Oral compositions / formulations of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-YL]piperidin-1-YL}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1h-benzimidazole-6-carboxylic acid or a pharmaceutically salt thereof

Abstract

The invention relates to immediate-release oral pharmaceutical compositions and oral controlled release swellable core technology (SCT) tablets of 2-({4-[(2S)-2-(4-chloro-2- fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid (Compound 1) or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1) and process of making such compositions and tablets. The present invention further relates to methods of using these compositions and tablets once daily for weight management control or for treating, e.g., T2DM, obesity, or overweight.

Description

[0001] ORAL COMPOSITIONS / FORMULATIONS OF 2-({4-[(2S)-2-(4-CHLORO-2-FLUOROPHENYL)-2-METHYL-1 ,3-BENZODIOXOL-4- YL]PIPERIDIN-1-YL}METHYL)-1-[(2S)-OXETAN-2-YLMETHYL]-1H-BENZIMIDAZOLE-6- CARBOXYLIC ACID OR A PHARMACEUTICALLY SALT THEREOF

[0002] FIELD OF INVENTION

[0003] The present invention provides an oral composition or formulation containing 2-({4-[(2S)- 2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan- 2-yl methyl]- 1 H-benzimidazole-6-carboxylic acid, or a pharmaceutically salt thereof [such as its 2-amino-2-(hydroxymethyl)propane-1 ,3-diol salt, also known as its tris salt]. Moreover, the invention provides a method for treating type 2 diabetes mellitus or for weight management control (e.g. treating obesity or overweight) using the oral compositions / formulations of the present invention.

[0004] BACKGROUND OF THE INVENTION

[0005] Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Two major forms of diabetes are recognized, Type 1 and Type 2. Type 1 diabetes (T1 D) develops when the body's immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. To survive, people with Type 1 diabetes must have insulin administered by injection or a pump. Type 2 diabetes mellitus (referred to generally as T2DM) usually begins with either insulin resistance or when there is insufficient production of insulin to maintain an acceptable glucose level.

[0006] Currently, various pharmacological approaches are available for treating hyperglycemia and subsequently, T2DM (Hampp, C. et al. Use of Antidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 2014, 37, 1367-1374). These may be grouped into six major classes, each acting through a different primary mechanism: (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin), and glucagon-like peptide-1 receptor (GLP-1 R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance secretion of insulin by acting on the pancreatic beta-cells. Sulphonyl-ureas and meglitinides have limited efficacy and tolerability, cause weight gain and often induce hypoglycemia. DPP-IV inhibitors have limited efficacy. Marketed GLP-1 R agonists are peptides primarily administered by subcutaneous injection. Semaglutide and liraglutide are additionally approved for the treatment of obesity. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism, subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents, and frequent use may also lead to weight gain and carries a risk of hypoglycemia. (F) sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit reabsorption of glucose in the kidneys and thereby lower glucose levels in the blood. This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.

[0007] With the exception of GLP-1 R agonists and SGLT2 inhibitors, the currently available drugs have limited efficacy and do not address the most important problems, the declining p-cell function and the associated obesity.

[0008] Obesity is a chronic disease that is highly prevalent in modern society and is associated with numerous medical problems including hypertension, hypercholesterolemia, and coronary heart disease. It is further highly correlated with T2DM and insulin resistance, the latter of which is generally accompanied by hyperinsulinemia or hyperglycemia, or both. In addition, T2DM is associated with a two to fourfold increased risk of coronary artery disease. Presently, the only treatment that eliminates obesity with high efficacy is bariatric surgery, but this treatment is costly and risky. Pharmacological intervention is generally less efficacious and associated with side effects. There is therefore an obvious need for more efficacious pharmacological intervention with fewer side effects and convenient administration.

[0009] Although T2DM is most commonly associated with hyperglycemia and insulin resistance, other diseases, disorders, and / or conditions associated with T2DM include, for example, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0010] NAFLD is the hepatic manifestation of metabolic syndrome, and is a spectrum of hepatic conditions encompassing steatosis, NASH, fibrosis, cirrhosis and ultimately hepatocellular carcinoma. NAFLD and NASH are considered the primary fatty liver diseases as they account for the greatest proportion of individuals with elevated hepatic lipids. The severity of NAFLD / NASH is based on the presence of lipid, inflammatory cell infiltrate, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with fatty liver disease (e.g. steatosis or NAFLD) progress to NASH, a substantial proportion do. GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cells in the intestine in response to ingestion of food. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate proliferation of beta-cells. In non-clinical experiments GLP-1 promotes continued beta-cell competence by stimulating transcription of genes important for glucose-dependent insulin secretion and by promoting beta-cell neogenesis (Meier, et al. Biodrugs. 2003; 17 (2): 93-102).

[0011] In a healthy individual, GLP-1 plays an important role regulating post-prandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas resulting in increased glucose absorption in the periphery. GLP-1 also suppresses glucagon secretion, leading to reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption. In people with T2DM, the normal postprandial rise in GLP-1 is absent or reduced (Vilsboll T, et al. Diabetes. 2001 . 50; 609-613).

[0012] Holst (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1 , liraglutide and exendin-4, have 3 major pharmacological activities to improve glycemic control in patients with T2DM by reducing fasting and postprandial glucose (PPG and PPG): (i) increased glucose-dependent insulin secretion (improved first- and second-phase), (ii) glucagon suppressing activity under hyperglycemic conditions, (iii) delay of gastric emptying rate resulting in retarded absorption of meal-derived glucose.

[0013] 2-({4-[(2S)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid (referred to herein as “Compound 1”) is a GLP1 agonist.

[0014] Compound 1

[0015] Compound 1 (both in the forms the free acid and as its tris salt) was prepared in Example 7 of US Patent Application No. 16 / 436,311 filed June 10, 2019 (granted as U.S. Patent No. 10934279), of US Pat. AppL No. 16 / 535, 553 filed August 08, 2019 (granted as U.S. Patent No. 10683281 ), and of International Application No. PCT / IB2019 / 054867 filed June 11 , 2019 (published as WO2019239319), each of which is hereby incorporated herein by reference in its entirety.

[0016] Tris salt of 2-({4-[(2S)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4- yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid means a salt of Compound 1 made by using 1 ,3-dihydroxy-2-(hydroxymethyl)propan-2-amine. The tris is associated with the carboxylic acid moiety of Compound 1 . Unless otherwise stated, when referencing the tris salt of 2-({4-[(2S)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4- yl]piperidin- 1 -yljmethyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid (“Compound 1”), the counterion and Compound 1 are in a stoichiometric ratio of about 1 :1 (i.e. from 0.9:1 .0 to 1 .0:0.9, for example, from 0.95:1 .00 to 1 .00:0.95, or from 0.99:1 .00 to 1 .00 : 1.01 ). Tris salt of Compound 1 can also be represented, for example, by one of the following structures.

[0017] Tris salt of Compound 1

[0018] In addition, US Patent Application No. 16 / 436,311 filed June 10, 2019 (granted as U.S. Patent No. 10934279) and International Application No. PCT / IB2019 / 054867, filed June 11 , 2019 (published as WO2019239319) reported an anhydrous crystalline form (designed as Form I) of tris salt of Compound 1 .

[0019] There remains a need for a safe and efficacious treatment for cardiometabolic and associated diseases and / or conditions, such as T2DM, obesity, and overweight.

[0020] The novel compositions / formulations described herein and their uses are directed toward this and other important ends.

[0021] SUMMARY OF THE INVENTION

[0022] The present invention provides, in part, an immediate-release oral pharmaceutical composition comprising 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4- yl]piperidin- 1 -yljmethyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid (Compound 1) or a pharmaceutically salt thereof.

[0023] The present invention further provides an oral controlled release swellable core technology (SCT) tablet comprising:

[0024] (a) a core that comprises: (i) an active layer comprising

[0025] (1) an active pharmacological ingredient (API) that comprises 2-({4-[(2S)- 2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)- 1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid (“Compound 1”) or a pharmaceutically salt thereof, and

[0026] (2) a viscosifying agent; and

[0027] (ii) a sweller layer comprising

[0028] (1) a swelling agent, and

[0029] (2) an osmogen; and

[0030] (b) a coating that at least partially covers the core wherein the coating comprises

[0031] (1) a film former, and

[0032] (2) a pore former.

[0033] The present invention further provides a process for preparing the immediate-release oral pharmaceutical composition of the present invention.

[0034] The present invention further provides a process for preparing the oral controlled release swellable core technology (SCT) tablet of the present invention.

[0035] The present invention further provides the immediate-release oral pharmaceutical composition of the invention or the oral controlled release swellable core technology (SCT) tablet for use in a method of once daily administration for weight management control or for use in a method of once daily administration for treating a condition, disease, or disorder by once daily oral administration, wherein the condition, disease, or disorder is selected from the group consisting of diabetes [e.g. Type 1 diabetes mellitus (T1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).

