consuming foods containing poppy seeds within 7 days prior to screening until completion of study assessments. Taking moderate or strong CYP3A4 inhibitors or inducers. Vigorous exercise >30 minutes per day from 3 days prior to Day 1 through the entire study. Blood loss >500 mL or blood donation within 3 months prior to admission. Amylase and / or lipase levels >2x ULN, alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) >2x ULN, total bilirubin >1.5x ULN (except in cases of known Gilbert's syndrome), and / or serum creatinine above the upper limit of normal. History of hypersensitivity reaction to any excipient in the study drug. Testing positive at screening or having a history of positive results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab). Female subjects with a positive serum pregnancy test or who are breastfeeding. Cohort 1 only: subjects classified as poor or ultrarapid metabolizers of CYP2C19.

[0216] Test product, dose, and mode of administration: 10 mg tablets (SDD). Depending on the dose assigned for a given period / cohort, multiple tablets were swallowed with water.

[0217] Reference therapy, dose, and mode of administration: A 10 mg HMG capsule formulation was used as the reference formulation. Multiple capsules were swallowed with water depending on the dose assigned for a given period / cohort. Plasma pharmacokinetic parameters:

[0218] Blood PK samples were collected to assess Compound A plasma concentrations.

[0219] PK parameters were calculated for Compound A and are shown in the table below: Area under the plasma concentration curve from 0 to 24 hours (AUC 0-24 ), maximum plasma concentration (C max ), time to achieve maximum plasma concentration (T max ).

[0220] result The results of this clinical trial showed that the coadministration of a proton pump inhibitor had only a small effect on the pharmacokinetics observed with SDD tablets, and that the shorter fasting period achieved with SDD tablets provided better dose-proportional pharmacokinetics.

[0221] The results for Cohort 1 are presented in Table 17.

[0222] [Table 17]

[0223] Cohort 1 (SDD 10 mg × 2 under different conditions): The observed exposures with and without PPI were nearly equivalent. Cohort 1 (SDD 10 mg × 2 vs. 10 mg × 6): A relatively dose-proportional increase in exposure was observed.

[0224] No relatively dose-proportional increase in exposure was observed with HMG capsules compared to SDD tablets. See Figure 1. Dose-proportionality data for HMG capsules from previous clinical trials are presented in Table 18.

[0225] [Table 18]

[0226] The results for Cohort 2 are presented in Table 19.

[0227] [Table 19]

[0228] Cohort 2 (SDD 10 mg × 2 vs. HMG, and different post-dose fasting periods): SDD tablets did not appear to provide better exposure than HMG capsules, and the two formulations were relatively comparable. For SDD tablets, AUC 0-24 (a measure of the extent of absorption) was reduced to 82% of the AUC observed with fasting for 2 hours post-dose, a relatively small reduction in exposure.

[0229] Compared to the performance of the SDD tablet under different post-dose fasting period scenarios, the HMG capsule performed poorly under different post-dose fasting period scenarios in a previously completed clinical trial. Pharmacokinetic data obtained after administration of a 20 mg dose (2 x 10 mg HMG capsules) to 12 subjects (N = 4 males, N = 8 females) are presented in Table 20.

[0230] [Table 20]

[0231] For the HMG capsule formulation, a loss of approximately 30% in absorption was observed between fasting for 1 hour after dosing and fasting for 2 hours after dosing.

[0232] HMG capsules with a 2-hour fast were evaluated in a phase 2 clinical trial. A 1-hour fast was preferred over a 2-hour fast. Compared to a 2-hour fast, a 1-hour fast resulted in a significantly higher AUC (0-24) Only an 18% loss of serotonin was observed. A 1-hour fasted SDD will be utilized in Phase 3. Importantly, the SDD tablet appears to have better dose proportionality than the HMG capsule, allowing for a 3.0-fold dose (i.e., 60 mg) to be administered in Phase 3 clinical trials.

[0233] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be within the spirit and scope of this application and the appended claims.

Claims

1. 1. A spray-dried solid dispersion comprising: (a) 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt thereof; (b) a pharmaceutically acceptable polymer; A spray-dried solid dispersion in which 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt thereof is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer, wherein the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA).

2. 10. The spray-dried solid dispersion of claim 1, wherein the HPMCAS has an acetyl content of 7-11%.

3. 2. The spray-dried solid dispersion of claim 1, wherein the pharmaceutically acceptable polymer is polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA64) in a weight ratio of polyvinylpyrrolidone to vinyl acetate of 6:

4.

4. 4. The spray-dried solid dispersion of claim 1, wherein the weight ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is from 1:10 to 10:

1.

5. 4. The spray-dried solid dispersion according to any one of claims 1 to 3, wherein the weight ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is from 1:1 to 1:

10.

6. 4. The spray-dried solid dispersion according to any one of claims 1 to 3, wherein the weight ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is from 1:4 to 1:

6.

7. 4. The spray-dried solid dispersion according to any one of claims 1 to 3, wherein the weight ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer is from 1:5 to 1:

6.

8. 4. The spray-dried solid dispersion of any one of claims 1 to 3, wherein the spray-dried solid dispersion comprises 15% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile.

9. The spray-dried solid dispersion of claim 1, wherein the spray-dried solid dispersion comprises 35% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile.

10. A tablet, The spray-dried solid dispersion according to any one of claims 1 to 9, one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegration aids, one or more lubricants, one or more glidants; Optionally, one or more film coating agents.

11. 11. The tablet of claim 10, wherein the one or more pharmaceutically acceptable ingredients comprise microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, colloidal silicon dioxide, and magnesium stearate.

12. The tablet 12. The tablet of claim 10 or 11, comprising 2% to 20% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, the percentages being calculated based on the weight of the free base of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile.

13. The tablet a spray-dried dispersion of 20% to 40% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, the % amount being calculated based on the weight of the free base of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile; 60% to 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegration aids, one or more lubricants, and one or more glidants; 13. The tablet of any one of claims 10 to 12, optionally comprising less than 5% by weight of one or more film coating agents.

14. The tablet A spray-dried dispersion of 20% to 35% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride dispersed in a polymeric matrix formed from a pharmaceutically acceptable polymer, a spray-dried dispersion of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) in a ratio of 15 / 85 to 35 / 65, the weight ratio of 15 / 85 to 35 / 65 being based on the weight of the free base of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile; 60% to 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, silicon dioxide, and magnesium stearate; 11. The tablet of claim 10, optionally comprising less than 5% by weight of one or more film coating agents.

15. The tablet of claim 10, wherein the tablet contains 5 mg to 80 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, the amount calculated based on the weight of the free base of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile.

16. 15. The tablet of any one of claims 10 to 14, wherein the tablet contains 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, or 80 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, the amount calculated based on the weight of the free base of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile.

17. 17. The tablet of any one of claims 10 to 16 for use in the treatment of acromegaly or neuroendocrine tumors or both in a human, said treatment comprising oral administration once daily of one or more of said tablets to said human having acromegaly or neuroendocrine tumors.

18. 18. The tablet for use according to claim 17, wherein the one or more tablets are administered at least 30 minutes or at least 60 minutes before a meal.

19. 10. The spray-dried solid dispersion of any one of claims 1 to 9 for use in the treatment of acromegaly or neuroendocrine tumors or both in humans.

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