Pharmaceutical formulations of GPR119 agonists and their use

Abstract

This disclosure relates to an oral pharmaceutical formulation comprising a compound of formula I or a pharmaceutically acceptable salt thereof. In formula JPEG2026528933000058.jpg30170, R, A, and n are as described herein. This disclosure also relates to the preparation processes thereof, as well as their use in the treatment of disorders such as cardiovascular and metabolic disorders, including diabetes.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of Indian Patent Application No. 202311054015, filed on 11 August 2023, the entirety of which is incorporated herein by reference.

[0002] The present invention relates to an oral pharmaceutical formulation comprising a compound of formula I or a pharmaceutically acceptable salt thereof. [ka] In the formulas, R, A, and n are as described herein. The present invention also relates to the preparation process thereof, as well as their use in the treatment of diseases such as cardiovascular and metabolic diseases, including diabetes. [Background technology]

[0003] Approximately 415 million people worldwide have diabetes, and an estimated 193 million are undiagnosed. Type 2 diabetes accounts for over 90% of diabetes cases and causes microvascular and macrovascular complications that result in severe mental and physical distress for both patients and caregivers, placing a significant burden on the healthcare system. Type 2 diabetes is a chronic metabolic disease characterized by chronic hyperglycemia resulting from a lack of insulin secretion and / or function (i.e., insulin resistance). Type 2 diabetes is known to be associated with a shorter life expectancy and increased morbidity. While cardiovascular disease is the most common cause of death and morbidity, in addition to microvascular and macrovascular complications, type 2 diabetes is also associated with an increased risk of other diseases, including cancer, chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD) (including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH)), dyslipidemia and related disorders, cognitive decline, and accelerated progression of arthritis.

[0004] As the disease progresses, the majority of patients with type 2 diabetes eventually become insulin-dependent, requiring daily injections and multiple daily blood glucose monitoring, as oral therapy becomes ineffective. Oral antidiabetic drugs conventionally used in treatment (e.g., first-line or second-line, as monotherapy or (initial or additional) combination therapy) include, for example, metformin, sulfonylureas, thiazolidinediones, glinides, and alpha-glucosidase inhibitors.

[0005] The high incidence of treatment failure significantly contributes to the high incidence of long-term hyperglycemia-related complications or chronic injuries (e.g., microvascular and macrovascular complications such as diabetic nephropathy, retinopathy, or neuropathy, or cardiovascular complications) in patients with type 2 diabetes.

[0006] U.S. Patent No. 10,208,030 describes a GPR119 agonist and its preparation process.

[0007] There remains a need to provide novel oral pharmaceutical formulations that can be used to treat diseases such as diabetes. This invention addresses this challenge. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Patent No. 10,208,030 [Overview of the project] [Means for solving the problem]

[0009] In one aspect, the present invention is [ka] The present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein, Each R can independently be H, halogen, substituted or unsubstituted C 1~4Alkyl, and substituted or unsubstituted C1 ~4 selected from alkoxy, Variable A is hydrogen, substituted or unsubstituted C 1~4 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted (C 1~4 alkyl)phenyl, substituted or unsubstituted 5- to 6-membered heteroaryl containing one or more heteroatoms selected from N, O, and S, substituted or unsubstituted heterocyclyl containing one or more heteroatoms selected from N, O, and S, and substituted or unsubstituted C 1~4 selected from alkoxycarbonyl, and the substituents are halogen, substituted or unsubstituted C 1~4 alkyl, and substituted or unsubstituted C 1~4 selected from alkoxy. n is 0, 1, 2, or 3, * indicates a stereocenter, and includes one or more pharmaceutically acceptable excipients, The compound of formula I optionally has a particle size D less than about 200 μm. 90 having.

[0010] In one embodiment of any of the compositions described herein, the compound of formula I is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0011] In one embodiment of any of the compositions described herein, the compound of formula I is a compound of formula IA (2-((S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)ethoxy)-6-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole):

Chemical formula

[0012] In one embodiment of any of the compositions described herein, the composition comprises a therapeutically effective amount of the compound of formula I.

[0013] In one embodiment of any of the compositions described herein, one or more pharmaceutically acceptable excipients are selected from diluents, disintegrants, binders, lubricants, fluidizing agents, pH adjusters, surfactants, solubilizers, antioxidants, or any combination thereof.

[0014] In one embodiment of any of the compositions described herein, the compound of formula I is, for example, a compound of formula IA, IB, IC, ID or IE, and has a particle size D of less than about 200 μm 90 and has.

[0015] In one embodiment of any of the compositions described herein, the compound of formula I is, for example, a compound of formula IA, IB, IC, ID or IE, and has a particle size D of about 60 μm to about 100 μm 90 and has.

[0016] In one embodiment of any of the compositions described herein, the compound of formula I is, for example, a compound of formula IA, IB, IC, ID or IE, and has a particle size D of about 0.1 μm to about 200 μm 90 and has.