[0036] The present invention further provides a method for weight management control of a human comprising once daily administering to the human the immediate-release oral pharmaceutical composition of the invention or the oral controlled release swellable core technology (SCT) tablet.

[0037] The present invention further provides a method for treating a condition, disease, or disorder described herein in a human comprising once daily administering to the human the immediate-release oral pharmaceutical composition of the invention or the oral controlled release swellable core technology (SCT) tablet.

[0038] BRIEF DESCRIPTION OF FIGURES

[0039] FIG. 1 shows a flow diagram of the preparation process of tris salt of Compound 1 (eqivalent to 15 mg of Compound 1) immediate release tablets in Example 1 .

[0040] FIG. 2 shows a flow diagram of the preparation process of tris salt of Compound 1 (eqivalent to 30 mg of Compound 1) modified release tablets in Examples 2 annd 3.

[0041] FIG. 3 shows a schematic diagram of an example of a swellable core technology (SCT) tablet of Example 2 or 3 (with a bilayer core). DETAILED DESCRIPTION OF THE INVENTION

[0042] In a first aspect, the present invention provides an immediate-release oral pharmaceutical composition comprising 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3- benzodioxol-4-yl]piperidin-1 -yljmethyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6- carboxylic acid (Compound 1 ) or a pharmaceutically salt thereof.

[0043] As use herein, the term "immediate release" or its abbreviated term "IR" [for example, in "immediate release tablet"] corresponds to the definition provided in European Pharmacopeia 6.0, part 01 / 2008: 1502 as relating to "conventional-release dosage forms" or "immediate- release dosage forms" in the form of a tablet showing a release of the active substance, which is not deliberately modified by a special formulation design and / or manufacturing method, thereby being distinct from "modified-release", "prolong-release", "delayed-release" and "pulsatile-release" dosage forms as defined in European Pharmacopeia 6.0. , part 01 / 2008: 1502. For example, more specifically, "immediate release" or "IR" means a release quantity of the active pharmacological ingredient of at least 75% within 30 minutes, as determined according to the USP release method using apparatus 2 (paddle), i.e. having a Q value (30 minutes) of at least 75 %.

[0044] In a second aspect, the present invention provides an immediate-release oral pharmaceutical composition comprising:

[0045] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid (Compound 1), or a pharmaceutically acceptable salt thereof; a filler; a disintegrant; and a lubricant.

[0046] As used herein, the term “filler” or “diluent” refers to one or more substances that act to dilute the active pharmacological ingredient / agent to the desired dosage and / or that act as a carrier for the active pharmacological ingredient / agent. In some embodiments, the filler comprises one or more filler substances. In some embodiments, the filler comprises at least one substance that improves the mechanical strength and / or compressibility of the pharmaceutical compositions of the invention. In some embodiments, the filler comprises one or more of mannitol, lactose (including e.g. lactose monohydrate), sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethylcellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, pregelatinized starch, sodium starch glycolate, a calcium phosphate, a metal carbonate, a metal oxide, or a metal aluminosilicate. In some embodiments, the filler comprises microcrystalline cellulose. As used herein, the term “disintegrant” refers to a substance that encourages disintegration in water (or water-containing fluid in vivo) of a pharmaceutical composition / formulation of the invention. Examples of disintegrant include croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, an ion exchange resin, an effervescent system based on food acids and an alkaline carbonate component, clay, talc, starch, pregelatinized starch, sodium starch glycolate, cellulose floc, carboxymethylcellulose, hydroxypropylcellulose, calcium silicate, a metal carbonate, sodium bicarbonate, calcium citrate, and / or calcium phosphate.

[0047] As used herein, the term “lubricant” refers to one or more substances that aids in preventing sticking to the equipment of the pharmaceutical formulations during processing and / or that improves powder flow of the formulation during processing. In some embodiments, suitable lubricants include one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, or polyalkylene glycol. In some embodiments, the lubricant comprises metallic stearate. In some embodiments, the lubricant comprises one or more of sodium stearyl fumarate, zinc stearate, calcium stearate, magnesium stearate, or sodium stearate. In some embodiments, the lubricant comprises magnesium stearate.

[0048] In some embodiments of the immediate-release oral pharmaceutical composition: the 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof is tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3- benzodioxol-4-yl]piperidin-1 -yljmethyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6- carboxylic acid; the filler comprises microcrystalline cellulose, lactose, or a combination thereof; the disintegrant is crospovidone; and the lubricant is magnesium stearate or sodium stearyl fumarate.

[0049] In some embodiments of the immediate-release oral pharmaceutical composition: the 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof is tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3- benzodioxol-4-yl]piperidin-1 -yljmethyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6- carboxylic acid; the filler comprises microcrystalline cellulose, lactose, or a combination thereof; the disintegrant is crospovidone; and the lubricant is magnesium stearate or sodium stearyl fumarate.

[0050] In some embodiments: the 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof comprises about 1 .0% to about 35.0% by weight; the filler comprises about 60% to about 95% by weight; the disintegrant comprises about 1 .0% to about 5.0% by weight; and lubricant comprises about 0.2% to about 3.5% by weight.

[0051] In some embodiments, the immediate-release oral pharmaceutical composition comprises tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4- yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid in an amount equivalent to about 5 mg to about 120 mg of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2- methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl} methyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole- 6-carboxylic acid.

[0052] In some embodiments, the immediate-release oral pharmaceutical composition comprises tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4- yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid in an amount equivalent to about 5 mg to about 100 mg of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2- methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl} methyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole- 6-carboxylic acid.

[0053] In some embodiments, the immediate-release oral pharmaceutical composition is in tablet dosage form.

[0054] In some embodiments, at least 80% by weight of the tris salt of 2-({4-[(2S)-2-(4-chloro-2- fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]- 1 H-benzimidazole-6-carboxylic acid in the composition dissolves within 60 minutes in a 50 mM sodium phosphate buffer (pH 6.8) with 0.5% sodium dodecyl sulfate (SDS) at about 37°C using a USPII apparatus with a paddle speed of 100 rpm (see e.g. the assay in Example AA).

[0055] In some embodiments, at least 80% by weight of the tris salt of 2-({4-[(2S)-2-(4-chloro-2- fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]- 1 H-benzimidazole-6-carboxylic acid in the composition dissolves within 30 minutes in a 50 mM sodium phosphate buffer (pH 6.8) with 0.5% sodium dodecyl sulfate (SDS) at about 37°C using a USPII apparatus with a paddle speed of 100 rpm. (see e.g. the assay in Example AA).

[0056] In a third aspect, the present invention provides an oral controlled release swellable core technology (SCT) tablet comprising:

[0057] (a) a core that comprises:

[0058] (i) an active layer comprising

[0059] (1 ) an active pharmacological ingredient (API) that comprises 2-({4-[(2S)- 2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)- 1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid (“Compound 1”) or a pharmaceutically salt thereof, and

[0060] (2) a viscosifying agent;

[0061] (ii) a sweller layer comprising

[0062] (1) a swelling agent, and

[0063] (2) an osmogen; and

[0064] (b) a coating that at least partially covers the core wherein the coating comprises

[0065] (1) a film former, and

[0066] (2) a pore former.

[0067] Swellable core technology (SCT) is known to those skilled in the art. See. e.g. A.G. Thombre, et. al, “Osmotic drug delivery using swellable-core technology”; Journal of Controlled Release 94 (2004) 75 - 89. Figure 3 shows a schematic diagram of a swellable core technology (SCT) tablet of Examples 2 or 3 (bi-layer core).

[0068] As used herein, the term "viscosifying agent" refers to a polymer that is believed to have enough viscosity to allow it to suspend or entrain the drug in the core of the tablet of the invention, while at the same time remaining sufficiently fluid to allow it to pass through the delivery port(s) of the coating of the tablet of the invention along with the drug. Some suitable viscosifying polymers include non-crosslinked polyethylene oxide (PEO), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and hydroxyethyl cellulose (HEC). The viscosifying polymer may be a single material or a mixture of materials. The molecular weight of HEC can be from about 300,000 to about 2,000,000, for example, between about 700,000 to about 1 ,500,000). In some embodiments, the viscosifying polymer may be polyethylene oxide (PEO) with a low molecular weight, for example, between about 150,000 to about 500,000 (e.g. 200,000).

[0069] As used herein, the term "swelling agent" refers to a substance (typically a polymer) that swells and expands in volume after absorption of water. Suitable swelling agents include nonionic polymer (e.g., polyethylene oxide or HPMC) or an ionic polymer (e.g., croscarmellose sodium or sodium starch glycolate). In some embodiments, Suitable swelling agents include polyethylene oxide with a molecular weight of great than about 2,000,000; about 3,000,000; about 4,000,000; about 5,000,000; or about 6,000,000.

