Formulations of somatostatin modulating agents

Abstract

A spray-dried solid dispersion comprising: (a) 3-[4-(4-amino-piperidin-l-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 by the pharmaceutically acceptable polymer. A tablet comprising the spray-dried solid dispersion and one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants. The tablet is for use in the treatment of acromegaly or a neuroendocrine tumor or both in a human by oral administration.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 076,024, filed September 9, 2020, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] Described herein are pharmaceutical compositions and medicaments comprising 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 modulation of somatostatin activity. BACKGROUND

[0004] Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation by interacting with G protein-coupled somatostatin receptors and inhibiting the release of many secondary hormones. Six subtypes of somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) have been identified, encoded by five different somatostatin receptor genes. Modulation of a particular subtype of somatostatin receptor or combinations thereof is attractive for treating conditions, diseases, or disorders that would benefit from modulation of somatostatin activity. SUMMARY

[0005] In one aspect, provided herein is a spray-dried solid dispersion comprising: (a) 3-[4-(4-amino-piperidin-l-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 3-[4-(4-amino-piperidin-l-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 by 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 the following polymers: cellulose, optionally functionalized with any combination of alkyl ethers, alkyl esters, phthalates; vinyl alcohol; vinyl acetate; propylene glycol; pyrrolidone; vinyl pyrrolidone; ethylene oxide; propylene oxide; methacrylic acid; methyl methacrylate; ethylene glycol; glyceryl ethylene glycol; oxirane; oxetane; 2-ethyl-2-oxazoline; maleic acid; methyl vinyl ether; vinyl caprolactam; or combinations thereof.

[0006] 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 ethylcellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA), polyvinyl polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), copolymer of methacrylic acid and methyl methacrylate, polyethylene glycol glycerol esters consisting of mono-, di- and triglycerides and mono- and di-esters of polyethylene glycol, copolymer of hydroxypropyl cellulose, 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 a combination 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 at a ratio of 6:4 (PVP / VA 64).

[0007] In some embodiments, the weight ratio of 3-[4-(4-amino-piperidin-l-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-l-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-l-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-l-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.

[0008] In some embodiments, the spray-dried solid dispersion comprises at least about 5% by weight of 3-[4-(4-amino-piperidin-l-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-l-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 about 15% by weight of 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro- phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile or a pharmaceutically acceptable salt or solvate thereof.

[0009] 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 t-butyl alcohol, n-propyl alcohol, n-butyl alcohol, isopropyl alcohol, 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.

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

[0011] In some embodiments, 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxy-benzyl nitrile or a pharmaceutically acceptable salt or solvation thereof is 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxy-benzyl nitrile monohydrochloride or a solvation thereof.

[0012] In another aspect, this article provides a tablet comprising: the spray-dried solid dispersion described herein; one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more gliding agents; and optionally one or more film coating agents.

[0013] In another aspect, this document provides a tablet comprising: 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxy-benzyl nitrile monohydrochloride or a solvation thereof dispersed in a polymer matrix formed of a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more flow aids; and optionally one or more film coating agents. In some embodiments, the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxy-benzyl nitrile monohydrochloride or a solvation thereof dispersed in a polymer matrix formed of a pharmaceutically acceptable polymer is a spray-dried solid dispersion as described herein. In some embodiments, one or more pharmaceutically acceptable ingredients include microcrystalline cellulose, mannitol, crospovidone, colloidal silica, and magnesium stearate. In some implementations, one or more pharmaceutically acceptable ingredients include microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, croscarmellose, sodium chloride, a 1:1 sodium chloride:potassium chloride ratio, colloidal silica, and magnesium stearate.

[0014] In some embodiments, the tablet comprises 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 comprises 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 comprises 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 comprises about 10% to about 30% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer. In some embodiments, the tablet comprises about 20% to about 35% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer.

[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 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 one or more diluents, one or more disintegrants, one or more lubricants, 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 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 one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants; and optionally less than about 5% by weight of one or more film coating agents.

[0017] 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 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 one or more diluents, one or more disintegrants, one or more disintegration aids, one or more lubricants, one or more glidants; and optionally less than about 5% by weight of one or more film coating agents.

[0018] In some embodiments, the spray-dried dispersion comprises 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof in a polymer matrix ratio of about 15 / 85 to about 35 / 65 with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA).

[0019] In some embodiments, the tablet comprises: about 20% to about 35% 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 solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; wherein the spray-dried dispersion comprises 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof in a polymer matrix ratio of about 15 / 85 to about 35 / 65 with 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 microcrystalline cellulose, mannitol, pregelatinized starch, sodium croscarmellose, 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.

[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 a spray-dried dispersion of 3-[4-(4-amino-piperidin-l-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 spray-dried dispersion comprises 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof in a polymer matrix ratio of about 15 / 85 or about 35 / 65 with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone acetate copolymer (PVP / VA); about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more disintegration aids, one or more lubricants, one or more glidants; and optionally less than about 5% by weight of one or more film coating agents.

[0021] 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 a spray-dried dispersion of 3-[4-(4-amino-piperidin-l-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 spray-dried dispersion comprises 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof in a polymer matrix ratio of about 15 / 85 or about 35 / 65 with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone acetate copolymer (PVP / VA); about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from microcrystalline cellulose, mannitol, pregelatinized starch, sodium croscarmellose, 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.

[0022] In some embodiments, the tablet comprises 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-l-yl)-3-(3,5-difluoro- phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof. In some embodiments, the tablet comprises 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-l-yl)-3-(3,5-difluoro- phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof.

[0023] In some embodiments, the tablet comprises about 10 mg of 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof. In some embodiments, the tablet comprises about 20 mg of 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof. In some embodiments, the tablet comprises about 30 mg of 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof. In some embodiments, the tablet comprises about 40 mg of 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof. In some embodiments, the tablet comprises about 50 mg of 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof. In some embodiments, the tablet comprises about 60 mg of 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof.

[0024] In one aspect, described herein is a method of treating acromegaly or a neuroendocrine tumor, or both, in a human comprising orally administering to a human having acromegaly or a neuroendocrine tumor any of the spray-dried dispersion tablets described herein.

[0025] In some embodiments, the tablet is administered once a day. 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 at least 30 minutes before a meal with a glass of water on an empty stomach. In some embodiments, the bioavailability of 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or solvate thereof in the tablet is not substantially affected by co-administration of a proton pump inhibitor, a histamine H2 receptor antagonist, or an antacid.

[0026] 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 the specific examples, while indicating specific 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 DESCRIPTION OF DRAWINGS

[0027] Figure 1 . shows the dose proportionality observed in humans administered HMG capsule formulations or SDD tablet formulations of Compound A-HCl.

[0028] Figure 2 . shows the performance of HMG capsule formulations and SDD tablet formulations of Compound A-HCl in dogs pretreated with or without pentagastrin. DETAILED DESCRIPTION

[0029] Somatostatin (SST), also known as growth hormone release-inhibiting factor (SRIF), was originally isolated as a 14-amino acid peptide from the hypothalamus of sheep (Brazeau et al., Science, vol. 179, pp. 77-79, 1973). A 28-amino acid peptide with an N-terminal extension was subsequently isolated that has similar biological activity to the 14-amino acid somatostatin (Pradayrol et al., FEBS Letters, vol. 109, pp. 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. U S A, vol. 77, pp. 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 affects its target cells through endocrine and paracrine pathways. Many of these effects are associated with the inhibition of the secretion of other hormones, most notably growth hormone (GH). They are produced by multiple cell types in the central nervous system (CNS) and the gut and have a variety of functions, including the regulation of the secretion of growth hormone (GH), insulin, glucagon, and many other antiproliferative hormones.

[0030] These pleiotropic effects of somatostatin are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5). The six somatostatin receptor proteins are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev., vol. 16, pp. 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab, vol. 8, pp. 398-405, 1997). All of the receptors are members of the class A subset of the G protein-coupled receptor (GPCR) superfamily. The SST2A receptor is the most widely expressed subtype in human tumors and is the primary receptor for the inhibition of GH secretion. Unless otherwise indicated, the term SSTR2 refers to SSTR2a.

