Preparations of somatostatin regulators

Abstract

The present invention provides a pharmaceutical composition containing a somatostatin regulator. [Solution] A pharmaceutical composition is provided for use in a method of inhibiting growth hormone (GH), insulin, glucagon, insulin-like growth factor 1 (IGF-1), prolactin, or a combination thereof in humans, wherein the pharmaceutical composition comprises a therapeutically effective amount of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable components, wherein the method comprises the step of orally administering the pharmaceutical composition to the human being in a fasted state at least 30 minutes before a meal.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 076,024, filed Sep. 9, 2020, which is hereby incorporated by reference in its entirety.

[0002] This specification describes pharmaceutical compositions and drugs containing somatostatin regulators, methods of making such pharmaceutical compositions and drugs, and methods of using such pharmaceutical compositions and drugs in the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity.

Background Art

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

Summary of the Invention

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

[0005] In some embodiments, pharmaceutically acceptable polymers include 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, and cellulose acetate copolymer. These include polyethylene glycol glycerides composed of tate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), copolymers of methacrylic acid and methyl methacrylate, mono, di, and triglycerides, and mono and diesters of polyethylene glycol, hydroxypropyl cellulose, copolymers of ethylene oxide block and propylene oxide block, poly(2-ethyl-2-oxazoline), poly(maleic acid / methyl vinyl ether), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide / propylene oxide tetrafunctional block copolymer, d-alpha-tocopheryl polyethylene glycol 1000 succinate, or combinations thereof. In some embodiments, pharmaceutically acceptable polymers are 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 (PVP / VA64) in a 6:4 ratio.

[0006] In some embodiments, the weight ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof to a pharmaceutically acceptable polymer is about 1:10 to about 10:1. In some embodiments, the weight ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof to a pharmaceutically acceptable polymer is about 1:4 to about 1:6. In some embodiments, the weight ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof to a pharmaceutically acceptable polymer is about 1:1.5 to about 1:6.

[0007] In some embodiments, the spray-dried solid dispersion contains at least about 5% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the spray-dried solid dispersion contains at least about 10% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the spray-dried solid dispersion contains at least about 15% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof.

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

[0009] In some embodiments, 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or its pharmaceutically acceptable salt or solvate is substantially amorphous.

[0010] In some embodiments, 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof is 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

[0011] In another embodiment, tablets are provided herein, each comprising a spray-dried solid dispersion described herein, one or more pharmaceutically acceptable components selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, and one or more lubricants, and optionally one or more film coating agents.

[0012] In another embodiment, tablets are provided herein, comprising 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, one or more pharmaceutically acceptable components selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, and one or more film coating agents, optionally one or more film coating agents. In some embodiments, the 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer is the spray-dried solid dispersion described herein. In some embodiments, one or more pharmaceutically acceptable components include microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate. In some embodiments, one or more pharmaceutically acceptable components include microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, colloidal silicon dioxide, and magnesium stearate.

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

[0014] In some embodiments, the tablet comprises about 2% to about 10% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate, 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 components selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants; and optionally, one or more film coating agents in less than about 5% by weight.

[0015] In some embodiments, the tablet comprises about 2% to about 10% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate, 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 components selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants; and optionally, one or more film coating agents in less than about 5% by weight.

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

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

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

[0019] In some embodiments, the tablet is a spray-dried dispersion of about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, or about 35% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3, The present invention comprises a spray-dried dispersion having a ratio of 5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) of about 15 / 85 or about 35 / 65; one or more pharmaceutically acceptable components in an amount of about 60% to about 80% by weight selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegration aids, one or more lubricants, and one or more film coating agents in an amount of about 5% by weight (optional).

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

[0021] In some embodiments, the tablet contains about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 60 mg, or about 80 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxy-benzonitrile monohydrochloride or its solvate. In some embodiments, the tablet contains about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxy-benzonitrile monohydrochloride or its solvate.

[0022] In some embodiments, the tablet contains about 10 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxy-benzonitrile monohydrochloride or its solvate. In some embodiments, the tablet contains about 20 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxy-benzonitrile monohydrochloride or its solvate. In some embodiments, the tablet contains about 30 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxy-benzonitrile monohydrochloride or its solvate. In some embodiments, the tablet contains about 40 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxy-benzonitrile monohydrochloride or its solvate. In some embodiments, the tablet contains about 50 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxy-benzonitrile monohydrochloride or its solvate. In some embodiments, the tablet contains about 60 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxy-benzonitrile monohydrochloride or its solvate.

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

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

[0025] Other features and advantages of the compositions, compounds, and methods described herein will become apparent from the following detailed description. However, since various changes and modifications within the spirit and scope of the present disclosure will be apparent to those skilled in the art from this detailed description, it should be understood that the detailed description and specific examples are given by way of illustration only and not for the purpose of limitation, showing specific embodiments.

Brief Description of the Drawings

[0026] [Figure 1] Illustrates the observed dose proportionality in humans administered with the HMG capsule formulation or the SDD tablet formulation of Compound A-HCl. [Figure 2] Illustrates the performance of the HMG capsule formulation and the SDD tablet formulation of Compound A-HCl in dogs with or without pentagastrin pretreatment.

Modes for Carrying Out the Invention

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

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

[0029] It is possible to selectively modulate one or a combination of somatostatin receptor subtypes. In some embodiments, selectively modulating one somatostatin receptor subtype to another somatostatin receptor subtype, or a combination thereof, is useful in a variety of clinical applications. In some embodiments, selectively modulating one somatostatin receptor subtype to another somatostatin receptor subtype reduces undesirable side effects in a variety of clinical applications.