[0070] As used herein, the term "osmogen" or "osmagent" refers to an osmotically effective solute, which is capable of imbibing (or being dissolved in) water to thereby establish an osmotic pressure gradient across the barrier of the surrounding coating of the tablet. Suitable osmogens include water-soluble salts (e.g. water-soluble inorganic salts), sugars, organic acids, and other low-molecule-weight organic compounds that are capable of imbibing water to thereby establish an osmotic pressure gradient across the barrier of the surrounding coating. Some suitable inorganic salts include magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate. Some suitable organic acids include ascorbic acid, 2- benzene carboxylic acid, benzoic acid, fumaric acid, citric acid, maleic acid, serbacic acid, sorbic acid, edipic acid, editic acid, glutamic acid, toluene sulfonic acid, and tartaric acid. Some suitable sugars include saccharides (including e.g. starch oligosaccharides), mannitol, sucrose, fructose, sorbitol, xylitol, lactose, dextrose (including e.g. dextrose monohydrate or anhydrous dextrose), and trehlaose. The osmogens can be used alone or in a combination of two or more osmogens.

[0071] The term "film former," as used herein, refers to a material added to the coating solution that has low or no volatility relative to the solvent such that it remains as part of the coating following the coating process, and is non-dissolving and non-eroding during release of the API, generally meaning that it be water-insoluble, such that the API is substantially entirely delivered through the delivery port(s), in contrast to delivery via permeation through the coating. Suitable film forms include hydrophilic polymers such as plasticized and unplasticized cellulose esters, ethers, and ester-ethers. In some embodiments, suitable filim forms include cellulose acetate (CA), cellulose acetate butyrate (CAB), and ethyl cellulose (EC). In some embodiments, cellulose acetates include cellulose acetates having acetyl contents of 25 to 42%, for example, those having an acetyl content of about 40%,

[0072] The term "pore former," as used herein, refers to a material added to the coating solution that has low or no volatility relative to the solvent such that it remains as part of the coating following the coating process but that is sufficiently water swellable or water soluble such that, in the aqueous use environment it provides a water-filled or water-swollen channel or "pore" to allow the passage of water, thereby enhancing the water permeability of the coating. Some suitable pore formers include hydroxypropyl cellulose (HPC), polyethylene glycol ("PEG"), poly (N-vinyl- 2-pyrrolidinone) (PVP), pectin, formamide, and poly(ethylene oxide) (PEO).

[0073] In some embodiments, the API of the active layer comprises tris salt of 2-({4-[(2S)-2-(4- chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2- ylmethyl]-1 H-benzimidazole-6-carboxylic acid in an amount equivalent to about 5 mg to about 120 mg of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yljmethyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid.

[0074] In some embodiments, the API in the active layer comprises tris salt of 2-({4-[(2S)-2-(4- chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2- ylmethyl]-1 H-benzimidazole-6-carboxylic acid in an amount equivalent to about 5 mg to about 100 mg of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yljmethyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid. In some embodiments, the API in the active layer comprises about 1% by weight to about 40% by weight of the active layer.

[0075] In some embodiments, the API in the active layer comprises about 1 .5% by weight to about 30% by weight of the active layer.

[0076] In some embodiments, the API in the active layer comprises about 3.0% by weight to about 30% by weight of the active layer. In some further embodiments, the API in the active layer comprises about 5.0% by weight to about 30% by weight of the active layer, for example, about 6% to about 27% by weight, or about 5% to about 20% by weight, or about 5% to about 15% by weight, or about 12% to about 20% by weight, of the active layer.

[0077] In some embodiments, the viscofiying agent in the active layer comprises about 50% by weight to about 98% by weight of the active layer.

[0078] In some embodiments, the viscofiying agent in the active layer comprises about 60% by weight to about 95% by weight of the active layer.

[0079] In some embodiments, the viscofiying agent in the active layer is selected from polyethylene oxide (PEO, for example, non-crosslinked EPO), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and hydroxyethyl cellulose (HEC), or a mixture thereof.

[0080] In some embodiments, the viscofiying agent in the active layer is selected from polyethylene oxide (PEO) and hydroxyethyl cellulose (HEC), or a mixture thereof.

[0081] In some embodiments, the viscosifying agent in the active layer is polyethylene oxide with a molecular weight less than about 500,000. In some further embodiment, the viscosifying agent in the active layer is polyethylene oxide with a molecular weight of about 200,000.

[0082] In some embodiments, the active layer further comprises a lubricant.

[0083] In some embodiments, the lubricant in the active layer is selected from metallic stearate and sodium stearyl fumarate, or a mixture thereof.

[0084] In some embodiments, the lubricant in the active layer is metallic stearate.

[0085] In some embodiments, the metallic stearate is magnesium stearate.

[0086] In some embodiments, the lubricant in the active layer comprises about 0.5% to about 3.0% by weight of the active layer.

[0087] In some embodiments, the lubricant in the active layer comprises about 0.5% to about 2.5% by weight of the active layer.

[0088] In some embodiments, the lubricant in the active layer comprises about 1% to about 2% by weight of the active layer.

[0089] In some embodiments, the swelling agent in the sweller layer comprises about 30% or more by weight of the sweller layer.

[0090] In some embodiments, the swelling agent in the sweller layer comprises about 40% or more by weight of the sweller layer. In some embodiments, the swelling agent in the sweller layer comprises about 50% or more by weight of the sweller layer.

[0091] In some embodiments, the swelling agent in the sweller layer is selected from polyethylene oxide (PEO) with a molecular weight greater than about 1 ,000,000.

[0092] In some embodiments, the swelling agent in the sweller layer is selected from polyethylene oxide (PEO) with a molecular weight greater than about 2,000,000.

[0093] In some embodiments, the swelling agent in the sweller layer is selected from polyethylene oxide (PEO) with a molecular weight of about 4,000,000 to about 6,000,000. In some further embodiments, the swelling agent in the sweller layer is selected from polyethylene oxide (PEO) with a molecular weight of about 5,000,000.

[0094] In some embodiments, the osmogen in the sweller layer comprises about 10% to about 50% by weight of the sweller layer.

[0095] In some embodiments, wherein the osmogen in the sweller layer is selected from magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, ascorbic acid, 2-benzene carboxylic acid, benzoic acid, fumaric acid, citric acid, maleic acid, serbacic acid, sorbic acid, edipic acid, editic acid, glutamic acid, toluene sulfonic acid, and tartaric acid, or is a mixture of two or more thereof.

[0096] In some embodiments, the osmogen in the sweller layer is selected from magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate, or is a mixture of two or more thereof.

[0097] In some embodiments, the osmogen in the sweller layer is sodium chloride.

[0098] In some embodiments, the sweller layer further comprises a filler. In some further embodiment, the filler in the sweller layer is selected from mannitol, lactose (including e.g. lactose monohydrate), sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethylcellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, pregelatinized starch, sodium starch glycolate, a calcium phosphate, a metal carbonate, a metal oxide, and a metal aluminosilicate, or is a mixture thereof. In some yet further embodiment, the filler in the sweller layer is microcrystalline cellulose.

[0099] In some embodiments, the sweller layer further comprises a lubricant. In some further embodiment, the lubricant in the sweller layer is selected from metallic stearate and sodium stearyl fumarate, or a mixture thereof. In some yet further embodiments, the lubricant in the active layer contains metallic stearate. In some still further embodiments, the lubricant in the active layer is magnesium stearate.

[0100] In some embodiments, the sweller layer further comprises a colorant. In some embodiments, the weight ratio of the coating to the core is about 2:100 to about

[0101] 8:100.

[0102] In some embodiments, the weight ratio of the film former to the pore former is about 60:40 to about 95:5.

[0103] In some embodiments, the film former is selected from cellulose acetate (CA), cellulose acetate butyrate (CAB), and ethyl cellulose (EC).

[0104] In some embodiments, the film former is cellulose acetate (CA).

[0105] In some embodiments, the pore former is selected from polyethylene glycol and hydroxypropylcellulose.

[0106] In some embodiments, the pore former is polyethylene glycol.

[0107] In some embodiments, the oral controlled release swellable core technology (SCT) tablet of the invention provides an extended release profile. In some embodiments, the oral controlled release swellable core technology (SCT) tablet of the invention provides a dissolution profile with T8o% (i.e. the time for 80% of the API, i.e. 80% of tris salt of Compound 1 to dissolve / release) greater than about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 1 1 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, or about 21 hours, using the dissolution test according to Example AA. In some embodiments, the oral controlled release swellable core technology (SCT) tablet of the invention provides a dissolution profile with T8o% [i.e. the time for 80% of the API (i.e. 80% of tris salt of Compound 1 ) to dissolve / release) from about 5 hours to about 21 hours, about 7 hours to about 16 hours, about 7 hours to about 15 hours, about 8 hours to about 12 hours, or from about 10 hours to about 18 hours, or from about 12 hours to about 18 hours, using the dissolution test according to Example AA.