[0017] In one embodiment of any of the compositions described herein, the compound of formula I is, for example, a compound of formula IA, IB, IC, ID or IE, and has a particle size D of about 2.0 μm to about 150 μm 90It has.

[0018] In any embodiment of the compositions described herein, the compound of formula I is, for example, a compound of formula IA, IB, IC, ID, or IE, and accounts for less than about 75% by mass (w / w) of the total weight of the composition, for example, less than about 60% by mass (w / w) or less than about 50% by mass (w / w) of the total weight of the composition.

[0019] In any embodiment of the compositions described herein, the compound of formula I is, for example, a compound of formula IA, IB, IC, ID, or IE, with a particle size D of less than about 200 μm. 90 It contains and accounts for approximately 75% by mass (w / w) or less of the total weight of the composition. In any embodiment of the compositions described herein, the composition is a solid, such as a tablet or capsule. In one embodiment, at least 90% of the compound of formula I in the composition is released within 30 minutes when tested in 900 mL of (i) simulated gastric juice (without pepsin) at 100 rpm and 37.0 ± 0.5°C according to the USPII (paddle method) in 900 mL of (i) pH 1.2 simulated gastric juice (without pepsin), (ii) 0.01 N HCl aqueous solution containing 1% sodium lauryl sulfate, (iii) 0.1 N HCl aqueous solution containing 1% sodium lauryl sulfate, (iv) pH 4.5 aqueous acetic acid solution and 1% sodium lauryl sulfate, or (v) pH 6.8 aqueous phosphoric acid solution and 1% sodium lauryl sulfate.

[0020] In any embodiment of the compositions described herein, the composition [ka] (a) Nonionic water-dispersible surfactants (e.g., a mixture of lauroyl polyoxyl-32 glyceride and PEG6000), (b) Colloidal silicon dioxide, (c) Crospovidone, (d) A compressed tablet comprising a compound of formula IA or a pharmaceutically acceptable salt thereof dispersed in spray-dried (i) D-mannitol, (ii) xylitol, (iii) microcrystalline cellulose, (iv) crospovidone, and (v) calcium hydrogen phosphate or magnesium aluminometasilicate, wherein the compound of formula IA has a particle size D of less than about 200 μm. 90 It has.

[0021] In any embodiment of the compositions described herein, the composition [ka] (a) Nonionic water-dispersible surfactants (e.g., a mixture of lauroyl polyoxyl-32 glyceride and PEG6000), (b) Colloidal silicon dioxide, (c) Crospovidone, (d) A compressed tablet comprising a compound of formula IA or a pharmaceutically acceptable salt thereof dispersed in spray-dried (i) D-mannitol, (ii) xylitol, (iii) microcrystalline cellulose, (iv) crospovidone, and (v) calcium hydrogen phosphate, wherein the compound of formula IA has a particle size of less than approximately 200 μm. 90 It has.

[0022] In any embodiment of the compositions described herein, the composition is a solution or suspension. The solution or suspension may contain a compound of formula I (e.g., a compound of formula IA) or a pharmaceutically acceptable salt thereof, in addition to a cyclodextrin such as 2-hydroxypropyl-β-cyclodextrin. In one embodiment, the solution contains a cyclodextrin (e.g., 2-hydroxypropyl-β-cyclodextrin) in an amount sufficient to solubilize the compound of formula I (e.g., a compound of formula IA) or a pharmaceutically acceptable salt thereof. In one embodiment, the ratio of the compound of formula IA to 2-hydroxypropyl-β-cyclodextrin in the solution or suspension is about 1:1 to about 1:20, for example, about 1:5 to about 1:10.

[0023] In another embodiment, the present invention relates to a process for preparing an oral pharmaceutical composition comprising a compound of formula I, such as a compound of formula IA, formula IB, formula IC, formula ID, or formula IE, wherein the process includes wet granulation, direct compression, dry granulation, solid dispersion, melt granulation, or extrusion. In one embodiment, the composition comprises a therapeutically effective amount of the compound of formula I.

[0024] In another embodiment, the present invention relates to a process for preparing an oral pharmaceutical composition comprising, for example, a compound of formula I such as a compound of formula IA, formula IB, formula IC, formula ID, or formula IE, and one or more pharmaceutically acceptable excipients, wherein the process is (a) For example, preparing mixtures or granules of compounds of formula I, such as compounds of formula IA, formula IB, formula IC, formula ID, and formula IE, and one or more pharmaceutically acceptable excipients, and (b) comprising compressing the product obtained in (a) to form a tablet, or filling the product obtained in (a) into a capsule.