[0030] For example, modulation of SSTR2 activity mediates the inhibition of growth hormone (GH) release from the anterior pituitary gland and glucagon release from the pancreas. SSTR2 is also involved in many other biological functions, including, but not limited to, cell proliferation, nociception, inflammation, and angiogenesis. In some embodiments, selective SSTR2 modulators are used to treat acromegaly, enteroendocrine tumors, pain, neuropathy, nephropathy, and inflammation, as well as retinopathy resulting from abnormal vascular growth. In some other embodiments, selective SSTR2 modulators are used, among other things, 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 diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, and Graves' ophthalmology.

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

[0032] Somatostatin peptides and their receptor subtypes are widely expressed in the brain, and interference with or reduction of their activity may be involved in several psychiatric and neurodegenerative disorders. For example, somatostatin concentrations in the cerebral cortex and hippocampus are reduced in schizophrenia, and one of the most consistent neuropathological findings in this patient group is the absence of inhibitory interneurons in the cortex that express somatostatin. Somatostatin is also highly expressed in brain regions associated with seizures and has been suggested to play an important role in epilepsy. Somatostatin levels are reduced in the hippocampus of patients with Alzheimer's disease and Parkinson's disease, suggesting that restoring its signaling may be a drug target for potential neurodegeneration.

[0033] In one embodiment, compound 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate is a selective non-peptide SST2 bias agonist suitable for oral administration to mammals requiring treatment with somatostatin modulotropes.

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

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

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

[0037] Compound A is a somatostatin regulator useful in the therapeutic methods described herein.

[0038] Compound A As used herein, compound A refers to 3-(4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl)-2-hydroxybenzonitrile, which has the chemical structure shown below.

[0039] [ka]

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

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

[0042] As used herein, "pharmaceutically acceptable" means a material such as a carrier or diluent that does not destroy the biological activity or properties of a compound and is relatively non-toxic; that is, the material is administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

[0043] The term "pharmaceutically acceptable salt" refers to a cationic form of a therapeutic activator combined with a suitable anion, or, in alternative embodiments, a form of a therapeutic activator consisting of an anionic form of a therapeutic activator combined with a suitable cation. (Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SMBerge, LDBighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PHStahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.) Pharmaceutical salts are typically more soluble in gastric and intestinal fluids and dissolve more rapidly than nonionic species, making them useful in solid dosage forms. Furthermore, since their solubility is often a function of pH, selective dissolution in one or another part of the digestive tract is possible, and this ability can be manipulated as one aspect of delayed-release and sustained-release behavior. In addition, salt-forming molecules can be in equilibrium in a neutral form, thus regulating their passage through biological membranes.

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

[0045] In some embodiments, compound A is incorporated into the formulations described herein as a pharmaceutically acceptable salt form selected from compound A hydrochloride and compound A methanesulfonic acid. In some embodiments, the salt form of compound A is compound A monohydrochloride. In some embodiments, the salt form of compound A is compound A dihydrochloride. In some embodiments, the salt form of compound A is compound A monomethanesulfonic acid. In some embodiments, the salt form of compound A is compound A dimethanesulfonic acid.

[0046] In one embodiment, compound A monohydrochloride (compound A-HCl) is incorporated into the pharmaceutical composition described herein. Compound A monohydrochloride (compound A-HCl) is also known as 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride and has the following structure.

[0047] [ka]

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

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

[0050] It should be understood that references to pharmaceutically acceptable salts include solvated forms. In some embodiments, the solvates are formed during a crystallization process using a pharmaceutically acceptable solvent, such as water or ethanol, containing either a stoichiometric or non-stoichiometric amount of solvent. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. The solvates of the compounds described herein can be easily prepared or formed during the processes described herein. In addition, the compounds provided herein exist in both non-solvated and solvated forms, optionally.

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

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

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

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

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

[0056] Residual solvents in active pharmaceutical ingredients (APIs) originate from the API's manufacturing process. In most cases, solvents are not completely removed by practical manufacturing techniques. Appropriate selection of solvents for API synthesis can enhance yield or determine properties such as crystalline form, purity, and solubility. Therefore, solvents are a crucial parameter in the synthesis process.

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

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

[0059] As used herein, the term "modulate" means, directly or indirectly, interacting with a target to alter its activity, including, by example, enhancing, inhibiting, limiting, or prolonging its activity.

[0060] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, counter-agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0061] Terms such as “administer,” “administering,” and “administration,” as used herein, refer to methods that may be used to enable the delivery of a compound or composition to a desired site of action. These methods include, but are not limited to, oral administration routes. Those skilled in the art will be familiar with administration techniques that may be used in conjunction with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

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

[0063] The terms “effective dose” or “therapeutic effective dose,” as used herein, refer to a sufficient amount of an administered drug or compound that will reduce, to some extent, one or more of the symptoms of the disease or condition being treated. Results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desirable alteration of the biological system. For example, for therapeutic use, the “effective dose” is the amount of a composition containing the compounds disclosed herein that is required to produce a clinically significant reduction in the symptoms of the disease. The appropriate “effective” dose in any individual case is determined at arbitrary discretion using techniques such as dose-escalation studies.

[0064] The terms “enhance” or “enhance” as used herein mean increasing or extending a desired effect in terms of either potency or duration. Therefore, with respect to the enhancement of a therapeutic effect, “enhance” refers to the ability to increase or extend the effect of another therapeutic agent on a system in terms of either potency or duration. “Enhancement dose” as used herein refers to an amount sufficient to enhance the effect of another therapeutic agent on a desired system.

[0065] When used herein, the term “pharmaceutical combination” means a product resulting from a mixture or combination of one or more active ingredients, and includes both fixed and unfixed combinations of active ingredients. “Fixed combination” means that both the active ingredient, e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof, and the concomitant drug are administered to the patient simultaneously in the form of a single entity or preparation. “Unfixed combination” means that the active ingredient, e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof, and the concomitant drug are administered to the patient simultaneously, concurrently, or successively without specific intervening time limitations, as separate entities, and such administration results in effective levels of the two compounds in the patient’s body. The latter also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0066] The terms "manufactured goods" and "kits" are used synonymously.