[0108] In some embodiments, at least 80% by weight of the tris salt of 2-({4-[(2S)-2-(4-chloro-2- fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]- 1 H-benzimidazole-6-carboxylic acid in the tablet dissolves in more than about 5 hours , about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 1 1 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, or about 20 hours, in a 50 mM sodium phosphate buffer (pH 6.8) with 0.5% sodium dodecyl sulfate (SDS) at about 37°C using a USPII apparatus with a paddle speed of 100 rpm.

[0109] In some embodiments, at least 80% by weight of the tris salt of 2-({4-[(2S)-2-(4-chloro-2- fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]- 1 H-benzimidazole-6-carboxylic acid in the tablet dissolves in about 5 to about 10 hours in a 50 mM sodium phosphate buffer (pH 6.8) with 0.5% sodium dodecyl sulfate (SDS) at about 37°C using a USPII apparatus with a paddle speed of 100 rpm. In some embodiments, at least 80% by weight of the tris salt of 2-({4-[(2S)-2-(4-chloro-2- fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]- 1 H-benzimidazole-6-carboxylic acid in the tablet dissolves in about 6 to about 10 hours in a 50 mM sodium phosphate buffer (pH 6.8) with 0.5% sodium dodecyl sulfate (SDS) at about 37°C using a USPII apparatus with a paddle speed of 100 rpm.

[0110] In some embodiments, at least 80% by weight of the tris salt of 2-({4-[(2S)-2-(4-chloro-2- fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]- 1 H-benzimidazole-6-carboxylic acid in the tablet dissolves in about 12 to about 20 hours in a 50 mM sodium phosphate buffer (pH 6.8) with 0.5% sodium dodecyl sulfate (SDS) at about 37°C using a USPII apparatus with a paddle speed of 100 rpm.

[0111] In some embodiments, at least 80% by weight of the tris salt of 2-({4-[(2S)-2-(4-chloro-2- fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]- 1 H-benzimidazole-6-carboxylic acid in the tablet dissolves in about 15 to about 20 hours in a 50 mM sodium phosphate buffer (pH 6.8) with 0.5% sodium dodecyl sulfate (SDS) at about 37°C using a USPII apparatus with a paddle speed of 100 rpm.

[0112] The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined herein. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject (e.g. a human).

[0113] In some embodiments of the immediate-release oral pharmaceutical composition of the first or second aspect of the invention, or of the oral controlled release swellable core technology (SCT) tablet of the third aspect of the invention, the tris salt of Compound 1 is present as a crystalline form, for example, the anhydrous crystalline form (designed as Form I) of tris salt of Compound 1 in US Patent Application No. 16 / 436,31 1 filed June 10, 2019 (granted as U.S. Patent No. 10934279) and International Application No. PCT / IB2019 / 054867, filed June 11 , 2019 (published as WO2019239319). In some further embodiment, the anhydrous crystalline form of the tris salt of Compound 1 has a powder X-ray diffraction pattern (CuKa radiation) comprising at least two characteristic peaks, in terms of 20, selected from at 3.7 ± 0.2°; 7.3 ± 0.2°; 8.5 ± 0.2°; 10.1 ± 0.2e; 14.7± 0.2e; and 16.9± 0.2e. In some further embodiment, the anhydrous crystalline form of the tris salt of Compound 1 has a powder X-ray diffraction pattern (CuKa radiation) comprising at least two characteristic peaks, in terms of 20, selected from at 3.7 ± 0.2°; 7.3 ± 0.2°; 8.5 ± 0.2°; 10.1 ± 0.2e; 14.7± 0.2e; and 16.9± 0.2e.

[0114] As used herein the term “controlled-release” formulation means a dosage form in which the release of the active pharmacological ingredient (API) is controlled or modified over a period of time. Controlled can mean, for example, extended, sustained, delayed, prolonged, or pulsed- release at a particular time. In some embodiments, controlled can mean that the release of the API is extended for longer time than that from an immediate-release dosage form having same amount of API, for example, 80% ±10% of API is dissolved after (or not before) about eight (8) hours of administration.

[0115] In some embodiments, the controlled-release formulation in the third aspect of the invention is an extended or sustained release formation.

[0116] TABLETING / PREPARATIONS

[0117] The tablets of the present invention are generally prepared using standard techniques well known in the art.

[0118] In some embodiments, the core of the tablet is prepared by compressing the active layer and sweller layer into, for example, a bilayer core. The active layer and sweller layer may have the same or different shapes. After the active layer and sweller layer are compressed to form the bilayer core, they are proximate to one another (e.g., at least partially in contact with one another). Tablet shapes may include any tablet shape known to those skilled in the art. Some tablet shapes include SRC (standard round concave), oval, modified oval, capsule, caplet, and almond.

[0119] Following formation of the core, the semi-permeable coating is applied. In some embodiments, the coating has high water permeability and a high strength, while at the same time be easily fabricated and applied. High water permeability helps permit water to enter the core in sufficient volume. High strength helps ensure the coating does not burst when the core swells as it imbibes water, leading to an uncontrolled delivery of the core contents. In some embodiments, the API is substantially or entirely delivered through the delivery port(s), in contrast to delivery via permeation through the coating. In some embodiments, the coating (and / or the process for coating) has high reproducibility and yield.

[0120] Coating may be conducted in conventional fashion by first forming a coating solution and then coating by dipping, fluidized bed coating, or by pan coating. To accomplish this, a coating solution is formed comprising the the coating polymer(s) (including the film former and / or pore former) and a solvent. Some useful solvents include acetone, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, nitroethane, nitropropane, tetrachloroethane, 1 ,4-dioxane, tetrahydrofuran, diglyme, and mixtures thereof. In some embodiments, the coating solution may also include a pore-former.

[0121] In some embodiments, the coating solution may also include a non-solvent for the coating polymer(s) (including the film former and / or pore former) in any amount as long as the coating polymer(s) (including the film former and / or pore former) remain soluble at the conditions used to form the coating and as long as the coating is water permeable (or will be water permeable when the tablet is in an aqueous environment) and has sufficient strength.

[0122] The term "non-solvent" refers to any material added to the coating solution that substantially dissolves in the coating solution and reduces the solubility of the coating polymer or polymers in the solvent. In some embodiments, the function of the non-solvent is to impart porosity to the resulting coating, as described below. In some embodiments, porous coatings have higher water permeability than an equivalent weight of a coating of the same composition that is not porous and this porosity is indicated by a reduction in the density of the coating (mass / volume). Although not wishing to be bound by any particular mechanism of pore formation, it is generally believed that addition of a non-solvent imparts porosity to the coating during evaporation of solvent by causing the coating solution to undergo liquid and liquid phase separation prior to solidification. The suitability and amount of a particular candidate material can be evaluated for use as a non-solvent by progressively adding the candidate non-solvent to the coating solution until it becomes cloudy. If this does not occur at any addition level up to about 50 wt % of the coating solution, it generally is not appropriate for use as a non-solvent. When clouding is observed, termed the "cloud point," an appropriate level of non-solvent for maximum porosity is the amount just below the cloud point. For acetone solutions comprising 7 wt % CA and 3 wt % PEG, the cloud point is at about 23 wt % water. When lower porosities are desired, the amount of non-solvent can be reduced as low as desired.

[0123] Suitable non-solvents are any materials that have appreciable solubility in the solvent and that lower the coating polymer solubility in the solvent. Choice of the non-solvent depends on the solvent and the coating polymer chosen. In the case of using a volatile polar coating solvent such as acetone, some suitable non-solvents include water, glycerol, alcohols such as methanol or ethanol.

[0124] Coatings formed from these coating solutions are generally porous. By "porous" is meant that the coating in the dry state has a density less than the density of the same material in a nonporous form. By "nonporous form" is meant a coating material formed by using a coating solution containing no non-solvent, or the minimal amount of non-solvent required to produce a homogeneous coating solution. The dry-state density of the coating can be calculated by dividing the coating weight (determined from the weight gain of the tablets before and after coating) by the coating volume (calculated by multiplying the coating thickness, as determined by physical measurement, optical microscopy or scanning electron microscopy, by the tablet surface area). The porosity of the coating is one of the factors that leads to the combination of high water permeability and high strength of the coating.