[0031] It is possible to selectively modulate any one or a combination of somatostatin receptor subtypes. In some embodiments, selectively modulating any one or a combination of somatostatin receptor subtypes relative to other somatostatin receptor subtypes is useful in a variety of clinical applications. In some embodiments, selectively modulating any one of somatostatin receptor subtypes relative to other somatostatin receptor subtypes reduces undesirable side effects in a variety of clinical applications.

[0032] For example, modulation of SSTR2 activity mediates inhibition of pituitary anterior lobe growth hormone (GH) release and pancreatic glucagon release. SSTR2 is also implicated in many other biological functions such as, 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 retinopathy caused by abnormal blood vessel growth. In some other embodiments, selective SSTR2 modulators are used to treat arthritis, pain, cancer, inflammatory bowel disease, irritable bowel syndrome, Crohn’s disease, Cushing’s disease, acute lung injury, acute respiratory distress syndrome, and ophthalmic disorders such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, and Graves’ ophthalmopathy, among others.

[0033] 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 also involved in the regulation of growth hormone release.

[0034] Somatostatin peptides and their receptor subtypes are also widely expressed in the brain, and disruption or attenuation of their activity can be associated with some psychiatric and neurodegenerative diseases. For example, somatostatin concentrations are reduced in the cerebral cortex and hippocampus of schizophrenic patients, and one of the most consistent neuropathological findings in this patient group is a deficit in cortical inhibitory interneurons that express somatostatin. Somatostatin is also highly expressed in brain regions associated with seizure activity and is also thought to play an important role in epilepsy. Somatostatin levels are reduced in the hippocampus of Alzheimer’s and Parkinson’s patients, suggesting that restoration of its signaling is a potential drug target for neurodegeneration.

[0035] In one aspect, the compound 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)- quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or 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.

[0036] In some embodiments, the somatostatin receptor modulators described herein have utility in 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, such as, but not limited to, acromegaly, neuroendocrine tumors, retinopathy and other ocular 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, a neuroendocrine tumor, 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 a neuroendocrine tumor.

[0037] In some embodiments, the somatostatin receptor modulators described herein inhibit the secretion of various hormonal and trophic factors in mammals. In some embodiments, the somatostatin receptor modulators described herein are used to inhibit the secretion of certain endocrine secretions, such as, but not limited to, GH, insulin, glucagon, and prolactin. Inhibition of the secretion of certain endocrine secretions can be used to treat disorders such as acromegaly; endocrine tumors such as carcinoid, vasoactive intestinal peptide tumors, insulinomas, and glucagonomas; or diabetes and diabetes-related pathologies, including retinopathy, neuropathy, and nephropathy. In some embodiments, the somatostatin receptor modulators described herein are used to inhibit exocrine secretion in the pancreas, stomach, and intestines for the treatment of disorders associated with such diseases as AIDS or cholera, such as pancreatitis, fistula, hemorrhagic ulceration, and diarrhea. Disorders involving autocrine or paracrine secretion of trophic factors such as IGF-1 (as well as some endocrine factors), including breast, prostate, and lung cancer (small cell and non-small cell epidermoid carcinoma), as well as liver cancer, neuroblastoma, colon and pancreatic adenocarcinoma (ductal type), chondrosarcoma, and melanoma, diabetic retinopathy, and atherosclerosis associated with vascular grafting and restenosis following angioplasty can be treated by administration of the compounds described herein.

[0038] In some embodiments, the somatostatin receptor modulators described herein are used to inhibit mediators of neurogenic inflammation (e.g., substance P or tachykinins) and can be used to treat rheumatoid arthritis; psoriasis; localized inflammation, such as that associated with sunburn, eczema, or other sources of itch; inflammatory bowel disease; irritable bowel syndrome; allergies, including asthma and other respiratory diseases. In some other embodiments, the somatostatin receptor modulators described herein act as neuromodulators in the central nervous system and can be used to treat Alzheimer's disease and other forms of dementia, pain, and headache. In some embodiments, the somatostatin receptor modulators described herein provide cytoprotection in disorders involving splanchnic blood flow, including cirrhosis and esophageal varices.

[0039] Compound A is a somatostatin modulator useful in the treatment methods described herein.

[0040] Compound A

[0041] As used herein, Compound A refers to 3-(4-(4-amino-piperidin-l-yl)-3-(3,5- difluoro-phenyl)-quinolin-6-yl)-2-hydroxy-benzonitrile, which has the chemical structure shown below.

[0042]

[0043] Compound A is a selective, non-peptide, SST2-biased agonist. In clinical studies, Compound A has shown an estimated bioavailability of about 70% and an observed half-life of about 42 hours to about 50 hours. In some embodiments, Compound A is used to treat acromegaly, a neuroendocrine tumor, or both. In some embodiments, Compound A is used to treat acromegaly. In some embodiments, Compound A is used to treat a neuroendocrine tumor.

[0044] In some embodiments, Compound A in free base form 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.

[0045] As used herein, "pharmaceutically acceptable" means that the substance, such as a carrier or diluent, does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is not deleterious to the individual when administered in the amounts necessary to achieve the intended effect of the composition containing it.

[0046] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent and a suitable anion or, in an alternative embodiment, a anionic form of the therapeutically active agent and 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 generally more soluble and faster dissolving in gastric and intestinal fluids than the non-ionic species, and thus can be useful in solid dosage forms. In addition, because their solubility is often a function of pH, selective solubilization in one or another part of the digestive tract is possible, and this ability can be manipulated as an aspect of delayed and sustained release behavior. In addition, because the salt-forming molecule can be in equilibrium in the neutral form, passage through biological membranes can be adjusted.

[0047] In some embodiments, the pharmaceutically acceptable salt is 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, but are not limited to, 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, cyclohexylsulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, 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.

[0048] 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 mesylate. In some embodiments, the Compound A salt form is Compound A monohydrochloride. In some embodiments, the Compound A salt form is Compound A dihydrochloride. In some embodiments, the Compound A salt form is Compound A monomethanesulfonate. In some embodiments, the Compound A salt form is Compound A dimethylsulfonate.

[0049] In one aspect, 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-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, has the following structure:

[0050]

[0051] In some embodiments, the Compound A salt form is amorphous. In some embodiments, the Compound A monohydrochloride is amorphous.

[0052] In some embodiments, the Compound A salt form is crystalline. In some embodiments, the Compound A monohydrochloride is crystalline.

[0053] It should be understood that reference to a pharmaceutically acceptable salt includes solvent addition forms. In some embodiments, solvates comprise either stoichiometric or non-stoichiometric amounts of a solvent, and are formed either during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like, or by contacting the substance with the solvent in its anhydrous form. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. 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, as well as solvated forms.

[0054] Therapeutic agents that can be administered to mammals, such as humans, must be prepared in accordance with regulatory guidelines. Such governmentally regulated guidelines are referred to as Good Manufacturing Practices (GMP). GMP guidelines outline acceptable levels of contamination for active therapeutic agents, for example, the amount of residual solvent in the final product. Preferred solvents are those that are suitable for use in GMP facilities and meet industry safety requirements. Classification of solvents is 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).

[0055] Solvents are classified into three categories. Category 1 solvents are toxic and should be avoided. Category 2 solvents are solvents that are limited in use during the manufacture of a therapeutic agent. Category 3 solvents are solvents that have low potential for toxicity and are of low risk to human health. Data for Category 3 solvents indicate that they are of low toxicity in acute or short-term studies and negative in genetic toxicity studies.

[0056] Category 1 solvents to be avoided include: benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0057] Examples of Category 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, tetrahydronaphthalene, toluene, 1,1,2-trichloroethene, and xylene.

[0058] Class 3 solvents with low toxicity include: acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, t-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl 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.

[0059] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of the API. In most cases, solvents cannot be completely removed by the actual manufacturing technique. The selection of the appropriate solvent for the synthesis of an API can improve the yield or determine properties such as crystalline form, purity, and solubility. Thus, solvents are a key parameter in the synthesis process.

[0060] 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, t-butyl methyl ether, heptane, isopropyl alcohol, methanol, acetone, dimethylformamide, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, and ethanol.