[0067] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other hominins and monkey species, domesticated animals such as cattle, horses, sheep, goats, and pigs, pet animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, a mammal is a human.

[0068] The terms “treat,” “treating,” or “treatment,” as used herein, include alleviating, reducing, or improving at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, for example, preventing the onset of a disease or condition, reducing a disease or condition, causing regression of a disease or condition, reducing a condition caused by a disease or condition, or cessating a preventive and / or therapeutic symptom of a disease or condition.

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

[0070] 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 carried out by any method that enables delivery of the compound to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral administration), although the most preferred route may depend, for example, on the recipient's condition and impairments.

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

[0072] Pharmaceutical compositions for oral use include tablets, compressible capsules made from gelatin, and soft, sealed capsules made from gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be prepared by compression or molding, with one or more optional adjuncts. Compressed tablets may be prepared by mixing an active ingredient in a free-flowing form, such as powder or granules, with an optional binder, inert diluent, or lubricant, surfactant, or dispersant, and compressing it in a suitable machine. Molded tablets may be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets are coated or scored to formulate them to result in the sustained or controlled release of the active ingredient therein. All formulations for oral administration should be in doses suitable for such administration. Compressible capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as a fatty acid, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The sugar-coated tablet core is coated with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally include gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablets for identification or to characterize different combinations of active compound dosages.

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

[0074] In particular, in addition to the components described above, the compounds and compositions described herein may also contain other drugs commonly used in the art, depending on the type of formulation. For example, formulations suitable for oral administration may contain flavoring agents.

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

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

[0077] In some embodiments, tablets prepared using the spray-dried solid dispersion described herein are described herein.

[0078] Spray-dried solid dispersion (SDD) The amorphous state of most small molecule drugs is thermodynamically unstable and kinetically unstable unless the glass transition temperature (Tg) is sufficiently high. However, the amorphous state can be stabilized by dilution of the drug in an excipient matrix. When amorphous molecules are dispersed in a high-Tg matrix, low molecular mobility provides a diffusion barrier that inhibits the molecular mobility required for phase separation during storage. Phase separation into drug-rich domains is a precursor to crystal nucleation, eventually leading to extensive crystallization and loss of solubility advantages. In some embodiments, pharmaceutically acceptable polymers for use in preparing spray-dried solid dispersions are polymers with high Tg. When the active pharmaceutical ingredient (API) and excipients are not thermodynamically miscible with each other in the solid state, the spray-dried dispersion (SDD) is formulated such that the resulting Tg of the mixture, including absorbed water, is at least 10°C to 20°C higher than under typical storage conditions. Furthermore, consideration must be given to moisture absorption during storage by selecting either a non-hygroscopic polymer or a packaging form, because absorbed water plasticizes the dispersion and lowers the Tg.

[0079] In some embodiments, compound A-HCl or its solvate in the spray-dried solid dispersion described herein is substantially amorphous.

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

[0081] In some embodiments, pharmaceutically acceptable polymers include 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, and cellulose acetate copolymer. These include tate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), copolymers of methacrylic acid and methyl methacrylate, polyethylene glycol glycerides composed of mono, di, and triglycerides and mono and diesters of polyethylene glycol, hydroxypropyl cellulose, copolymers of ethylene oxide block and propylene oxide block, poly(2-ethyl-2-oxazoline), poly(maleic acid / methyl vinyl ether), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide / propylene oxide tetrafunctional block copolymer, d-alpha-tocopheryl polyethylene glycol 1000 succinate, or combinations thereof.

[0082] In some embodiments, the spray-dried dispersion further comprises a dispersion polymer. The dispersion polymer is selected from hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (hydroxypropyl methylcellulose acetate succinate; HPMCAS, e.g., HPMCAS-H, HPMCAS-L, or HPMCAS-M), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl 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.

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

[0084] In some embodiments, pharmaceutically acceptable polymers are selected from PVP / VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit L100-55, poly(methacrylate-comethyl methacrylate) (PMMAMA, or trademark Eudragit L100), Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55, and Soluplus.

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

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

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

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

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

[0090] In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent. In some embodiments, the non-aqueous solvent is present in a detectable amount. In some embodiments, the spray-dried solid dispersion does not contain a non-aqueous solvent.

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

[0092] tablet In one embodiment, the following tablets are described herein, comprising a compound A-HCl or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, one or more pharmaceutically acceptable components selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, and one or more film coating agents, optionally one or more.

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

[0094] In some embodiments, the tablet contains about 2% to about 20% by weight of compound A-HCl or its solvate. In some embodiments, the tablet contains about 2% to about 15% by weight of compound A-HCl or its solvate.

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

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

[0097] In some embodiments, the tablet comprises about 2% to about 10% by weight of compound A-HCl or its solvate 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 components selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants; and optionally, one or more film coating agents in less than about 5% by weight.

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

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

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

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

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

[0103] In some embodiments, the tablet comprises one or more lubricants. The lubricants are selected from 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.

[0104] In some embodiments, one or more lubricants in the tablets described herein constitute about 0.1% to about 5% by weight of the total weight of the tablet. In some embodiments, one or more lubricants in the tablets described herein constitute about 0.1% to about 2% by weight of the total weight of the tablet. In some embodiments, one or more lubricants in the tablets described herein constitute about 0.1% to about 1% by weight of the total weight of the tablet. In some embodiments, one or more lubricants in the tablets described herein constitute 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 weight of the tablet. In some embodiments, one or more lubricants in the tablets described herein constitute about 0.5% by weight of the total weight of the tablet. In some embodiments, less than 2% by weight of the total weight of the tablet contains one or more lubricants. In some embodiments, less than 1% by weight of the total weight of the tablet contains one or more lubricants.