[0125] In some embodiments, the coating contains at least one delivery port in communication with the interior and exterior of the coating to allow for release of the tablet core contents to the exterior of the tablet, at least when the tablet is in an aqueous environment. The delivery port can range in size from about the size of the drug particles, and thus could be as small as 1 to 100 microns in diameter and may be termed pores, up to about 5000 microns in diameter. The shape of the port may be substantially circular, in the form of a slit, or other convenient shape to ease manufacturing and processing. The port(s) may be formed by post-coating mechanical or thermal means or with a beam of light (e.g., a laser), a beam of particles, or other high-energy source, or may be formed in situ by rupture of a small portion of the coating. Such rupture may be controlled by intentionally incorporating a relatively small weak portion into the coating. Delivery ports may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the coating over an indentation in the core. Delivery ports may be formed by coating the core such that one or more small regions remain uncoated. In addition, the delivery port can be a large number of holes or pores that may be formed during coating, as in the case of asymmetric membrane coatings, described in more detail herein, and of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220, the disclosures of which are incorporated by reference. When the delivery pathways are pores there can be a multitude of such pores that range in size from 1 micron to greater than 100 microns. During operation, one or more of such pores may enlarge under the influence of the hydrostatic pressure generated during operation. The location of the delivery port(s) may be located anywhere on the tablet surface. In some embodiments, the locations of the delivery port(s) include the face of the tablet and the tablet band. In some embodiments, the location includes approximately the center of the tablet band for round, SRC-shaped tablets and approximately the center of the tablet band along the major axis and / or approximately the center of the tablet band along the minor axis of the tablet band for capsule, caplet, oval, or modified oval shaped tablets. In some embodiments, the location of the delivery port(s) is the approximate center of the tablet band along the major axis of the tablet band for capsule, caplet, oval, or modified oval shaped tablets.

[0126] In some embodiments, the permeability of the coating may be adjusted by blending of two or more materials. A useful process for tailoring the porosity of the coating comprises adding a pre-determined amount of a finely-divided water-soluble material, such as sugars or salts or water-soluble polymers to a solution or dispersion (e.g., an aqueous latex) of the coating-forming polymer to be used. When the tablet is ingested into the aqueous medium of the Gl tract, these water soluble membrane additives are leached out of the membrane, leaving pores which facilitate release of the drug. The membrane coating can also be modified by the addition of plasticizers, as known in the art.

[0127] In a fourth aspect, the present invention provides an immediate-release oral pharmaceutical composition in the first or second aspect of the invention or an oral controlled release swellable core technology (SCT) tablet in the third aspect of the invention, including any one of the embodiments described herein, for use in a method of once daily administration for weight management or for use in a method of once daily administration for treating a condition, disease, or disorder, wherein the condition, disease, or disorder is selected from the group consisting of diabetes [e.g. Type 1 diabetes mellitus (T1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug). In some embodiments, the amount of the API in the immediate-release oral pharmaceutical composition or in the oral controlled release swellable core technology (SCT) tablet for use of the invention is equivalent to about 5 mg to about 200 mg of Compound 1 .

[0128] In some embodiments, the amount of the API in the tablet for use of the invention is equivalent to about 5 mg to about 150 mg of Compound 1 , about 5 mg to about 120 mg of Compound 1 , about 5 mg to about 100 mg of Compound 1 , about 10 mg to about 100 mg of Compound 1 , about 10 mg to about 80 mg of Compound 1 , about 10 mg to about 50 mg of

[0129] Compound 1 , about 20 mg to about 50 mg of Compound 1 , about 20 mg to about 40 mg of

[0130] Compound 1 , about 10 mg to about 40 mg of Compound 1 , about 10 mg to about 30 mg of

[0131] Compound 1 , about 40 mg to about 80 mg of Compound 1 , about 40 mg to about 60 mg of

[0132] Compound 1 , or about 50 mg to about 80 mg of Compound 1 , or about 50 mg to about 70 mg of Compound 1.

[0133] In some embodiments, the immediate-release oral pharmaceutical composition or the oral controlled release swellable core technology (SCT) tablet is used in a method for weight management control or for treating T2DM.

[0134] In some embodiments, the immediate-release oral pharmaceutical composition or the oral controlled release swellable core technology (SCT) tablet for use is used in a method for weight management control.

[0135] In some embodiments, the immediate-release oral pharmaceutical composition or the oral controlled release swellable core technology (SCT) tablet for use is used in a method for treating T2DM. In some further embodiments, treating T2DM includes improving glycemic control.

[0136] In some embodiments, the immediate-release oral pharmaceutical composition or the oral controlled release swellable core technology (SCT) tablet for use is used in a method for treating obesity. In some further embodiments, treating obesity includes weight management control.

[0137] In some embodiments, the immediate-release oral pharmaceutical composition or the oral controlled release swellable core technology (SCT) tablet for use is used a method for treating overweight. In some further embodiments, treating overweight includes weight management control.

[0138] In a fifth aspect, the present invention provides a method for treating a condition, disease, or disorder in a patient comprising once daily administering to the patient an immediate-release oral pharmaceutical composition in the first or second aspect of the invention or an oral controlled release swellable core technology (SCT) tablet in the third aspect of the invention, including any one of the embodiments described herein, or a method for weight management of a human comprising once daily administering to the human an immediate- release oral pharmaceutical composition in the first or second aspect of the invention or an oral controlled release swellable core technology (SCT) tablet in the third aspect of the invention, including any one of the embodiments described herein, wherein the condition, disease, or disorder is selected from the group consisting of diabetes [e.g. Type 1 diabetes mellitus (T1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug). In some embodiments, the amount of the API in in the method of the invention is equivalent to about 5 mg to about 200 mg of Compound 1 .

[0139] In some embodiments, the amount of the API in in the method of the invention is equivalent to about 5 mg to about 150 mg of Compound 1 , about 5 mg to about 120 mg of Compound 1 , about 5 mg to about 100 mg of Compound 1 , about 10 mg to about 100 mg of Compound 1 , about 10 mg to about 80 mg of Compound 1 , about 10 mg to about 50 mg of

[0140] Compound 1 , about 20 mg to about 50 mg of Compound 1 , about 20 mg to about 40 mg of

[0141] Compound 1 , about 10 mg to about 40 mg of Compound 1 , about 10 mg to about 30 mg of

[0142] Compound 1 , about 40 mg to about 80 mg of Compound 1 , about 40 mg to about 60 mg of

[0143] Compound 1 , or about 50 mg to about 80 mg of Compound 1 , or about 50 mg to about 70 mg of Compound 1.

[0144] In some embodiments, the method of the invention is for weight management control or for treating T2DM.

[0145] In some embodiments, the method of the invention is for weight management control. In some further embodiments, the method is an adjunct to a reduced-calorie diet and / or increased physical activity.

[0146] In some embodiments, the weight management control includes chronic weight management control.

[0147] In some embodiments, the method for weight management control includes reducing the body weight of the human, for example, greater than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0148] In some embodiments, the method for weight management control includes reducing the body weight of the human, for example, greater than about 10%, 12%, 15%, 20%, 25%, or 30%.

[0149] In some embodiments, the method for weight management control includes reducing the body mass index (BMI) of the human, for example, greater than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0150] In some embodiments, the method for weight management control includes reducing the body mass index (BMI) of the human, for example, greater than about 10%, 15%, 20%, 25%, or 30%.

[0151] In some embodiments of method for weight management control, the initial body mass index (BMI) of the human is 24 kg / m2or greater (the initial BMI is the BMI when the the weight the management control starts). In some embodiments, the initial BMI of the human is 24 kg / m2to 30 kg / m2.

[0152] In some embodiments of method for weight management control, the initial BMI of the human is 27 kg / m2or greater. In some embodiments of method for weight management control, the initial BMI of the human is 30 kg / m2or greater. In some embodiments, the initial BMI of the human is 30.0 kg / m2to 45 kg / m2.

[0153] In some embodiments of method for weight management control, the human has at least one weight- related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).

[0154] In some embodiments of method for weight management control, the human is overweight and has at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).

[0155] In some embodiments of method for weight management control, the human is obesity and has at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).

[0156] In some embodiments, the method of the invention is for treating T2DM. In some further embodiments, treating T2DM includes improving glycemic control. In some further embodiments, the method is an adjunct to a reduced-calorie diet and / or increased physical activity.

[0157] In some embodiments, the method for treating T2DM includes reducing the fasting plasma glucose level of the human, for example, to about 126 mg / dL or lower. In some embodiments, the method treating T2DM includes reducing glycated hemoglobin (HbA1c), for example, to about 7.0 % or less, about 6.5% or less, or about 5.7% or less. In some embodiments, the method treating T2DM includes reducing the mean daily glucose level to about 157 mg / dL or less. In some embodiments, the method for treating T2DM has low or no risk of hypoglycemia.

[0158] In some embodiments, the method of the invention is for treating obesity. In some further embodiments, treating obesity includes weight management control.

[0159] In some embodiments, the method of the invention is for treating overweight. In some further embodiments, treating overweight includes weight management control.

[0160] In some embodiments, the method of the invention comprises once daily administering one immediate-release oral pharmaceutical composition in the first or second aspect of the invention or one oral controlled release swellable core technology (SCT) tablet in the third aspect of the invention, including any one of the embodiments described herein.