[0061] The following terms, as used in this application, have the following given meanings unless a different meaning is plainly at odds with such copyrighted terminology in the context in which it is used. The use of the term "comprising" and other forms such as "comprise," "comprises," "include," "includes" and "including," as used herein, is not

[0062] As used herein, the term "modulate" means to interact, directly or indirectly, with a target, thereby altering 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.

[0063] As used herein, the term "modulator" refers to a molecule that interacts, directly or indirectly, with a target. The interaction includes, but is not limited to, the interaction of an agonist, a partial agonist, an inverse agonist, an antagonist, a degrader, or a combination thereof. In some embodiments, the modulator is an agonist.

[0064] As used herein, the term "administering" refers to methods that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral administration routes. Those of skill in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0065] The term "co-administration" as used herein is intended to encompass administration of the selected therapeutic agents to a single patient and is intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0066] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound being administered which 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 signs, symptoms, or causes of a disease, or any other desired biological parameter. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case is optionally determined using techniques such as a dose escalation study.

[0067] The term "enhance" as used herein means to increase or prolong either the effect of a desired effect. Thus, with regard to enhancing the effect of a therapeutic agent, the term "enhance" refers to the ability to increase or prolong the effect of another therapeutic agent in the system. An "enhancing effective amount" as used herein refers to an amount that is sufficient to enhance the effect of another therapeutic agent in the desired system.

[0068] The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients (e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof), and active co-agent, are packaged together in a single entity or dose. The term "non- fixed combination" means that the active ingredients (e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof), and active co-agent, are provided in separate entities or doses for administration to a patient simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapies that involve the administration of three or more active ingredients.

[0069] The terms "article of manufacture" and "kit" are used synonymously.

[0070] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0071] As used herein, the term "treatment" includes alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or preventing the symptoms of the disease or condition from worsening or from becoming symptomatic.

[0072] Pharmaceutical composition

[0073] 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 processing of the active compounds into preparations that can be used pharmaceutically. Suitable preparations depend on the chosen route of administration. An overview of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th ed. (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, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference.

[0074] In some embodiments, the compounds described herein are administered alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in pharmaceutical compositions. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, but are not limited to, administration through enteral routes (including oral), although the most suitable route can depend on, for example, the condition and disorder being treated.

[0075] In some embodiments, pharmaceutical compositions suitable for oral administration are in the form of discrete units (such as capsules or tablets each containing a predetermined amount of the active ingredient; or powders or granules).

[0076] Orally administrable pharmaceutical compositions include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The tablets can be compressed or molded, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricating, surface- active, or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and / or are formulated to provide slow or controlled release of the active ingredient therefrom. All orally administrable formulations should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starch and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in a suitable liquid, such as fatty oil, 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 can be used, which can 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 can be added to the tablets or dragee cores to be in the different combinations of the active compound doses.

[0077] Conventional techniques for manufacturing solid oral dosage forms include, but are not limited to, one or a combination of the following methods: (1) dry mixing, (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, e.g., spray-drying, pan coating, melt granulation, granulation, fluid bed spray-drying or coating (e.g., Wurster coating), tangential coating, top-spray, tableting, extrusion, etc.

[0078] It should be understood that, in addition to the ingredients particularly mentioned above, the compounds and compositions described herein can include other agents conventional in art of formulation, for example, those suitable for oral administration can include flavoring agents.

[0079] Provided herein are tablets comprising Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets comprise: Compound A-HCl or a solvate thereof dispersed in a polymeric matrix formed from a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants; and optionally one or more film coating agents.

[0080] 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 Compound A-HCl or a solvate thereof is dispersed in a polymeric matrix formed from a pharmaceutically acceptable polymer.

[0081] In some embodiments, described herein is a tablet prepared with a spray-dried solid dispersion described herein.

[0082] Spray-dried solid dispersion (SDD)

[0083] The amorphous state of most small molecule drugs is thermodynamically unstable and, unless the glass transition temperature (Tg) is sufficiently high, also kinetically unstable. However, the amorphous state can be stabilized by diluting 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 upon storage. Phase separation into domains rich in drug is a precursor to the formation of crystal nuclei and eventual extensive crystallization, which leads to loss of solubility advantage. In some embodiments, the pharmaceutically acceptable polymer used to prepare the spray-dried solid dispersion is a polymer with a high Tg. When the active pharmaceutical ingredient (API) and excipient are not thermodynamically miscible with each other in the solid state, the spray-dried dispersion (SDD) is formulated such that the final Tg of the mixture, including absorbed water, is at least 10°C to 20°C higher than typical storage conditions. In addition, the hygroscopicity during storage must be taken into account by selecting a non-hygroscopic polymer or packaging configuration, as adsorbed water will plasticize the dispersion and lower the Tg.

[0084] In some embodiments, Compound A-HCl or a solvate thereof in the spray-dried solid dispersion described herein is substantially amorphous.

[0085] In some embodiments, the pharmaceutically acceptable polymer comprises a polymer that is optionally functionalized with any combination of alkyl ethers, alkyl esters, phthalates; vinyl alcohol; vinyl acetate; propylene glycol; pyrrolidone; vinyl pyrrolidone; ethylene oxide; propylene oxide; methacrylic acid; methyl methacrylate; ethylene glycol; glyceryl ethylene glycol; oxirane; oxetane; 2-ethyl-2-oxazoline; maleic acid; methyl vinyl ether; vinyl caprolactam; or combinations thereof.

[0086] 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 ethylcellulose, 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), copolymer of methacrylic acid and methyl methacrylate, polyethylene glycol glyceryl ester consisting of mono- and di-esters of polyethylene glycol, glycerides and glyceryl triesters, copolymer of hydroxypropyl cellulose, oxirane and oxetane blocks, poly(2-ethyl-2-oxazoline), poly(maleic acid / methyl vinyl ether), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, oxirane / oxetane tetrafunctional block copolymer, d-alpha tocopherol polyethylene glycol 1000 succinate, or combinations thereof.

[0087] In some embodiments, the spray-dried dispersion further comprises a dispersion polymer. The dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate; HPMCAS, such as HPMCAS-H, HPMCAS-L, or HPMCAS-M), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, 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.

[0088] HPMCAS is a cellulose polymer with four types of semi-random substituents on the hydroxyl groups: methoxy, hydroxypropoxy, acetate, and succinate. The polymer has three grades: L, M, and H, based on the content (wt%) of acetyl and succinoyl groups in the HPMCAS molecule. Grade L: 5 to 9 wt% acetate, 14 to 18 wt% succinate, 20 to 24 wt% methoxy, 5 to 9 wt% hydroxypropoxy. Grade M: 7 to 11 wt% acetate, 10 to 14 wt% succinate, 21 to 25 wt% methoxy, 5 to 9 wt% hydroxypropoxy. Grade H: 10 to 14 wt% acetate, 4 to 8 wt% succinate, 22 to 26 wt% methoxy, 6 to 10 wt% hydroxypropoxy.

[0089] 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(methyl methacrylic acid-methyl methacrylate copolymer) (PMMAMA or trade name Eudragit L100), Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55, and Soluplus.

[0090] 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.

[0091] In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 : 10 to about 10: 1. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 : 1 to about 1 : 10. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :3 to about 1 :8. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :4 to about 1 :7. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :4 to about 1 :6. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :5 to about 1 :6. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 : 10. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :9. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :8. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :7. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :6. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :5. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :4. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :3. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 :2. In some embodiments, the weight ratio of Compound A-HCl or solvate thereof to dispersion polymer is about 1 : 1.

[0092] In some embodiments, the spray-dried solid dispersion comprises at least 5% by weight of Compound A-HCl or solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 10% by weight of Compound A-HCl or solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 15% by weight of Compound A-HCl or solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 20% by weight of Compound A-HCl or solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 25% by weight of Compound A-HCl or solvate thereof. The % amount is calculated based on the free base (i.e., Compound A).

[0093] 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 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 solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 15% of Compound A-HCl or solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 35% of Compound A-HCl or solvate thereof. The % amount is calculated based on the free base (i.e., Compound A).

[0094] 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 % amount is calculated based on the free base (i.e., Compound A).

[0095] 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 non-aqueous solvent.