[0105] In some embodiments, the tablet contains one or more lubricants. Lubricants are substances added to the powder to improve its fluidity. Examples of lubricants include magnesium stearate, colloidal silicon dioxide, starch, and talc. In some embodiments, the tablet contains colloidal silicon dioxide.

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

[0107] Additional excipients In some embodiments, the tablets described herein include, but are not limited to, buffers, lubricants, preservatives, and colorants, additional excipients. Additional excipients such as bulking agents, isotonic agents, and chelating agents are within the scope of these embodiments.

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

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

[0110] In some embodiments, the tablets described herein include a colorant for identifying and / or aesthetic purposes of the resulting liquid form. Suitable colorants include, as examples, FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide, and mixtures thereof.

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

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

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

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

[0115] This specification provides a film-coated tablet form comprising an active ingredient (e.g., compound A-HCl) and one or more tableting excipients for forming a tablet core and subsequently coating the core. The tablet core is produced using a conventional tableting process, which is then compressed and coated.

[0116] Enteric coatings are coatings that are resistant to the action of stomach acid but dissolve or break down in the intestines.

[0117] In one embodiment, the oral solid dosage forms disclosed herein include an enteric coating. The enteric coating comprises 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 versions); styrene maleate copolymer; polymethacrylic acid / acrylic acid copolymer, hydroxyethyl ethylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate tetrahydrophthalate; acrylic resin; and shellac.

[0118] Enteric coating is a process that coats tablets, pills, capsules, pellets, beads, granules, and particles to prevent them from dissolving until they reach the small intestine.

[0119] Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant flavors or odors and protecting the tablets from oxidation.

[0120] Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets produced by one or more compression cycles, including layered tablets and press-coated or dry-coated tablets. In some embodiments, tablets are coated with a water-soluble, pH-independent film coating (e.g., Opadry products) that allows for rapid degradation to release the active ingredient quickly.

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

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

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

[0124] In certain embodiments, compositions containing compound A as described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially cessate at least one of the symptoms of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, previous therapies, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective dose may be determined by methods including, but not limited to, dose escalation and / or dose determination clinical trials, at the discretion of the treating physician.

[0125] However, generally speaking, the dose used for treating adult humans is typically compound A in the range of about 10 mg to about 100 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered consecutively or at appropriate intervals, for example, as two, three, four, or more partial doses per day.

[0126] Any of the embodiments described above includes a further embodiment in which the compound is administered once daily, and a further embodiment including a single dose of an effective amount of the compound. [Examples]

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

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

[0129] [Table 1]

[0130] A typical description of the manufacturing process for hot-melt granulated capsules is as follows:

[0131] 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 filled into a high-shear wet granulator and mixed. The melted vitamin E TPGS is sprayed onto the granulated components.

[0132] Stage 2: Grinding: The wet granules are ground through a screening mill using a screen of the appropriate size.

[0133] Stage 3: Blending:Sodium stearyl fumarate is sieved using a screen of the appropriate size. The crushed granules are then packed into a diffusion mixer (tumbler) with sodium stearyl fumarate and blended.

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

[0135] Example 2: Spray-dried solid dispersion Spray-dried solid dispersions were prepared using 15 wt% compound A-HCl: 15 / 85 compound A-HCl / HPMCAS-M and 15 / 85 compound A-HCl / PVP VA64. Production was completed using a BLD-150 Bend Lab Dryer with a drying gas capacity of 150 kg / hour. Modified parameters were solution solid loading for the HPMCAS-M SDD formulation to help reduce nozzle bearing, and the dryer outlet temperature for the PVP VA64 SDD to eliminate the risk of variability that may occur during clinical production. The original process parameter screening plan stipulated that the reduced dryer outlet temperature conditions should be manufactured using a larger orifice nozzle to produce larger particles; however, based on the results of the first spray, it was determined that the spray pressure required to achieve the desired solution flow rate was too low to completely atomize the solution with the larger orifice. Since the dryer outlet temperature tends to be more variable than the solution flow rate, the parameter screening was shifted to focus on eliminating the risk of dryer outlet temperature only, while ensuring complete atomization of the droplets. Fluctuations in the dryer outlet temperature can affect the residual solvent level in the SDD, which can impact physical and chemical stability. All spraying was completed successfully with good yields, demonstrating a robust process space for both formulations.

[0136] Details of the manufacturing process for compound A HPMCAS-M SDD formulation, 15 / 85. Three subbatches of compound A-HCl / HPMCAS-M SDD (15 / 85) were sprayed to explore the manufacturing process space and prepare for clinical trial production. When the subbatches were first sprayed with 10 wt% solid, significant nozzle bearing, which appeared to affect the spray plume, was observed on the solution after approximately 45 minutes.

[0137] The solution was diluted to 8 wt% and sub-batches were prepared over a period of 1 hour to ensure a reduction in bearing. After approximately 50 minutes on the solution, a very small amount of bearing was observed in this batch, but since this did not appear to affect the atomizing plume, 8 wt% solid loading was chosen.

[0138] Cooling water at 2 GPM and approximately 7°C was flowed through all sprays onto the spray dryer lid to keep it cool and prevent adhesion and browning. No significant buildup or browning of the lid was observed throughout the entire production process. No washing was performed between sprays, and all sprays were completed from a single solution to which additional solvent had been added before the production of batches 2A and 2C. A summary of the production parameters used for all three sub-batches is shown in Table 2.

[0139] [Table 2]

[0140] Details of the manufacturing process for compound A-HCl / PVP VA64 SDD formulation, 15 / 85. Process parameter screening spraying and FPN demonstration batches were also completed for compound A-HCl / PVP VA64 SDD formulation 15 / 85. The dryer outlet temperature was changed to eliminate the risk of process parameter variability, and preparations for clinical trial manufacturing were made.