[0161] In some embodiments, the method of the invention comprises once daily administering two or more immediate-release oral pharmaceutical compositions in the first or second aspect of the invention or two or more oral controlled release swellable core technology (SCT) tablets in the third aspect of the invention, including any one of the embodiments described herein. In some embodiments, the method of the invention comprises once daily administering two immediate-release oral pharmaceutical compositions in the first or second aspect of the invention or two oral controlled release swellable core technology (SCT) tablets in the third aspect of the invention, including any one of the embodiments described herein,.

[0162] The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined herein. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject (e.g. a human).

[0163] As used herein, a patient or human with a BMI of 30 kg / m2or greater is obese (i.e. having obesity).

[0164] As used herein, a patient or human with a BMI of 25.0 to 29.9 kg / m2is overweight (i.e. having overweight).

[0165] In some embodiment, the treating obsesity or overweight includes weight management control.

[0166] In some embodiments, the method of invention further includes administering to the patient or human an additional therapeutic agent.

[0167] The term “about” generally means within 5%, preferably within 3%, and more preferably within 1% of a given value or range. Alternatively, the term “about” means within an acceptable standard error of the mean, when considered by one skilled in the art.

[0168] The term “tris” means 1 ,3-dihydroxy-2-(hydroxymethyl)propan-2-amine, also known as THAM, tromethamine, 2-amino-2-(hydroxymethyl)propane-1 ,3-diol, tris(hydroxymethyl)aminomethane.

[0169] Pharmaceutically acceptable salts include acid addition and base salts.

[0170] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1 ,5-naphathalenedisulfonic acid and xinafoate salts.

[0171] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium, 2-Amino-2-(hydroxymethyl)propane-1 ,3-diol (tris or tromethamine) and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0172] Pharmaceutically acceptable salts may be prepared by one or more of three methods:

[0173] (i) by reacting a compound with the desired acid or base;

[0174] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

[0175] (iii) by converting one salt of a compound to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0176] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

[0177] Compounds and pharmaceutically acceptable salts, may exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising a compound or its salt, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water. For example, a hydrate crystalline form of tris salt of Compound 1 disclosed herein refers to a crystalline material / complex that includes both tris salt of Compond 1 and water (hydrate water) in the crystal lattice of the crystalline material / complex.

[0178] A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0179] When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0180] Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drughost inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Common, 17, 1889-1896, by O. Almarsson and M. J.

[0181] Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

[0182] The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order (‘melting point’).

[0183] A compound may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO Na+, -COO K+, or -SO3Na+) or non-ionic (such as -N N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

[0184] Some compounds may exhibit polymorphism and / or one or more kinds of isomerism (e.g. optical, geometric or tautomeric isomerism). The crystalline forms of the invnetions may also be isotopically labelled. Such variation is implicit to Compound 1 or its salt defined as they are by reference to their structural features and therefore within the scope of the invention.

[0185] Compounds containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0186] Certain pharmaceutically acceptable salts of Compound 1 may also contain a counterion which is optically active (e.g. d-lactate or l-lysine) or racemic (e.g. dl-tartrate or dl-arginine). Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

[0187] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, a racemic precursor containing a chiral ester may be separated by enzymatic resolution (see, for example, Int J Mol Sci 29682-29716 by A. C. L. M. Carvaho et. al. (2015)). In the case where a compound contains an acidic or basic moiety, a salt may be formed with an optically pure base or acid such as 1 -phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by fractional crystallization and one or both of the diastereomeric salts converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Alternatively, the racemate (or a racemic precursor) may be covalently reacted with a suitable optically active compound, for example, an alcohol, amine or benzylic chloride. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization by means well known to a skilled person to give the separated diastereomers as single enantiomers with 2 or more chiral centers. Chiral compounds (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (SFC with Packed Columns), pp. 223-249 and references cited therein). In some relevant examples herein, columns were obtained from Chiral Technologies, Inc, West Chester, Pennsylvania, USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.

[0188] When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994). Although Compound 1 and its salts have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the invention.

[0189] The present invention includes all pharmaceutically acceptable isotopically-labeled Compound 1 or a salt thereof wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

[0190] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36CI, nitrogen, such as13N and15N, and oxygen, such as150,17O and18O.

[0191] Certain isotopically-labelled Compound 1 or a salt thereof, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0192] Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0193] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0194] Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0195] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6- DMSO.

[0196] Administration and Dosing

[0197] Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

[0198] The compounds of the invention may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.

[0199] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0200] The dosage regimen for the compounds of the invention and / or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Multiple doses per day may be used to increase the total daily dose, if desired.

[0201] For oral administration, the compositions may be provided, for example, in the form of tablets containing the active ingredient for the symptomatic adjustment of the dosage to the patient.

[0202] Suitable subjects according to the invention include mammalian subjects. In one embodiment, humans are suitable subjects. Human subjects may be of either sex and at any stage of development.

[0203] Pharmaceutical Compositions

[0204] In another embodiment, the invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically acceptable carrier. Other pharmacologically active substances can also be present. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition. Pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.

[0205] In some embodiments, pharmaceutically acceptable carriers include one or more components select from diluents / fillers, disintegrants, binders, wetting agents, and lubricants.

[0206] As used herein, the term “diluent or filler” refers to a substance that acts to dilute the active pharmacological agent to the desired dosage and / or that acts as a carrier for the active pharmacological agent. Examples of diluent or filler include mannitol, lactose (including e.g. lactose monohydrate), sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethylcellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodium starch glycolate, pregelatinized starch, a calcium phosphate, a metal carbonate, a metal oxide, and / or a metal aluminosilicate. As used herein, the term “binder” refers to a substance that increases the mechanical strength and / or compressibility of a pharmaceutical composition / formulation of the invention. Examples of binder include polyvinylpyrrolidone, copovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, crosslinked poly(acrylic acid), gum arabic, gum acacia, gum tragacanath, lecithin, casein, polyvinyl alcohol, gelatin, kaolin, cellulose, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose, methylhydroxyethylcellulose, silicified microcrystalline cellulose, starch, maltodextrin, dextrins, microcrystalline cellulose, and / or sorbitol.

[0207] As used herein, the term “wetting agent” refers to a substance that increases the water permeability of a pharmaceutical composition / formulation of the invention. In another aspect, the term, “wetting agent” refers to a substance that increases dissolution of the active pharmacological agent in water (or water containing fluid in vivo). In yet another aspect, the term “wetting agent” refers to a substance that increases the bioavailability of the active pharmacological agent after administration of a pharmaceutical composition / formulation of the invention. Examples of wetting agent include metallic lauryl sulfate, polyethylene glycol, glycerides of fatty ester, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene-alkyl ether, metal alkyl sulfate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sugar ester of fatty acid, polyglycolized glyceride, quaternary ammonium amine compound, lauroyl macrogol glycerides, caprylocaproyl macrogolglycerides, stearoyl macrogol glycerides, linoleoyl macrogol glycerides, oleoyl macrogol glycerides, polyethoxylated vegetable oil, polyethoxylated sterol, polyethoxylated cholesterol, polyethoxylated glycerol fatty acid ester, polyethoxylated fatty acid ester, sulfosuccinate, taurate, and / or docusate sodium.

[0208] As used herein, the term “lubricant” refers to a substance that aids in preventing sticking to the equipment of the pharmaceutical formulations / composition during processing and / or that improves powder flow of the composition / formulation during processing. Examples of lubricant include stearic acid, metallic stearate (e.g. magnesium stearate), sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, polyalkylene glycol, and / or sodium chloride.

[0209] In some embodiments, a composition of the invention comprises a filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof], a disintegrant (e.g. croscarmellose sodium, sodium alginate, potassium alginate, or sodium starch glycolate), and a lubricant [e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate]. In some embodiments, a composition of the invention comprises microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), sodium starch glycolate, and sodium stearyl fumarate.

[0210] The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions, dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0211] Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of a pharmacological active ingredient (API, for example, Compound 1 or a pharmaceutical acceptable salt thereof such as tris salt of Compound 1 ). In one embodiment, the oral administration may be in tablet form. In one embodiment, the oral administration may be in capsule form. In one embodiment, the oral administration may be in a powder or granule form. In one embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the invention are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain an immediate release formulation. In other embodiments, such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

[0212] In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and / or perfuming agents.

[0213] Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et aL, Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et aL, Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0214] Co-administration

[0215] The compositions of the invention can be used alone, or in combination with other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein wherein the compound of any embodiment herein, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, is used in combination with one or more other therapeutic agent discussed herein. This would include a pharmaceutical composition for the treatment of a disease or condition for which an agonist of the GLP-1 R is indicated, comprising a composition of the invention, as defined in any of the embodiments described herein, and one or more other therapeutic agent discussed herein.