[0096] In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent selected from the group consisting of t-butyl alcohol, n-propyl alcohol, n-butyl alcohol, isopropyl alcohol, 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.

[0097] Tablets

[0098] In one aspect, described herein is a tablet comprising: Compound A-HCl or a solvate thereof dispersed in a polymeric matrix formed from a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants; and optionally one or more film coating agents.

[0099] In some embodiments, the Compound A-HCl or a solvate thereof dispersed in a polymeric matrix formed from a pharmaceutically acceptable polymer is a spray-dried solid dispersion described herein.

[0100] In some embodiments, the tablet comprises about 2% to about 20% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the tablet comprises about 2% to about 15% by weight of Compound A-HCl or a solvate thereof.

[0101] In some embodiments, the tablet comprises about 10% to about 30% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer. In some embodiments, the tablet comprises about 20% to about 35% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer.

[0102] 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.

[0103] 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 one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants; and optionally less than about 5% by weight of one or more film coating agents.

[0104] In some embodiments, the 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, the additional excipients in the tablet in addition to the spray-dried solid dispersion include microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate.

[0105] In some embodiments, the tablet comprises one or more fillers / binders / diluents. The fillers / binders / diluents are selected from celluloses such as microcrystalline cellulose, carboxymethylcellulose, ethyl cellulose, and methyl cellulose, starches, gelatin, sugars such as sucrose, glucose, dextrose, mannitol, and lactose, natural and synthetic gums such as acacia, sodium alginate, gum tragacanth, and gum ghatti, polyvinylpyrrolidone, polyethylene glycol, waxes, and any combination thereof. In some embodiments, the tablet comprises microcrystalline cellulose and mannitol.

[0106] In some embodiments, one or more fillers / adhesives / 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 / adhesives / 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 / adhesives / 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 / adhesives / 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 / adhesives / 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 / adhesives / diluents. In some embodiments, less than 60% by weight of the total tablet weight comprises one or more fillers / adhesives / diluents.

[0107] In some embodiments, a tablet comprises one or more disintegrants. Disintegrants are selected from the group consisting of sodium croscarmellose, crospovidone, sodium starch glycolate, veegum HV, methylcellulose, agar, bentonite, cellulose, carboxymethylcellulose, and any combination thereof. In some embodiments, a tablet comprises crospovidone.

[0108] In some embodiments, one or more disintegrants in a tablet described herein comprise about 2% to about 30% by weight of the total tablet weight. In some embodiments, one or more disintegrants in a tablet described herein comprise about 5% to about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in a tablet described herein comprise about 10% to about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in a tablet described herein comprise 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%, or about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in a tablet 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.

[0109] In some embodiments, the tablet comprises one or more lubricants. The lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, and any combination thereof. In some embodiments, the tablet comprises magnesium stearate.

[0110] In some embodiments, the one or more lubricants in the tablet described herein comprises about 0.1% to about 5% by weight of the total tablet weight. In some embodiments, the one or more lubricants in the tablet described herein comprises about 0.1% to about 2% by weight of the total tablet weight. In some embodiments, the one or more lubricants in the tablet described herein comprises about 0.1% to about 1% by weight of the total tablet weight. In some embodiments, the one or more lubricants in the tablet described herein comprises 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, the one or more lubricants in the tablet described herein comprises 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.

[0111] In some embodiments, the tablet comprises one or more glidants. Glidants are substances added to powders to improve their flow properties. Examples of glidants include magnesium stearate, colloidal silicon dioxide, starch, and talc. In some embodiments, the tablet comprises colloidal silicon dioxide.

[0112] 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%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 1% 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 1.5% by weight of the total tablet weight comprises one or more lubricants.

[0113] Additional excipients

[0114] In some embodiments, the tablets described herein comprise additional excipients, including but not limited to buffering agents, glidants, preservatives, and colorants. Additional excipients such as fillers, tonicity agents, and chelating agents are also within the scope of embodiments.

[0115] Non-limiting examples of buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate co-precipitate, mixtures of amino acids and buffers, mixtures of glycine aluminum and buffers, mixtures of acid salts of amino acids and buffers, and mixtures of base salts of amino acids and buffers. 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, glycerophosphate calcium, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0116] In some embodiments, the tablets described herein comprise a preservative. Preservatives include antimicrobials, 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 bisulfate, sodium metabisulfite, sodium sulfite, parabens (methyl-, ethyl-, butyl-), benzoic acid, potassium sorbate, vanillin, and the like.

[0117] In some embodiments, the tablets described herein comprise a colorant for identification and / or aesthetic purposes in the resulting liquid form. Suitable colorants illustratively include 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.

[0118] Additional excipients are contemplated in tablet embodiments. These additional excipients are selected based on functionality and compatibility with the tablet compositions described herein, and can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th 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, 7th ed. (Lippincott Williams & Wilkins 1999), the entire contents of which are incorporated herein by reference.

[0119] In further embodiments, the tablets described herein are coated tablets, such as enteric-coated tablets, sugar-coated tablets, or film-coated tablets.

[0120] In one embodiment, the individual unit dosage also includes a film coating that disintegrates upon oral administration or contact with a diluent. In one embodiment, these formulations are manufactured by conventional techniques.

[0121] Compressed tablets are solid dosage forms prepared by compacting the bulk mixed formulation described above. In various embodiments, compressed tablets designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, compressed tablets will include a film that wraps the final compressed tablet. In some embodiments, the film coating aids patient compliance (e.g., Film coatings comprising Film coatings typically comprise about 1% to about 5% of the tablet weight. In other embodiments, compressed tablets include one or more excipients.

[0122] Provided herein are film-coated tablet dosage forms comprising: a combination of an active ingredient (e.g., Compound A-HCl) and one or more tabletting excipients to form a tablet core, followed by coating the tablet core. The tablet core is produced using conventional tabletting processes, followed by compression and coating.

[0123] An enteric coating is a coating that resists the action of gastric acid but dissolves or disintegrates in the intestine.

[0124] In one aspect, the oral solid dosage forms disclosed herein include an enteric coating. The enteric coating includes one or more of the following: 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 types), styrene maleic acid copolymer, polymethacrylic acid / acrylic acid copolymer, hydroxyethyl ethylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate tetrahydrophthalate, acrylic acid resin, shellac.

[0125] An enteric coating is a coating placed on tablets, pills, capsules, pellets, beads, granules, granulates, and the like, so that it does not dissolve until it reaches the small intestine.

[0126] Sugar-coated tablets are compressed tablets that are wrapped by a sugar coating, which can be beneficial to mask an unpleasant taste or odor and protect the tablet from oxidation.

[0127] Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film-coating includes, but is not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film-coating has the same general properties as sugar-coating. 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, the tablets are coated with a water-soluble, pH-independent film coating that allows for immediate disintegration for fast, active release (e.g., Opadry products).

[0128] Dosage in tablets

[0129] In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 5 mg to about 100 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 5 mg to about 80 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 5 mg to about 60 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 10 mg to about 40 mg.

[0130] In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 10 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 20 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 30 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 40 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 50 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 60 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 70 mg. In some embodiments, the amount of Compound A-HCl, or solvate thereof, in the tablet is about 80 mg.

[0131] Methods of administration and treatment regimens

[0132] In one embodiment, the pharmaceutical compositions disclosed herein are used as medicaments for treating a disease or condition in a mammal that would benefit from modulation of somatostatin activity. Methods of treating any of the diseases or conditions described herein in a mammal in need of such treatment include administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof.

[0133] In certain embodiments, compositions containing Compound A described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount and for a time sufficient to cure or at least partially arrest symptoms of at least one of the disease or condition. Effective amounts for this use depend on the severity of the disease or condition, the duration of the symptoms, the previous treatments, the health status of the patient, the body weight of the patient and the response to the drug of the patient, 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 ranging clinical trials.

[0134] However, in general, the dosage for adult treatment is typically in the range of about 10 mg to about 100 mg of Compound A per day. In one embodiment, the required dosage is conveniently administered in a single dose or in divided doses simultaneously or at appropriate intervals, for example, two, three, four or more times per day.

[0135] 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 per day.