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

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

[0143] To prevent cap buildup and browning, cooling water was circulated over all sprays at 2 GPM and approximately 7°C, but neither was recorded. No nozzle bearing was observed across all three production batches. All sprays were completed from a single solution. Production details for each subbatch are summarized in Table 3.

[0144] [Table 3]

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

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

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

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

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

[0150] Thermal properties by DSC: All six SDDs were characterized by controlled DSC. The results are summarized in Table 4. All manufactured SDDs were amorphous and homogeneous by DSC, as evidenced by the presence of a single glass transition in the reverse thermal signal. None of the formulations showed any signs of crystallization after Tg, suggesting that compound A has a low tendency to crystallize at these temperatures for both formulations. Furthermore, both formulations showed high Tg compared to ambient temperature, suggesting a low risk of physical instability under dry conditions. The PVP VA64 formulation requires packaging to minimize humidity.

[0151] [Table 4]

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

[0153] Chemical stability observations: Potential degradation of HPMCAS-M formulation due to acid catalysts. Some degradation is also observed in PVP VA64 formulation, but not as pronounced as in HPMCAS-M SDD. PVPVA SDD requires broadcasting due to concerns about physical stability.

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

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

[0156] Conclusions from PXRD analysis of 12-month SDD-stabilized samples: No evidence of crystallinity was found in samples stored for 12 months under each of the stability conditions.

[0157] Conclusions from SEM analysis of 12-month SDD-stabilized samples: No particle fusion was observed across all stability conditions at 12 months. No evidence of crystallinity was found in samples stored for 12 months under any of the stability conditions.

[0158] Conclusions from SEM analysis of 12-month SDD-stabilized samples: No particle fusion was observed across all stability conditions at 12 months. No evidence of crystallinity was found in samples stored for 12 months under each of the stability conditions.

[0159] Conclusions from mDSC analysis of 12-month stable SDD samples: Thermograms obtained from repeated analyses of 12-month SDD samples held at 5°C were non-reproducible, and the reason for this result is currently unknown. The 5°C samples were determined to be physically stable by all other characterization techniques. 12-month SDD samples held at 25°C / 60%RH and 40°C / 75%RH showed a single, reproducible Tg at 124–125°C, supporting the conclusion that SDD is stable after 12 months of storage with desiccant under these conditions.

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

[0161] Details of the manufacturing process for compound A-HCl / PVP VA64 SDD formulation with a 35 / 65 pH. A spray-dried solid dispersion was prepared using 35% by weight of compound A-HCl to create a compound A-HCl / PVP VA64 formulation with a 35 / 65 ratio.

[0162] The manufacturing of SDDs was completed using an SD-180 experimental dryer. Secondary drying was completed using a Binder Convection Dryer. Manufacturing details are summarized in Table 5.

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

[0164] [Table 5]

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

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

[0167] [Table 6]

[0168] [Table 7]

[0169] [Table 8]

[0170] [Table 9]

[0171] [Table 10]

[0172] [Table 11]

[0173] [Table 12]

[0174] [Table 13]

[0175] [Table 14]

[0176] A typical non-restrictive description of the manufacturing process for SDD tablets is as follows:

[0177] 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.

[0178] Stage 2: Roller compression: A granular blend consisting of compound A-HCl SDD, a filler, a disintegrant, a lubricant, and a moistener is blended. In some embodiments, a granular blend consisting of compound A-HCl SDD, mannitol, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide is prepared and blended. The granular portion of magnesium stearate is passed through a screen and added to the granular blend. The resulting blend is blended. The granular blend is filled into a roller-compression hopper and compressed into a ribbon. The ribbon is passed through a mesh screen using an in-line vibrating mill to break and crush the ribbon into granules.

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

[0180] Stage 3: Blending: The granular material is mixed with the extragranular excipient. The extragranular excipient includes one or more excipients selected from fillers, disintegrants, lubricants, and lubricants. The extragranular components include microcrystalline cellulose, crospovidone, and colloidal silicon dioxide. Magnesium stearate, an extragranular lubricant, is sieved using an appropriately sized screen, then added to the blend and mixed.

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

[0182] Stage 5: Bread coating: A film-coated suspension of Opadry White 03K18416 is prepared in purified water, and tablets are coated with Opadry White 03K18416 in a perforated coating pan.

[0183] Example 4: Evaluation of formulation performance in dogs Test design Two conditions were evaluated in dogs*: +Pg pretreatment (mimicking a human empty stomach, pH 1-2) and -Pg pretreatment (mimicking a human ingesting a PPI or antacid, pH 3-5). (*: One week of drug-free rest between each condition; Pg = pentagastrin.)

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

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

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

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

[0188] [Table 15]

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

[0190] [Table 16]

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

[0192] Cohort 1: Characterize the performance of 10 mg tablets prepared using a spray-dried dispersion (SDD) of compound A-HCl salt.

[0193] Cohort 2: Evaluate the relative bioavailability of 10 mg SDD tablets compared to compound A-HCl hot-melt granules (HMG) and 10 mg capsules. Determine the effect of food administration timing on the pharmacokinetics of low-dose 10 mg SDD tablets.

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

[0195] Test design: Up to 36 healthy men and women were enrolled. Cohorts 1 and 2 each consisted of four periods, while Cohort 3 consisted of three periods.

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

[0197] Phase 1: In the evening before medication (-1 day), subjects were administered a 15 mg evening dose of lansoprazole, and dinner was provided at least 30 minutes after the administration of lansoprazole. Subsequently, on -1 day, subjects were required to fast overnight (10 hours or more). On day 1, subjects were administered a morning dose (final dose) of 15 mg of lansoprazole, and at least 60 minutes later, compound A (two 10 mg SDD tablets) was administered. After compound A, subjects were required to fast for two hours, after which they were permitted to consume a standard meal.

[0198] Phase 2: Participants were asked to fast overnight (more than 10 hours) on day 7. On day 8, 20 mg of compound A (two 10 mg SDD tablets) was administered orally. After compound A, participants were required to fast for two hours, after which they were permitted to consume a standard diet.