[0216] The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time that each may generate a biological effect in the same time frame. The presence of one agent may alter the biological effects of the other compound(s). The two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration.

[0217] The phrases “concurrent administration,” “co-administration,” “simultaneous administration,” and “administered simultaneously” mean that the compounds are administered in combination.

[0218] In another embodiment, the invention provides methods of treatment that include administering compounds of the present invention in combination with one or more other pharmaceutical agents, wherein the one or more other pharmaceutical agents may be selected from the agents discussed herein.

[0219] In one embodiment, the compounds of this invention are administered with an antidiabetic agent including but not limited to a biguanide (e.g., metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazone, rosiglitazone, or lobeglitazone), a glitazar (e.g., saroglitazar, aleglitazar, muraglitazar or tesaglitazar), a meglitinide (e.g., nateglinide, repaglinide), a dipeptidyl peptidase 4 (DPP-4) inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, or omarigliptin), a glitazone (e.g., pioglitazone, rosiglitazone, balaglitazone, rivoglitazone, or lobeglitazone), a sodium-glucose linked transporter 2 (SGLT2) inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a GPR40 agonist (FFAR1 / FFA1 agonist, e.g. fasiglifam), glucose-dependent insulinotropic peptide (GIP) and analogues thereof, an alpha glucosidase inhibitor (e.g. voglibose, acarbose, or miglitol), or an insulin or an insulin analogue, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

[0220] In another embodiment, the compounds of this invention are administered with an antiobesity or other agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1 R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g. obeticholic acid), zonisamide, phentermine (alone or in combination with topiramate), a norepinephrine / dopamine reuptake inhibitor (e.g., buproprion), an opioid receptor antagonist (e.g., naltrexone), a combination of norepinephrine / dopamine reuptake inhibitor and opioid receptor antagonist (e.g., a combination of bupropion and naltrexone), a GDF-15 analog, sibutramine, a cholecystokinin agonist, amylin and analogues therof (e.g., pramlintide), leptin and analogues thereof (e.g., metroleptin), a serotonergic agent (e.g., lorcaserin), a methionine aminopeptidase 2 (MetAP2) inhibitor (e.g., beloranib or ZGN-1061 ), phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a dual SGLT2 / SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, a GIP (gastric inhibitory polypeptide, also called glucosedependent insulinotropic polypeptide) receptor antagonist or agonist, or a glucagon receptor agonist (alone or in combination with another GLP-1 R agonist, e.g., liraglutide, exenatide, du lag lutide, albiglutide, lixisenatide, or semaglutide), including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

[0221] In another embodiment, the compounds of this invention are administered in combination with one or more of the following: an agent to treat NASH including but not limited to PF-05221304, an FXR agonist (e.g., obeticholic acid), a PPAR a / 5 agonist (e.g., elafibranor), a synthetic fatty acid-bile acid conjugate (e.g., aramchol), a caspase inhibitor (e.g., emricasan), an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody (e.g., simtuzumab), a galectin 3 inhibitor (e.g., GR-MD-02), a MAPK5 inhibitor (e.g., GS-4997), a dual antagonist of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), a fibroblast growth factor 21 (FGF21) agonist (e.g., BMS-986036), a leukotriene D4 (LTD4) receptor antagonist (e.g., tipelukast), a niacin analogue (e.g., ARI 3037MO), an ASBT inhibitor (e.g., volixibat), an acetyl-CoA carboxylase (ACC) inhibitor (e.g., NDI 010976 or PF-05221304), a ketohexokinase (KHK) inhibitor, a diacylglyceryl acyltransferase 2 (DGAT2) inhibitor, a CB1 receptor antagonist, an anti-CB1 R antibody, or an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

[0222] Some specific compounds that can be used in combination with the compounds of the present invention for treating diseases or disorders described herein include: 4-(4-(1 -lsopropyl-7-oxo-1 ,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1 '-carbonyl)-6- methoxypyridin-2-yl)benzoic acid, which is an example of a selective ACC inhibitor and was prepared as the free acid in Example 9 of U.S. Patent No. 8,859,577, which is the U.S. national phase of International Application No. PCT / IB2011 / 054119, the disclosures of which are hereby incorporated herein by reference in their entireties for all purposes. Crystal forms of 4-(4-(1 - lsopropyl-7-oxo-1 ,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1 '-carbonyl)-6-methoxypyridin- 2-yl)benzoic acid, including an anhydrous mono-tris form (Form 1 ) and a trihydrate of the monotris salt (Form 2), are described in International PCT Application No. PCT / IB2018 / 058966, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes;

[0223] (S)-2-(5-((3-Ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5- carboxamide, or a pharmaceutically acceptable salt thereof, and its crystalline solid forms (Form 1 and Form 2) is an example of a DGAT2 inhibitor described in Example 1 of U.S. Patent No. 10,071 ,992, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes;

[0224] [(1 R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1 -yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3- azabicyclo[3.1 .0]hex-6-yl]acetic acid, or a pharmaceutically acceptable salt thereof, (including a crystalline free acid form thereof) is an example of a ketohexokinase (KHK) inhibitor and is described in Example 4 of U.S. Patent No. 9,809,579, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes; and the FXR agonist Tropifexor or a pharmaceutically acceptable salt thereof is described in Example 1 -1 B of U.S. Patent No. 9,150,568, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes.

[0225] These agents and compounds of the invention can be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual’s medical history.

[0226] Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or Igs; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0227] Liposomes containing these agents and / or compounds of the invention are prepared by methods known in the art, such as described in U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0228] These agents and / or the compounds of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and polymethylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

[0229] Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing Compound 1 or a pharmaceutically acceptable salt thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3- hydroxybutyric acid.

[0230] The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0231] Suitable emulsions may be prepared using commercially available fat emulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion can comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0232] The emulsion compositions can be those prepared by mixing a compound of the invention with Intralipid™ or the components thereof (soybean oil, egg phospholipids, glycerol and water).

[0233] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0234] KITS

[0235] Another aspect of the invention provides kits comprising a pharmaceutical composition of the invention. A kit may include, in addition to a pharmaceutical composition of the invention, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes a pharmaceutical composition of the invention and a diagnostic agent. In other embodiments, the kit includes a pharmaceutical composition and instructions for use in a therapeutic method.

[0236] In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains one or more of solid forms of the invention in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises one or more solid forms of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage.

[0237] EXAMPLES

[0238] The following examples illustrate the oral pharmaceutical compositions / formulations and methods of the present invention.

[0239] Example 1. Preparation of Immediate Release (IR) Tablets

[0240] Immediate release (IR), non-film-coated tablets of tris salt of Compound 1 (e.g. crystalline Form I in US Patent Application No. 16 / 436,311 filed June 10, 2019 (granted as U.S. Patent No. 10934279) and International Application No. PCT / IB2019 / 054867, filed June 11 , 2019 (published as WO2019239319)) in dosage strengths of 15 mg were prepared [the dosage strength weight expressed in milligram is the weight equivalent to Compound 1].

[0241] The compositions of these tablets are shown in Table 1 -1 .

[0242] Table 1-1. Composition of tris salt of Compound 1 Tablet 15 mg a. The dosage strength of the API (tris salt of Compound 1) is expressed in its equivalent to Compound 1 (i.e., 18.072 mg of tris salt of Compound 1 is equivalent to 15 mg of Compound 1)b. Intra-granular.c. Extra-granular.

[0243] Process of preparing IR tablets

[0244] The following steps were carried out in preparing the IR tablets (See also Figure 1 / FIG. 1 ).

[0245] 1 . Blend approximately half of the microcrystalline cellulose

[0246] 2. Add tris salt of Compound 1 to the microcrystalline cellulose, followed by the lactose monohydrate and crospovidone Type B and mix.

[0247] 3. Mill the blend and pass the remaining amount of microcrystalline cellulose through the mill. Blend the milled powder.

[0248] 4. Add the intra-granular sodium stearyl fumarate and blend.

[0249] 5. Compact and mill, then blend.

[0250] 6. Add the extra-granular sodium stearyl fumarate and blend.

[0251] 7. Compress using a suitable tablet press.

[0252] Example 2. Preparation of Controlled Release (CR) Tablets (Short Duration)

[0253] A film-coated controlled release (CR) tablet of tris salt of Compund 1 in dosage strength of 30 mg was prepared [the weight expressed in milligram is the weight equivalent to Compound 1]- The compositions of this CR tablet are shown in Table 2-1 .

[0254] Table 2-1 . Composition of tris salt of Compound 1 CR Tablet (equivalent to 30 mg of

[0255] Compound 1) aIntra-granular.bExtra-granular.cRemoved during processing

[0256] Process of preparing CR tablets

[0257] 1 . The following steps were carried out in preparing the CR tablets (See Figure 2).