[0136] Examples

[0137] The following examples are for illustrative purposes only and do not limit the scope of the claims provided herein.

[0138] Example 1 : Oral Capsules

[0139] Representative capsules are described in Table 1 below.

[0140] Table 1.

[0141]

[0142] a Amounts corrected for assay and moisture, chloride and isopropanol content;

[0143] b Capsule fill weights adjusted based on blend assay;

[0144] c Consists of red iron oxide, titanium dioxide and gelatin.

[0145] A representative description of the manufacturing process for hot melt granulated capsules is as follows:

[0146] Stage 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 to a high shear wet granulator and mixed. The melted Vitamin E TPGS is sprayed onto the granulation components.

[0147] Stage 2: Milling: Grind the wet granulation through a screen mill using an appropriate size screen.

[0148] Stage 3: Mixing: Sieve the sodium stearyl fumarate using an appropriate size screen. Load the milled granulation into a diffusion blender (tumble) along with the sodium stearyl fumarate and mix.

[0149] Stage 4: Encapsulation: Automatically encapsulate 10 mg capsules in size 2 gelatin capsules.

[0150] Example 2: Spray-dried solid dispersion

[0151] Spray dried solid dispersions were prepared with 15% w / w Compound A-HCl: 15 / 85 Compound A-HCl / HPMCAS-M and 15 / 85 Compound A-HCl / PVP VA64 formulations. Manufacturing was completed using a BLD-150 (bend lab dryer with a drying gas capacity of 150 kg / h). The parameters changed were the solution solids loading for the HPMCAS-M SDD formulation (to help reduce nozzle bearding) and the dryer outlet temperature for the PVP VA64 SDD (to eliminate the risk of fluctuations that can occur during clinical manufacturing). The initial process parameter screening plan specified manufacturing the reduced dryer outlet temperature condition using a larger orifice nozzle to produce larger particles, however, based on the results of the first spray, it was determined that the atomization pressure required to achieve the desired solution flow rate was too low to fully atomize the solution using the larger orifice. Since the dryer outlet temperature tends to have more variability than the solution flow rate, the parameter screen was shifted to focus on reducing the dryer outlet temperature alone while ensuring complete droplet atomization. Changes in the dryer outlet temperature affect the residual solvent levels in the SDD, which in turn affect the physical and chemical stability. All sprays were successfully completed with good yield, indicating that both formulations have strong processing space.

[0152] 15 / 85 Compound A HPMCAS-M SDD formulation manufacturing details

[0153] Three sub-batches of 15 / 85 Compound A-HCl / HPMCAS-M SDD were sprayed to explore the manufacturing processing space and to prepare for clinical trial manufacturing. The first sub-batch was sprayed at 10% w / w solids, and significant nozzle bearding was observed after approximately 45 minutes on solution, which appeared to affect the spray plume.

[0154] The solution was diluted to 8% w / w, and one sub-batch was manufactured with a 1 hour duration to ensure reduced bearding. Very little bearding was observed in this batch after approximately 50 minutes on solution, but it did not appear to affect the atomized plume, and a 8% w / w solids loading was selected.

[0155] Throughout all spraying processes, cooling water flowed at 2 GPM and approximately 7°C over the spray dryer caps to keep the caps cool and prevent sticking and browning. No significant cap buildup or browning was observed throughout the manufacturing process. No cleaning was performed between sprays, and all spraying was completed from a solution with added solvent prior to manufacturing batches 2A and 2C. A summary of the manufacturing parameters used for all three sub-batches is shown in Table 2.

[0156] Table 2.15 / 85 Summary of the manufacture of compound A-HCl / HPMCAS-M SDD.

[0157]

[0158]

[0159] 1 The drying yield is calculated by dividing the collected SDD sample and the dried bulk by the amount of solids sprayed.

[0160] Manufacturing details of compound A-HCl / PVP VA64 SDD formulation (15 / 85)

[0161] Process parameter screening for the 15 / 85 compound A-HCl / PVP VA64 SDD formulation, including spray and FPN demonstration batches, has also been completed. The dryer outlet temperature has been adjusted to reduce the risk of process parameter variability, preparing for clinical trial manufacturing.

[0162] The process space is limited by the maximum dryer outlet temperature, the minimum required solution flow rate, and the specified maximum inlet temperature of 160°C to prevent SDD adhesion or browning on the spray dryer cover. The minimum flow rate is set at 100 g / min to ensure sufficient yield. The minimum and maximum dryer outlet temperatures are selected as 40°C and 65°C, respectively, to ensure thorough drying of the particles and that the dryer outlet temperature does not exceed the Tg of the wet particles.

[0163] Screening process parameters for the PVP VA64 formulation was conducted by spraying the product and exploring the manufacturing space by varying the dryer outlet temperature. This allowed for investigation of the effects of the dryer's relative saturation on the residual solvent content, morphology, density, and stability of the particles.

[0164] Cooling water was flowed through all sprays at 2 GPM and approximately 7°C to prevent cap buildup and browning, but neither was observed. Nozzle whiskers were observed in any of the three manufacturing processes. All sprays were produced from a single solution. Manufacturing details for each sub-batch are summarized in Table 3.

[0165] Table 3. Compound A-HCl* / PVP VA64 SDD Process Parameters

[0166]

[0167] Compound A-HCl was formulated on a free base basis.

[0168] 1 Dry yield was calculated as the amount of SDD sample collected and dry bulk divided by the amount of solid sprayed.

[0169] SDD Characterization

[0170] Particle Properties: The particle size distribution, bulk density, and tap density of each batch of Compound A-HCl SDD were measured. The HPMCAS-M SDD had a larger particle size, as expected, since the HPMCAS-M solution was more viscous than the PVP VA64 solution, which resulted in larger droplets for a given nozzle configuration. The increased solid loading in the solution for batch 2B resulted in larger particles than batches 2A and 2C, also due to the higher viscosity of the spray solution. As expected, the particle size distribution was similar for all PVP VA-64 batches.

[0171] The bulk and tap densities were similar for 2A and 2C, while batch 2B had slightly lower densities, likely due to the larger particles. The bulk and tap densities were similar for all PVP VA-64 batches, indicating that the effect of the dryer outlet temperature on powder properties was a robust process.

[0172] Residual Solvents and Water Content: Residual methanol and water were measured in the six SDDs using GC and KF methods, respectively. After secondary drying, all SDDs contained less than 0.3 wt% residual methanol, in line with the ICH guidelines, indicating sufficient drying at 40 °C / 15% relative humidity.

[0173] Morphology by SEM: The particle morphology of all six SDDs was evaluated by SEM. Each SDD showed typical morphology with no evidence of irregular particles, indicating sufficient atomization under all conditions tested. The HPMCAS-M particles were primarily collapsed spheres, while the PVP VA64 SDDs contained a larger proportion of spherical particles.

[0174] Crystallinity by PXRD: The crystallinity of all six SDDs was evaluated using PXRD. All SDDs were amorphous by PXRD, as evidenced by the lack of sharp diffraction peaks.

[0175] Thermal properties by DSC: All six SDDs were characterized by modulated DSC. Results are listed in Table 4. The manufactured SDDs were amorphous and homogeneous by DSC, as evidenced by the presence of a single glass transition in both the heating and reversing heat signals. Neither formulation showed signs of crystallization after the Tg, indicating a low propensity for crystallization of Compound A at these temperatures for both formulations. Additionally, both formulations showed a high Tg relative to ambient temperature, indicating a low risk of physical stability under dry conditions. The PVP VA64 formulation would need to be packaged to reduce humidity.

[0176] Table 4. Thermal properties of six batches of tablets measured by DSC.

[0177]

[0178] Summary

[0179] Physical stability observations: PVP VA64 SDDs showed deliquescence and crystals were observed after 3 months of storage (40°C / 75% relative humidity open). It is recommended to store with a desiccant. HPMCAS-M SDDs remained physically stable for 6 months at 40°C / 75% relative humidity open.

[0180] Chemical stability observations: The HPMCAS-M formulation showed possible acid catalyzed degradation in stability. The PVP VA64 formulation also showed some degradation, but not as significantly as the HPMCAS-M SDD. The PVP VA SDDs would need to be packaged for physical stability considerations.