[0199] Phase 3: Participants were asked to fast overnight (for more than 10 hours) on day 14. On day 15, participants were permitted to consume a high-fat, high-calorie meal within 30 minutes. After completing the meal, compound A (two 10 mg SDD tablets) was administered (within 30 minutes of starting the meal). No additional food was provided for at least 4 hours after the administration of compound A.

[0200] Participants were prohibited from engaging in more than 30 minutes of strenuous exercise per day, starting three days before day 1 and continuing throughout the entire test.

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

[0202] Cohort 2: The cohort consisted of four periods. In each period, a single dose of 20 mg of compound A (10 mg of SDD x 2) was administered orally.

[0203] Phase 1: Participants were asked to fast overnight (10 hours or more) on day 1. On day 1, a low-fat diet was given 2 hours after administration of 20 mg of compound A (two 10 mg HMG capsules, reference formulation).

[0204] Phase 2: Participants were asked to fast overnight (for more than 10 hours) on day 7. On day 8, participants were given a low-fat diet two hours after administration of 20 mg of compound A (two 10 mg SDD tablets, the test formulation).

[0205] Phase 3: On day 14, subjects were asked to fast overnight (for more than 10 hours). On day 15, subjects were given a low-fat diet one hour after being administered 20 mg of compound A (two 10 mg SDD tablets).

[0206] Phase 4: On day 21, subjects were asked to fast overnight (for more than 10 hours). On day 22, subjects were given a low-fat diet 0.5 hours after administration of 20 mg of compound A (two 10 mg SDD tablets).

[0207] The final trial visit was on day 29. Participants were prohibited from engaging in more than 30 minutes of strenuous exercise per day for three days prior to day -1 throughout the trial. PK and safety assessments, including adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, 12-lead ECG, and physical examination, were performed at scheduled times throughout the trial.

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

[0209] Phase 1: Participants were asked to fast overnight (more than 10 hours) on day 1. On day 1, participants were given a standard meal one hour after being administered 40 mg of compound A (four 10 mg SDD tablets).

[0210] Phase 2: Participants were asked to fast overnight (10 hours or more) on day 10. On day 11, participants were given a standard meal 1 or 2 hours after administration of compound A (8 x 10 mg SDD tablets). The timing of the meal (1 or 2 hours after administration of compound A) was determined by the mean AUC determined in Phase 1. 0-24 It was influenced by that.

[0211] Phase 3: Participants were asked to fast overnight (10 hours or more) on day 20. On day 21, participants were given a standard meal 1 or 4 hours after administration of 60 or 80 mg of compound A (6 x 10 mg SDD tablets or 8 x 10 mg SDD tablets). The amount and timing of the standard meal were determined based on the mean AUC determined in Phase 2. 0-24 It was influenced by that.

[0212] The final trial visit was on day 29. Participants were prohibited from engaging in more than 30 minutes of strenuous exercise per day for three days prior to day -1 throughout the trial. PK and safety assessments, including adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, 12-lead ECG, and physical examination, were performed at scheduled times throughout the trial.

[0213] Clinical trial population: Up to 36 healthy men or women aged 18-55 (including the endpoint) were enrolled. Cohort 2 only included men and women aged 18-65 (including the endpoint) at the time of screening.

[0214] Inclusion Criteria Each participant had to meet all of the following inclusion criteria to be enrolled in the study: males and females aged 18–55 years (including the endpoint) at the time of screening. Cohort 2 only: males and females aged 18–65 years (including the endpoint) at the time of screening. Body Mass Index (BMI) 18–30 kg / m² 2 (Including the endpoints). - From three days prior to day 1 throughout the trial, participants must be willing to refrain from strenuous, unfamiliar exercise and sports, defined as more than 30 minutes per day. If the participant is a heterosexual or bisexual woman, she must be non-fertile or agree to use two highly effective or clinically acceptable methods of contraception.

[0215] Exclusion criteria Healthy subjects meeting any of the following criteria were excluded from the study: Prior treatment with compound A; Uncontrolled or active major systemic disease that could jeopardize participation in the study or interfere with the evaluation of the study's endpoints; History or presence of malignancy within the past 5 years, excluding well-treated basal cell carcinoma or squamous cell carcinoma of the skin; Active acute or chronic infection; Use of any investigational drug within the past 60 days or 5 half-lives, whichever is longer, prior to the first dose of the investigational drug; Use of tobacco and / or nicotine-containing products, recreational drugs, or alcohol within 48 hours prior to hospitalization, and consent to refrain from use throughout the study; History of alcohol abuse and / or other drug dependence or ongoing abuse and / or dependence within 1 year prior to screening; Use of any prescription, over-the-counter (OTC), or alternative medication within 14 days of day 1; Use of caffeine-containing beverages or foods within 48 hours prior to day 1 and within 48 hours prior to each health check-up day in all subsequent periods. Ingestion of foods containing poppy seeds within 7 days prior to screening until completion of the study evaluation. Use of moderate or strong CYP3A4 inhibitors or inducers. More than 30 minutes of strenuous exercise per day from 3 days prior to day 1 throughout the study. More than 500 mL of blood loss or blood donation within 3 months prior to hospitalization. Having amylase and / or lipase levels greater than 2 × ULN, alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) greater than 2 × ULN, total bilirubin greater than 1.5 × ULN (except in known Gilbert's syndrome), and / or serum creatinine above the upper limit of normal. History of hypersensitivity reaction to any excipient in the study drug. Positive or a history of positive results on screening tests for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab). The study included women who had a positive serum pregnancy test or who were breastfeeding. Cohort 1 only included women classified as having poor or extremely rapid CYP2C19 metabolism.

[0216] Test product, dosage, and mode of administration: 10 mg tablets (SDD). Multiple tablets were swallowed with water according to the dose specified for the given period / cohort.