[0258] Active Layer

[0259] 1 . Perform Blend-Mill-Blend Process of tris salt of Compound 1 , Polyethylene Oxide, and a portion of the Magnesium Stearate (Intra-granular portion) using a suitable screen.

[0260] 2. Dry granulate mixture from Step 1 by roller compaction.

[0261] 3. Add the extra-granular Magnesium Stearate and blend the mixture to yield the active layer granulation.

[0262] Sweller Layer

[0263] 4. Perform Blend-Mill-Blend Process of Polyethylene Oxide, Microcrystalline Cellulose, Sodium Chloride, and FD&C Blue Aluminum Lake #2 using a suitable screen.

[0264] 5. Add Magnesium Stearate and blend the mixture to yield the sweller layer blend.

[0265] Bilayer Tablet

[0266] 6. Compress the active layer and sweller layer into bilayer cores.

[0267] 7. Film coat the bilayer cores using a suitable pan coater to produce the osmotic membrane.

[0268] 8. Dry the tablets in a tray dryer to remove any residual amount of processing solvents.

[0269] 9. Produce the delivery port on the active-layer face of the bilayer tablet using a suitable laser.

[0270] Example 3. Preparation of Controlled Release (CR) Tablets (Long Duration)

[0271] A film-coated controlled release (CR) tablet of tris salt of Compund 1 in dosage strength of 30 mg was prepared [the weight expressed in milligram is the weight equivalent to Compound 1]-

[0272] The compositions of this CR tablet are shown in Table 3-1 .

[0273] Table 2-1 . Composition of tris salt of Compound 1 CR Tablet -long duration (equivalent to 30 mg of Compound 1 ) aIntra-granular.bExtra-granular.

[0274] 0Removed during processing

[0275] Process of preparing CR tablets

[0276] The following steps were carried out in preparing the CR tablets (See Figure 2).

[0277] Active Layer

[0278] 10. Perform Blend-Mill-Blend Process of tris salt of Compound 1 , Polyethylene Oxide, and a portion of the Magnesium Stearate using a suitable screen.

[0279] 11 . Dry granulate mixture from Step 1 by roller compaction.

[0280] 12. Add the extra-granular Magnesium Stearate and blend the mixture to yield the active layer granulation.

[0281] Sweller Layer 13. Perform Blend-Mill-Blend Process of Polyethylene Oxide, Microcrystalline Cellulose, Sodium

[0282] Chloride, and FD&C Blue Aluminum Lake #2 using a suitable screen. 14. Add Magnesium Stearate and blend the mixture to yield the sweller layer blend.

[0283] Bilayer Tablet

[0284] 15. Compress the active layer and sweller layer into bilayer cores.

[0285] 16. Film coat the bilayer cores using a suitable pan coater to produce the osmotic membrane. 17. Dry the tablets in a tray dryer to remove any residual amount of processing solvents.

[0286] 18. Produce the delivery port on the active-layer face of the bilayer tablet using a suitable laser.

[0287] Example AA. In Vitro Dissolution Tests

[0288] The dissolution profiles of the API of the immediately release tablets described in Example 1 and the modified release tablets described in Example 2 and Example 3 can be studied in 900 mL of 50 mM sodium phosphate buffer (pH 6.8) with 0.5% sodium dodecyl sulfate (SDS) at 37°C using a USPII apparatus with a paddle speed of 100 rpm, measured using fiber optic UV detection. All patents, patent applications and references referred to herein are hereby incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:1 . An immediate-release oral pharmaceutical composition comprising 2-({4-[(2S)-2-(4- chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2- ylmethyl]- 1 H-benzimidazole-6-carboxylic acid (Compound 1 ) or a pharmaceutically salt thereof.

2. An immediate-release oral pharmaceutical composition comprising:2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid (Compound 1 ), or a pharmaceutically acceptable salt thereof; a filler; a disintegrant; and a lubricant.

3. The immediate-release oral pharmaceutical composition of claim 2 wherein: the 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof is tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3- benzodioxol-4-yl]piperidin-1 -yljmethyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6- carboxylic acid; the filler comprises microcrystalline cellulose, lactose, or a combination thereof; the disintegrant is crospovidone; and the lubricant is magnesium stearate or sodium stearyl fumarate.

4. The immediate-release oral pharmaceutical composition of claim 2 or 3, wherein: the 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 - yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof comprises about 1 .0% to about 35.0% by weight; the filler comprises about 60% to about 95% by weight; the disintegrant comprises about 1 .0% to about 5.0% by weight; and lubricant comprises about 0.2% to about 3.5% by weight.

5. The immediate-release oral pharmaceutical composition of any one of claims 1 to 4, wherein the composition comprises tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl- 1 ,3-benzodioxol-4-yl]piperidin-1 -yl} methyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6- carboxylic acid in an amount equivalent to about 5 mg to about 120 mg of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2- ylmethyl]-1 H-benzimidazole-6-carboxylic acid.

6. The immediate-release oral pharmaceutical composition of any one of claims 2 to 5, wherein at least 80% by weight of the tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2- methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl} methyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole- 6-carboxylic acid in the composition dissolves within 60 minutes in a 50 mM sodium phosphate buffer (pH 6.8) with 0.5% sodium dodecyl sulfate (SDS) at about 37°C using a USPII apparatus with a paddle speed of 100 rpm.

7. An oral controlled release swellable core technology (SCT) tablet comprising:(a) a core that comprises:(i) an active layer comprising(1 ) an active pharmacological ingredient (API) that comprises 2-({4-[(2S)- 2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl}methyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid (“Compound 1 ”) or a pharmaceutically salt thereof, and(2) a viscosifying agent;(ii) a sweller layer comprising(1 ) a swelling agent, and(2) an osmogen; and(b) a coating that at least partially covers the core wherein the coating comprises(1 ) a film former, and(2) a pore former.

8. The oral controlled release SCT tablet of claim 7 wherein the API of the active layer comprises tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4- yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid in an amount equivalent to about 5 mg to about 120 mg of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2- methyl-1 ,3-benzodioxol-4-yl]piperidin-1 -yl} methyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole- 6-carboxylic acid.

9. The oral controlled release SCT tablet of claim 7 wherein the API in the active layer comprises tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4- yl]piperidin-1 -yl}methyl)-1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid in an amount equivalent to about 5 mg to about 100 mg of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl- 1 ,3-benzodioxol-4-yl]piperidin-1 -yl} methyl)- 1 -[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole- 6-carboxylic acid.

10. The oral controlled release SCT tablet of any one of claims 7 to 9 wherein the API in the active layer comprises about 1% by weight to about 40% by weight of the active layer.11 . The oral controlled release SCT tablet of any one of claims 7 to 10 wherein the viscofiying agent in the active layer comprises about 50% by weight to about 98% by weight of the active layer.

12. The oral controlled release SCT tablet of any one of claims 7 to 1 1 wherein the viscofiying agent in the active layer is selected from polyethylene oxide (PEO) and hydroxyethyl cellulose (HEC), or a mixture thereof.

13. The oral controlled release SCT tablet of any one of claims 7 to 12 wherein the viscosifying agent in the active layer is polyethylene oxide with a molecular weight less than about 500,000.

14. The oral controlled release SCT tablet of any one of claims 7 to 13 wherein the active layer further comprises a lubricant that is selected from metallic stearate and sodium stearyl fumarate, or a mixture thereof.

15. The oral controlled release SCT tablet of any one of claims 7 to 14 wherein the swelling agent in the sweller layer comprises about 30% or more by weight of the sweller layer.

16. The oral controlled release SCT tablet of any one of claims 7 to 15 wherein the swelling agent in the sweller layer is selected from polyethylene oxide (PEO) with a molecular weight greater than about 1 ,000,000.

17. The oral controlled release SCT tablet of any one of claims 7 to 16 wherein the osmogen in the sweller layer is selected from magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, ascorbic acid, 2-benzene carboxylic acid, benzoic acid, fumaric acid, citric acid, maleic acid, serbacic acid, sorbic acid, edipic acid, editic acid, glutamic acid, toluene sulfonic acid, and tartaric acid, or is a mixture of two or more thereof.

18. The oral controlled release SCT tablet of any one of claims 7 to 17 wherein the film former is selected from cellulose acetate (CA), cellulose acetate butyrate (CAB), and ethyl cellulose (EC).

19. The oral controlled release SCT tablet of any one of claims 7 to 18 wherein the pore former is selected from polyethylene glycol and hydroxypropylcellulose.

20. The immediate-release oral pharmaceutical composition of any one of claims 1 to 6 or the oral controlled release SCT tablet of any one of claims 7 to 19 for use in a method of once daily administration for weight management or for use in in a method of once daily administration for treating a condition, disease, or disorder, wherein the condition, disease, or disorder is selected from the group consisting of diabetes [e.g. Type 1 diabetes mellitus (T1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration,cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug);

Images