[0181] Select 15% Compound A / PVP VA64 by weight as the primary SDD formulation.

[0182] 12 month stability: 15% Compound A-HCl / PVP-VA64 SDD

[0183] The 12 month SDD samples were stored with a desiccant at 5°C, 25°C / 60% relative humidity, and 40°C / 75% relative humidity. Water analysis samples for Karl Fisher titration were prepared and analyzed immediately; the remaining samples were vacuum dried overnight to remove residual moisture and preserve the physical state of the SDDs for further characterization. The list of analytical tests for characterization included: appearance, water content by Karl Fisher titration, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), thermal characterization by modulated differential scanning calorimetry (mDSC), dissolution performance by mini centrifuge (MCT) testing, assay and related substances by HPLC.

[0184] PXRD analysis of the 12 month SDD stability samples concluded that there was no evidence of crystallization in the samples stored for 12 months under each stability condition.

[0185] SEM analysis of the 12 month SDD stability samples concluded that no particle fusion was observed at all stability conditions for 12 months. There was no indication of crystallization in the samples stored for 12 months at each stability condition.

[0186] SEM analysis of the 12 month SDD stability samples concluded that no particle fusion was observed at all stability conditions for 12 months. There was no indication of crystallization in the samples stored for 12 months at each stability condition.

[0187] mDSC analysis of the 12 month SDD stability samples concluded that the repeat analysis of the 12 month SDD sample stored at 5°C resulted in a non-reproducible thermogram, the cause of which is currently unknown. The 5°C sample was determined to be physically stable by all other characterization techniques. The SDD samples stored at 25°C / 60% relative humidity and 40°C / 75% relative humidity for 12 months showed a single, reproducible Tg of 124°C to 125°C, supporting the conclusion that the SDD was still stable after storage with desiccant at these conditions for 12 months.

[0188] MCT dissolution analysis of the 12 month SDD stability samples concluded that the non-sink dissolution performance of the 12 month stability samples was consistent with the initial (to) sample stored at -20°C.

[0189] 35 / 65 Compound A-HCl / PVP VA64 SDD formulation manufacturing details

[0190] Spray dried solid dispersions were prepared with 35% by weight of Compound A-HCl: 35 / 65 Compound A-HCl / PVP VA64 formulation.

[0191] Manufacture of the SDD was accomplished using an SD-180 lab dryer. Secondary drying was accomplished using a binder fluid bed dryer. Manufacturing details are summarized in Table 5.

[0192] Spraying was successfully accomplished with high yield.

[0193] Table 5. 35 / 65 Compound A-HCl* / PVP VA64 SDD process parameters

[0194] Parameter Value Bulk SDD collected (g) 2796 Solid loading in solution (% by weight) 10.8 Solvent Methanol Spray SD-90 with pressure vortex Atomization pressure (psig) 320 Solution flow rate (g / min) 115 Drying gas rate 80 Drier inlet temperature (°C) 100 Drier outlet temperature (°C) 45 Condenser set point (°C) -20 Bulk secondary tray drying 40 °C / ambient pressure for 48 hours

[0195] *Compound A-HCl formulated on a free base basis

[0196] Example 3: Oral Tablets

[0197] Representative 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg spray-dried dispersion tablets are listed in Tables 6, 7, 8, 9, 10, 11, 12, and 13.

[0198] Typical excipients for preparing tablets include: microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate, and Opadry White 03K184116 (film coating).

[0199] Table 6. Representative 10 mg spray-dried dispersion tablets.

[0200]

[0201]

[0202] a Methanol removed during drying in the spray-drying process.

[0203] b Composed of hypromellose 2910, titanium dioxide, and triacetin.

[0204] c Purified water removed during drying in the film coating process.

[0205] Table 7. Representative 20 mg spray-dried dispersion (HPMCAS-M) tablets.

[0206]

[0207] Table 8. Representative 20 mg spray-dried dispersion (PVPVA 64) tablets.

[0208]

[0209]

[0210] Table 9. Additional representative 20 mg spray-dried dispersion tablets.

[0211]

[0212] Table 10. Representative 30 mg and 40 mg spray-dried dispersion (PVPVA 64) tablets.

[0213]

[0214] Table 11. Additional representative 40 mg spray-dried dispersion (PVPVA 64) tablets.

[0215]

[0216] Table 12. Representative 60 mg spray-dried dispersion (PVPVA 64) tablets.

[0217]

[0218] Table 13. Additional representative 60 mg spray-dried dispersion (PVPVA 64) tablets.

[0219]

[0220]

[0221] Table 14. Exemplary spray-dried dispersion tablets.

[0222]

[0223]

[0224] A representative non-limiting description of the manufacturing process for SDD tablets is as follows:

[0225] Stage 1 : Spray-drying: Compound A-HCl and copovidone were dissolved in MeOH. The solution was spray-dried. The spray-dried dispersion (Compound A-HCl SDD) was collected.

[0226] Stage 2: Roller compactor compaction: A granulation mixture consisting of Compound A-HCl SDD, filler, disintegrant, glidant, and lubricant was mixed. In some embodiments, a granulation mixture consisting of Compound A-HCl SDD, mannitol, microcrystalline cellulose, crospovidone, colloidal silicon dioxide was prepared and mixed. The granulation intra-granulation of magnesium stearate was sieved and added to the granulation mixture. The resulting mixture was mixed. The granulation mixture was loaded into the hopper of a roller compactor and compacted into a ribbon. The ribbon was passed through a screen using an in-line vibration mill to break up the ribbon and mill into granules.

[0227] In some embodiments, the granulation mixture comprises about 20% to about 35% (weight / weight of the final tablet weight) of Compound A-HCl SDD. In some embodiments, the granulation mixture comprises about 21%, about 22%, about 28%, 29%, about 33%, about 34% (weight / weight of the final tablet weight) of 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 / PVPVA 64, or 35 / 65 Compound A-HCl / PVPVA 64 SDD.

[0228] Stage 3: Mixing:The intragranular material is mixed with the extragranular excipients. The extragranular excipients include one or more excipients selected from the group consisting of fillers, disintegrants, glidants, and lubricants. The extragranular components include microcrystalline cellulose, crospovidone, colloidal silicon dioxide. The extragranular lubricant magnesium stearate is sieved using an appropriate size sieve and then added to the mixture and mixed.

[0229] Stage 4: Compression: The final mixture is compressed into tablets.

[0230] Stage 5: Pan coating: The 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.

[0231] Example 4: Evaluation of formulation performance in dogs

[0232] Study design

[0233] Two conditions were evaluated in dogs: +Pg pretreatment (simulating a fasted stomach in humans, pH 1-2) and -Pg pretreatment (simulating a human taking a PPI or antacid, pH 3-5). (*: there was a 1-week washout period between each condition; Pg = pentagastrin.)

[0234] Compound A-HCl solution

[0235] N = 4 immunized dogs. Vehicle: propylene glycol. Condition: -Pg.

[0236] Compound A-HCl HMG Capsules

[0237] N = 4 immunized dogs. Condition: +Pg, -Pg.

[0238] Compound A-HCl spray-dried dispersion tablets: PVPVA

[0239] N = 6 immunized male dogs, divided into 2 groups. Condition: +Pg, -Pg.

[0240] The results of this study are listed in Tables 15 and 16.

[0241] Table 15. Canine pharmacokinetic evaluation of formulations of Compound A-HCl

[0242]

[0243] As shown in Tables 15 and Figure 2As shown, the HMG capsule formulation performed poorly in dogs without pentagastrin pretreatment, while the spray-dried dispersion tablet performed better; for the HMG capsule formulation, the AUC without pentagastrin was only 11% of the AUC with pentagastrin (98.2 ng*h / mL vs. 917 ng*h / mL). In contrast, the AUC for the PVPVA SDD tablet formulation without pentagastrin was 185% and 124%, respectively, of the AUC with pentagastrin. These data suggest that the PVPVA SDD tablet is superior in a high gastric pH environment (e.g., in subjects taking a PPI or antacid).