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

[0218] Blood PK samples were collected, and the plasma concentration of compound A was evaluated.

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

[0220] result The results of this clinical trial showed that co-administration of proton pump inhibitors had only a slight effect on the pharmacokinetics observed with SDD tablets, enabling shorter fasting times and demonstrating that SDD tablets provide better dose-proportional pharmacokinetics.

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

[0222] [Table 17]

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

[0224] Compared to SDD tablets, HMG capsules did not show a relatively dose-proportional increase in exposure. See Figure 1. Dose-proportional data for HMG capsules obtained from previous clinical trials are presented in Table 18.

[0225] [Table 18]

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

[0227] [Table 19]

[0228] Cohort 2 (SDD 10 mg x 2 vs. HMG, and different post-dosing fasting periods): SDD tablets did not appear to provide better exposure than HMG capsules, and the two formulations were relatively comparable. For SDD tablets, the AUC after 1 hour of fasting after dosing was measured. 0-24 The AUC (measure of the degree of absorption) decreased to 82% of the AUC observed after fasting for 2 hours post-administration, which is a relatively small reduction in exposure.

[0229] Compared to the performance of SDD tablets in different post-dose fasting scenarios, the function of HMG capsules was poor in different post-dose fasting scenarios in previously completed clinical trials. Pharmacokinetic data obtained after administering a 20 mg dose (2 x 10 mg HMG capsules) to 12 subjects (N=4 males, N=8 females) are presented in Table 20.

[0230] [Table 20]

[0231] With HMG capsule formulations, a loss of approximately 30% of the absorption rate was observed between fasting for 1 hour after administration and fasting for 2 hours after administration.

[0232] HMG capsules administered after a 2-hour fast were evaluated in a Phase 2 clinical trial. A 1-hour fast was preferable to a 2-hour fast. Compared to a 2-hour fast, a 1-hour fast resulted in a higher AUC. (0-24) Losses were observed in only 18% of cases. SDD was used in Phase 3 with a 1-hour fast. Importantly, the SDD tablets appeared to have better dose-proportionality than the HMG capsules, which allowed for a 3.0-fold increase in dose (i.e., 60 mg) in the Phase 3 clinical trial.

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

Claims

1. A spray-dried solid dispersion, (a) 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof, (b) comprising a pharmaceutically acceptable polymer, A spray-dried solid dispersion in which 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer.

2. The spray-dried solid dispersion according to claim 1, wherein the pharmaceutically acceptable polymer has a high glass transition temperature (Tg).

3. The spray-dried solid dispersion according to claim 1 or 2, wherein the pharmaceutically acceptable polymer comprises a polymer of cellulose, vinyl alcohol, vinyl acetate, propylene glycol, pyrrolidone, vinylpyrrolidone, oxyethylene, oxypropylene, methacrylic acid, methyl methacrylate, ethylene glycol, ethylene glycol glyceride, ethylene oxide, propylene oxide, 2-ethyl-2-oxazoline, maleic acid, methyl vinyl ether, vinyl caprolactam, or a combination thereof, optionally functionalized with any combination of alkyl ether, alkyl ester, or phthalate ester.

4. The aforementioned pharmaceutically acceptable polymers include 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), and hydroxypropyl methylcellulose. A spray-dried solid dispersion according to claim 1 or 2, comprising roxypropyl methylcellulose phthalate (HPMCP), a copolymer of methacrylic acid and methyl methacrylate, a polyethylene glycol glyceride composed of mono, di, and triglycerides and mono and diesters of polyethylene glycol, hydroxypropyl cellulose, a copolymer of ethylene oxide block and propylene oxide block, poly(2-ethyl-2-oxazoline), poly(maleic acid / methyl vinyl ether), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide / propylene oxide tetrafunctional group block copolymer, d-alpha-tocopheryl polyethylene glycol 1000 succinate, or a combination thereof.

5. The spray-dried solid dispersion according to claim 1 or 2, wherein the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA).

6. The spray-dried solid dispersion according to claim 1 or 2, wherein the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate grade M (HPMCAS-M).

7. The spray-dried solid dispersion according to claim 1 or 2, wherein the pharmaceutically acceptable polymer is polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA64) in a 6:4 ratio.

8. A spray-dried solid dispersion according to any one of claims 1 to 7, wherein the weight ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof to the pharmaceutically acceptable polymer is about 1:10 to about 10:

1.

9. A spray-dried solid dispersion according to any one of claims 1 to 7, wherein the weight ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof to the pharmaceutically acceptable polymer is about 1:1 to about 1:

10.

10. A spray-dried solid dispersion according to any one of claims 1 to 7, wherein the weight ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof to the pharmaceutically acceptable polymer is about 1:4 to about 1:

6.

11. A spray-dried solid dispersion according to any one of claims 1 to 7, wherein the weight ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof to the pharmaceutically acceptable polymer is about 1:1.5 to about 1:

6.

12. The spray-dried solid dispersion according to any one of claims 1 to 7, wherein the spray-dried solid dispersion comprises at least about 5% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof.

13. The spray-dried solid dispersion according to any one of claims 1 to 7, wherein the spray-dried solid dispersion comprises at least about 10% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof.

14. The spray-dried solid dispersion according to any one of claims 1 to 7, wherein the spray-dried solid dispersion contains about 15% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof.

15. The spray-dried solid dispersion according to any one of claims 1 to 7, wherein the spray-dried solid dispersion comprises about 35% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof.

16. A spray-dried solid dispersion according to any one of claims 1 to 15, further comprising a non-aqueous solvent.

17. The spray-dried solid dispersion according to claim 16, wherein the non-aqueous solvent is selected from the group consisting of tert-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, and mixtures thereof.

18. The spray-dried solid dispersion according to claim 16 or 17, wherein the non-aqueous solvent is selected from the group consisting of methanol, acetone, and mixtures thereof.

19. The spray-dried solid dispersion according to any one of claims 16 to 18, wherein the non-aqueous solvent is methanol.

20. A spray-dried solid dispersion according to any one of claims 1 to 19, wherein 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof is substantially amorphous.

21. The spray-dried solid dispersion according to any one of claims 1 to 20, wherein 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile or a pharmaceutically acceptable salt or solvate thereof is 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

22. It is a tablet, A spray-dried solid dispersion according to any one of claims 1 to 21, One or more pharmaceutically acceptable components selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, A tablet comprising one or more optional film coating agents.

23. It is a tablet, 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, One or more pharmaceutically acceptable components selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegrant aids, one or more lubricants, A tablet comprising one or more optional film coating agents.

24. The tablet according to claim 23, wherein the 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, is a spray-dried solid dispersion.

25. The tablet according to any one of claims 22 to 24, wherein the one or more pharmaceutically acceptable components include microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, colloidal silicon dioxide, and magnesium stearate.

26. The aforementioned tablet, A tablet according to any one of claims 22 to 25, comprising approximately 2% to approximately 20% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

27. The aforementioned tablet, A tablet according to any one of claims 22 to 25, comprising approximately 2% by weight, approximately 3% by weight, approximately 4% by weight, approximately 5% by weight, approximately 6% by weight, approximately 7% by weight, approximately 8% by weight, approximately 9% by weight, approximately 10% by weight, approximately 11% by weight, approximately 12% by weight, approximately 13% by weight, approximately 14% by weight, or approximately 15% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

28. The tablet according to any one of claims 23 to 27, wherein the tablet comprises about 10% to about 35% by weight of the polymer matrix formed from the pharmaceutically acceptable polymer.

29. The aforementioned tablet, A polymer matrix formed from a pharmaceutically acceptable polymer in which approximately 2% to approximately 15% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate is dispersed, wherein the dispersed 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate in the polymer matrix constitutes approximately 20% to approximately 35% by weight of the tablet, and One or more pharmaceutically acceptable components selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, in an amount of approximately 40% to approximately 80% by weight, A tablet according to any one of claims 23 to 28, optionally comprising one or more film coating agents in an amount of less than approximately 5% by weight.

30. The aforementioned tablet, A spray-dried dispersion of approximately 20% to 40% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, One or more pharmaceutically acceptable components selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegrant aids, one or more lubricants, in an amount of approximately 60% to approximately 80% by weight, A tablet according to claim 23 or 24, optionally comprising one or more film coating agents in an amount of less than approximately 5% by weight.

31. The tablet according to claim 30, wherein the spray-dried dispersion has a ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) of about 15 / 85 to about 35 / 65.

32. The aforementioned tablet, A spray-dried dispersion of about 20% to about 35% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, The spray-dried dispersion comprises a spray-dried dispersion in which the ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) is approximately 15 / 85 to approximately 35 / 65. One or more pharmaceutically acceptable components selected from the group consisting of microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, silicon dioxide, and magnesium stearate, in an amount of approximately 60% to approximately 80% by weight, The tablet according to claim 23, comprising, optionally, one or more film coating agents in an amount of less than approximately 5% by weight.

33. The aforementioned tablet, A spray-dried dispersion of about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, or about 35% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, The spray-dried dispersion comprises a spray-dried dispersion in which the ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) is approximately 15 / 85 or approximately 35 / 65. One or more pharmaceutically acceptable components selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegrant aids, one or more lubricants, in an amount of approximately 60% to approximately 80% by weight, A tablet according to any one of claims 23 to 32, comprising, optionally, one or more film coating agents in an amount of less than approximately 5% by weight.

34. The aforementioned tablet, A spray-dried dispersion of about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, or about 35% by weight of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, The spray-dried dispersion comprises a spray-dried dispersion in which the ratio of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) is approximately 15 / 85 or approximately 35 / 65. One or more pharmaceutically acceptable components selected from the group consisting of microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, silicon dioxide, and magnesium stearate, in an amount of approximately 60% to approximately 80% by weight, A tablet according to any one of claims 23 to 32, comprising, optionally, one or more film coating agents in an amount of less than approximately 5% by weight.

35. The tablet according to any one of claims 22 to 34, wherein the tablet contains about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

36. The tablet according to any one of claims 22 to 35, wherein the tablet contains about 10 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

37. The tablet according to any one of claims 22 to 35, wherein the tablet contains about 20 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

38. The tablet according to any one of claims 22 to 35, wherein the tablet contains about 30 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

39. The tablet according to any one of claims 22 to 35, wherein the tablet contains about 40 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

40. The tablet according to any one of claims 22 to 35, wherein the tablet contains about 50 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

41. The tablet according to any one of claims 22 to 35, wherein the tablet contains about 60 mg of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or a solvate thereof.

42. A method for treating acromegaly or neuroendocrine tumor or both in a human, comprising orally administering a tablet according to any one of claims 22 to 41 to the human having acromegaly or neuroendocrine tumor.

43. The method according to claim 42, wherein the tablet is administered once a day.

44. The method according to claim 42 or 43, wherein the tablet is administered at least 30 minutes before a meal.

45. The method according to claim 43 or 44, wherein the tablet is administered at least 60 minutes before a meal.

46. The method according to any one of claims 42 to 45, wherein the tablet is administered with a glass of water on an empty stomach at least 30 minutes before a meal.

47. The method according to any one of claims 42 to 46, wherein the bioavailability of 3-[4-(4-amino-piperidine-1-yl)-3-(3,5-difluorophenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride or its solvate is substantially unaffected by the co-administration of a proton pump inhibitor, a histamine H2 receptor antagonist, or an antacid.

48. The method according to any one of claims 42 to 47, wherein the tablet is administered simultaneously with a proton pump inhibitor, a histamine H2 receptor antagonist, or an antacid.

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