[0244] Table 16. Canine pharmacokinetic evaluation of 60 mg 35 / 65 PVP-VA SDD tablets of Compound A-HCl

[0245]

[0246] Example 5: Evaluation of Compound A Phase I, multi-cohort, single-dose study of the relative bioavailability, performance, and safety of two formulations of

[0247] The study was conducted in up to 3 cohorts, each with a specific primary objective:

[0248] Cohort 1: To characterize the performance of a 10 mg tablet prepared by spray-dried dispersion (SDD) of Compound A-HCl salt.

[0249] Cohort 2: To assess the relative bioavailability of a 10 mg SDD tablet compared to a Compound A-HCl hot melt granulation (HMG) formulation (10 mg capsule). To determine the effect of food administration time on the pharmacokinetics of the low-dose 10 mg SDD tablet.

[0250] Cohort 3: To determine the effect of food administration time on the pharmacokinetics of the SDD tablet and dose proportionality at doses higher than 20 mg. To determine the optimal dosing regimen that can produce adequate systemic exposure within a short post-dose fast duration.

[0251] Study design:

[0252] Up to thirty-six (36) healthy male and female subjects were enrolled. Cohorts 1-2 each consisted of four periods, and Cohort 3 consisted of three periods.

[0253] Cohort 1:

[0254] SDD tablets were evaluated. Up to twelve (12) healthy male and female subjects per cohort were enrolled. Cohort 1 consisted of 4 periods: In Period 1, subjects were administered a proton pump inhibitor (lansoprazole, 15 mg BID, for 3 consecutive days (starting on Day 3), taken orally at least 30 minutes before meals, once in the morning and once in the evening). On the fourth day (Day 1 of the study), fasted subjects will take the last dose of lansoprazole (15 mg) 60 minutes prior to taking 20 mg of Compound A (2 x 10 mg SDD tablets). In Period 2, fasted subjects were administered 20 mg of Compound A (2 x 10 mg of SDD tablets). In Period 3, fasted subjects were administered 20 mg of Compound A (2 x 10 mg of SDD tablets) and a high-fat, high-calorie meal. In Period 4, fasted subjects will take up to 80 mg of Compound A (up to 8 x 10 mg of SDD tablets). The actual dose was selected based on pharmacokinetic data from Period 2.

[0255] For Period 1: On the evening before dosing (Day -1), subjects were administered an evening dose of 15 mg lansoprazole, provided a dinner at least 30 minutes after administration of lansoprazole, and then asked to fast overnight (≥ 10 hours) on Day -1. On Day 1, they were administered a morning dose (last dose) of 15 mg lansoprazole at least 60 minutes prior to administration of Compound A (2 x 10 mg SDD tablets). Subjects continued to fast for 2 hours after taking Compound A, after which they were allowed to ingest a standard meal.

[0256] For 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 administered orally. Subjects continued to fast for 2 hours after taking Compound A, after which they were allowed to ingest a standard meal.

[0257] For Period 3: Subjects were asked to fast overnight (≥ 10 hours) on Day 14. On Day 15, they were allowed to ingest a high-fat, high-calorie meal within 30 minutes. After completion of meal ingestion, Compound A (2 x 10 mg SDD tablets) was administered (no more than 30 minutes after the start of the meal). No additional food was provided for at least 4 hours after administration of Compound A.

[0258] Subjects were not allowed to perform strenuous exercise for more than 30 minutes / day for 3 days prior to Day -1 and throughout the study.

[0259] Pharmacokinetic and safety assessments, including adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, 12-lead electrocardiogram, Holter electrocardiogram, and telemetry monitoring (for Period 4 only), and physical examinations were performed at scheduled times throughout the study.

[0260] Cohort 2:

[0261] This cohort consists of four periods. In each period, a single dose of 20 mg Compound A (2 x 10 mg SDD) is administered orally.

[0262] For Period 1 : Subjects are required to fast overnight (> 10 hours) on Day -1. On Day 1, they are given a low-fat meal 2 hours after administration of 20 mg Compound A (2 x 10 mg HMG capsules; reference formulation).

[0263] For Period 2: Subjects are required to fast overnight (> 10 hours) on Day 7. On Day 8, they are given a low-fat meal 2 hours after administration of 20 mg Compound A (2 x 10 mg SDD tablets; test formulation).

[0264] For Period 3: Subjects are required to fast overnight (> 10 hours) on Day 14. On Day 15, they are given a low-fat meal 1 hour after administration of 20 mg Compound A (2 x 10 mg SDD tablets).

[0265] For Period 4: Subjects are required to fast overnight (> 10 hours) on Day 21. On Day 22, they are given a low-fat meal 0.5 hours after administration of 20 mg Compound A (2 x 10 mg SDD tablets).

[0266] The last study visit occurs on Day 29. Subjects are not allowed to perform strenuous exercise for more than 30 minutes / day for the 3 days prior to Day -1 and throughout the study. Pharmacokinetic and safety assessments, including adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, 12-lead electrocardiogram, and physical examination are performed at scheduled times throughout the study.

[0267] Cohort 3:

[0268] This cohort consists of three periods. In each period, a single dose of Compound A SDD (40 mg, 60 mg, or 80 mg) (4 x 10 mg SDD tablets, 6 x 10 mg SDD tablets, or 8 x 10 mg SDD tablets) is administered orally. There is a washout period of at least 10 days between each dose of Compound A.

[0269] For Period 1 : Subjects are required to fast overnight (> 10 hours) on Day -1. On Day 1, they are given a standard meal 1 hour after administration of 40 mg Compound A (4 x 10 mg SDD tablets).

[0270] For Period 2: Subjects were required to fast overnight (>10 hours) on Day 10. On Day 11, they were given a standard meal 1 hour or 2 hours after administration of 80 mg Compound A (8 x 10 mg SDD tablets). The timing of the meal (1 hour or 2 hours after Compound A administration) was dependent on the mean AUC determined in Period 1 0-24 .

[0271] For Period 3: Subjects were required to fast overnight (>10 hours) on Day 20. On Day 21, they were given a standard meal 1 hour or 4 hours after administration of 60 mg or 80 mg Compound A (6 x 10 mg SDD tablets or 8 x 10 mg SDD tablets). The dose and timing of the standard meal was dependent on the mean AUC determined in Period 2 0-24 .

[0272] The last study visit occurred on Day 29. Subjects were not to perform strenuous exercise for more than 30 minutes / day for 3 days prior to Day -1 and throughout the study. Pharmacokinetic and safety assessments, including adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, 12-lead electrocardiogram, and physical examination were performed at scheduled times throughout the study.

[0273] Study Population:

[0274] Up to 36 healthy male or female subjects between the ages of 18 and 55 years, inclusive, were enrolled. For Cohort 2 only, male and female subjects between the ages of 18 and 65 years, inclusive, were screened.

[0275] Inclusion Criteria

[0276] Each subject must meet all of the following inclusion criteria to participate in the study: Male and female subjects between the ages of 18 and 55 years, inclusive, at the time of screening. For Cohort 2 only, male and female subjects between the ages of 18 and 65 years, inclusive, at the time of screening. Body mass index (BMI) between 18 kg / m 2 and 30 kg / m 2 , inclusive. Willing to avoid strenuous, unaccustomed exercise and exertion, defined as more than 30 minutes per day for 3 days prior to Day -1 and throughout the study. If the subject is a heterosexual or bisexual female, she must be infertile or agree to use one highly effective or two clinically acceptable methods of birth control.

[0277] Exclusion Criteria

[0278] Health subjects meeting any of the following criteria will be excluded from the study: pre-treatment with Compound A. Any uncontrolled or active major systemic illness that makes participation in the study unsafe or can interfere with the assessment of study endpoints. History of malignancy or presence of malignancy, except for adequately treated basal cell or squamous cell carcinoma of the skin within the past 5 years. Active acute or chronic infection. Use of any investigational drug within the past 60 days or 5 half-lives, whichever is longer, prior to first dose of study drug. Use of tobacco and / or nicotine-containing products, recreational drugs, or alcohol within 48 hours prior to admission and agreement to refrain from use throughout the study. History of alcohol abuse and / or other drug addiction less than 1 year prior to screening or current situation. Use of any prescription or over-the-counter (OTC) medications or alternative medicines within the previous 14 days prior to Day -1. Use of caffeinated beverages or foods within 48 hours prior to Day -1 and 48 hours prior to each check-in day for all subsequent periods. Consumption of food containing poppy seeds within 7 days prior to screening until completion of study assessments. Taking moderate or strong CYP3A4 inhibitors or inducers. Engaging in strenuous exercise for more than 30 minutes / day within 3 days prior to Day 1 and throughout the study. Loss of blood > 500 mL or donation of blood within 3 months prior to admission. Amylase and / or lipase levels > 2 x ULN, alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) > 2 x ULN, total bilirubin > 1.5 x ULN (except in known cases of Gilbert’s syndrome), and / or serum creatinine above the upper limit of normal. History of hypersensitivity to any excipients in the study drug. Positive screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab), or history of positive results. Female subjects with a positive serum pregnancy test or who are lactating. For Cohort 1 only, subjects are categorized as CYP2C19 poor or ultra-rapid metabolizers.

[0279] Test product, dose, and mode of administration:

[0280] 10 mg tablets (SDD). Multiple tablets are swallowed with water according to the dose specified in the given period / cohort.

[0281] Reference therapy, dose, and mode of administration:

[0282] 10 mg HMG capsule formulation is used as the reference formulation. Multiple capsules are swallowed with water according to the dose specified in the given period / cohort.

[0283] Plasma pharmacokinetic parameters:

[0284] Blood pharmacokinetic samples are collected to assess plasma concentrations of Compound A.

[0285] The pharmacokinetic parameters for Compound A were calculated and are shown in the table below: Area under the plasma concentration curve from 0 hours to 24 hours (AUC 0-24 ), maximum plasma concentration (C max ), time to reach maximum plasma concentration (T max );

[0286] Results

[0287] The results of this clinical trial indicate that co-administration of a proton pump inhibitor has only a small effect on the pharmacokinetics observed when SDD tablets are administered, SDD tablets achieve shorter fasted times, and SDD tablets provide better dose-proportionate pharmacokinetics.

[0288] Results from Cohort 1 are listed in Table 17.

[0289] Table 17. Results from Cohort 1

[0290]

[0291]

[0292] Median and range of T max are reported. Mean and range of P4 / P2 ratio are reported. All doses were administered with overnight fast and 2h fast after administration. Food: high fat meal.

[0293] Cohort 1 (SDD 10mg x 2, different conditions): observed exposures with and without PPIs were comparable in comparability. Cohort 1 (SDD 10mg x 2 vs 10mg x 6): relative dose proportionate increase in exposure was observed.

[0294] No relative dose proportionate increase in exposure was observed for HMG capsules compared to SDD tablets. See Figure 1 . Dose proportionate data for HMG capsules obtained from previous clinical studies are shown in Table 18.

[0295] Table 18. Comparative data: dose proportionality observed for HMG capsule formulation after single dose (4h fast post-dose).

[0296]

[0297] Data shown are mean ± standard deviation

[0298] Results from Cohort 2 are listed in Table 19.

[0299] Table 19. Results from Cohort 2

[0300]

[0301]

[0302] All doses were administered with overnight fasting.

[0303] Cohort 2 (SDD 10 mg x 2 vs. HMG, different post-dose fasting durations): SDD tablets do not appear to have better exposure than HMG capsules, and the two formulations are relatively comparable. For SDD tablets, AUC 0-24 (a measure of the extent of absorption) drops to 82% of the post-dose fast 2h, which is a relatively small drop in exposure.

[0304] In a previously completed clinical study, HMG capsules performed poorly under different post-dose fasting duration regimens compared to the performance of SDD tablets under different post-dose fasting duration regimens. Pharmacokinetic data obtained after administration of a 20 mg dose (10 mg HMG capsule x 2) to 12 subjects (N=4 males, N=8 females) are listed in Table 20.

[0305] Table 20. Comparative data: HMG capsule performance under different post-dose fasting durations

[0306]

[0307] For the HMG capsule formulation, it was noted that there was an approximately 30% loss in the extent of absorption for the post-dose 1h fast compared to the post-dose 2h fast.

[0308] HMG capsules with a 2h fast were evaluated in a Phase II clinical study. A 1h fast is more desirable than a 2h fast. Only an 18% loss in AUC (0-24) was observed for the 1h fast compared to the 2h fast. SDD 1h fast will be used in Phase III. Importantly, SDD tablets appear to have a better dose proportionality than HMG capsules, allowing for a 3.0-fold dose (i.e., 60 mg) to be administered in the Phase III clinical study.

[0309] The embodiments and implementations described herein are for illustrative purposes only and various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

1. A spray-dried solid dispersion, said spray-dried solid dispersion comprising: (a) 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzyl nitrile or a pharmaceutically acceptable salt thereof; and (b) Pharmaceutically acceptable polymers; 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzyl nitrile or a pharmaceutically acceptable salt thereof is dispersed in a polymer matrix formed from said pharmaceutically acceptable polymer; The pharmaceutically acceptable polymer is a polyvinylpyrrolidone / polyvinyl acetate copolymer (PVP / VA 64) in a ratio of 6:4; and The spray-dried solid dispersion comprises 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzanilonitrile or a pharmaceutically acceptable salt thereof in a weight ratio of 15 / 85 or 35 / 65 to PVP / VA 64, wherein the weight ratio is based on the weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzanilonitrile.

2. The spray-dried solid dispersion of claim 1, wherein 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzyl nitrile or a pharmaceutically acceptable salt thereof is 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzyl nitrile monohydrochloride.

3. The spray-dried solid dispersion of claim 1, wherein the spray-dried dispersion comprises 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxy-benzyl nitrile monohydrochloride in a weight ratio of 15 / 85 to PVP / VA 64, wherein the 15 / 85 weight ratio is based on the weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxy-benzyl nitrile.

4. The spray-dried solid dispersion of claim 1, wherein the spray-dried solid dispersion comprises 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxy-benzyl nitrile monohydrochloride in a weight ratio of 35 / 65 to PVP / VA 64, wherein the 35 / 65 weight ratio is based on the weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxy-benzyl nitrile.

5. A tablet comprising: 20% to 35% by weight of the spray-dried solid dispersion according to any one of claims 1 to 4; 60% to 80% by weight of one or more pharmaceutically acceptable ingredients selected from microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, croscarmellose, sodium chloride, a 1:1 ratio of sodium chloride to potassium chloride, silicon dioxide, and magnesium stearate; and Optional, less than 5% by weight of one or more film coating agents.

6. A tablet comprising: 20% to 35% by weight of the spray-dried solid dispersion of claim 3; 60% to 80% by weight of one or more pharmaceutically acceptable ingredients selected from microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, croscarmellose, sodium chloride, a 1:1 ratio of sodium chloride to potassium chloride, silicon dioxide, and magnesium stearate; and Optional, less than 5% by weight of one or more film coating agents.

7. The tablet as claimed in claim 5 or claim 6, wherein: The tablets contain 5 mg to 80 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzyl nitrile monohydrochloride.

8. The tablet of claim 6, wherein the tablet comprises: 20% to 35% by weight of the spray-dried solid dispersion as described in claim 3; 50% to 65% by weight of microcrystalline cellulose, mannitol or a combination thereof; 10% to 20% by weight of cross-linked polyvinylpyrrolidone; 0.1% to 1% by weight of magnesium stearate; Colloidal silica; and Optional, less than 5% by weight of one or more film coating agents.

9. Use of the tablet of any one of claims 5 to 8 in the preparation of a medicament for treating acromegaly or neuroendocrine tumors or both in humans, wherein said treatment comprises orally administering one or more tablets once daily to a person suffering from acromegaly or neuroendocrine tumors or both.

10. Use of the spray-dried solid dispersion of any one of claims 1 to 4 in the preparation of a medicament for treating acromegaly or neuroendocrine tumors in humans, or both.

11. Use of the tablet of any one of claims 5 to 8 in the preparation of a medicament for treating acromegaly in humans, wherein the treatment comprises orally administering one or more tablets once daily to a person suffering from acromegaly.

12. Use of the spray-dried solid dispersion according to any one of claims 1 to 4 in the preparation of a medicament for treating acromegaly in humans.

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