[0025] In another embodiment, the present invention relates to a process for preparing an oral pharmaceutical composition comprising, for example, a compound of formula I such as a compound of formula IA, formula IB, formula IC, formula ID, or formula IE, and one or more pharmaceutically acceptable excipients, wherein the process is (a) Prepare a solution or suspension containing, for example, a compound of formula I such as a compound of formula IA, formula IB, formula IC, formula ID, or formula IE, a solvent, and optionally one or more pharmaceutically acceptable excipients. (b) Adding the solution or suspension obtained in (a) to one or more pharmaceutically acceptable excipients to obtain granules, or coating an inert core with the solution or suspension obtained in (a) to obtain a drug-coated core. (c) optionally, the granules or drug-coated cores obtained in (b) are mixed with one or more pharmaceutically acceptable excipients, and (d) This includes compressing the granules or drug-coated core obtained in (b) or the mixture obtained in (c) to form a tablet, or filling the granules or drug-coated core obtained in (b) or the mixture obtained in (c) into a capsule.

[0026] In another aspect, the present invention relates to a method for treating diabetes or obesity, comprising orally administering a composition according to any embodiment described herein to a patient in need of treatment for diabetes or obesity. [Modes for carrying out the invention]

[0027] As used herein, the singular forms "a," "an," and "the" have plural meanings unless the context specifically indicates otherwise. For example, a reference to "a method" or "a process" includes one or more methods, one or more processes, and / or steps of the kind described herein, and / or steps that would be obvious to a person skilled in the art who has read this disclosure.

[0028] As used herein, “compound of formula I” includes “compounds of formulas IA-IE,” “compounds of formulas IA, IB, IC, ID, and IE,” and “active ingredient,” and refers to the compounds described herein, as well as their pharmaceutically acceptable or therapeutically active salts, esters, amides, prodrugs, metabolites, enantiomers, polymorphs, and analogues that induce the desired pharmacological or physiological effect. As used herein, the terms “activity,” “activator,” “therapeutic agent,” “therapeutic component,” “therapeutic substance,” and “active substance” may be used synonymously with “active ingredient” (where “active ingredient” refers to compounds of formula I, which include compounds of formulas IA, IB, IC, ID, and IE).

[0029] As used herein, the term “compound of formula I” means a compound of formula I, where, [ka] Each R can independently be H, halogen, substituted or unsubstituted C 1~4 Alkyl 、 and substituted or unsubstituted C 1~4 Selected from alkoxy, A is H, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted (C 1~4 Substituted or unsubstituted 5-6 membered heteroaryls containing one or more heteroatoms selected from alkyl)phenyl, N, O, and S, substituted or unsubstituted heterocyclines containing one or more heteroatoms selected from N, O, and S, and substituted or unsubstituted C 1~4 Selected from alkoxycarbonyls, Here, the substituent is a halogen, substituted or unsubstituted C 1~4 Alkyl, and substituted or unsubstituted C 1~4 Selected from alkoxy, n is 0, 1, 2, 3, * indicates the center of the solid.

[0030] The substituents in the above-mentioned "substituted" group cannot be further substituted. For example, "substituted C 1~4 The substituent in "alkyl" is "substituted C 1~4 If it is "alkoxy", then "substituted C 1~4 The substituents in "alkoxy" include "substituted C 1~4 It does not contain alkyl.

[0031] When used herein, "C 1~4 The term "alkyl," unless otherwise specified, refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, without unsaturated bonds, containing 1 to 4 carbon atoms, and the remainder of the molecule bonded by single bonds. Examples include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), and n-butyl.

[0032] Unless otherwise specified, "C 1~4The term "alkoxy" refers to a molecule in which the alkyl group, as defined above, is bonded to the remainder of the molecule via an oxygen bond. The term "substituted alkoxy" refers to an alkoxy group in which the alkyl portion is substituted (i.e., -O-(substituted alkyl)), where the term "substituted alkyl" is the same as that defined for "alkyl" above. For example, "alkoxy" refers to an -O-alkyl group, including alkyl groups containing 1 to 4 carbon atoms having a linear or branched configuration, and combinations thereof, bonded to the parent structure via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, and butoxy. The term "alkoxy" also includes groups in which the alkyl group is cyclic, such as cyclopropoxy and cyclobutoxy.

[0033] As used herein, the term “aryl” includes aromatic radicals having 6 to 20 carbon atoms, unless otherwise specified, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0034] In any particular embodiment of the formulations described herein, the compound of formula I is [ka] [ka] [ka] [ka] [ka] It is selected from the following compounds.

[0035] In any embodiment of the formulations described herein, the compound of formula I is the compound of formula IA.

[0036] As used herein, the term “approximately” in relation to a number means that a variation of 10% above or below that number falls within the range to which that number is assigned.

[0037] As used herein, the term “therapeutic dose” means the amount or quantitative range of a compound selected from the compounds of formula I, e.g., formulas IA, IB, IC, ID, and IE, that is sufficient to induce a desired biological response when administered to a patient. It is understood that the exact value of the therapeutic dose depends on the patient’s age and condition, the nature of the condition being treated, and is ultimately at the discretion of the attending physician.

[0038] As used herein, the terms “formulation,” “composition,” “oral formulation,” “oral composition,” “dosage form,” “pharmaceutical formulation,” and “pharmaceutical composition” are interchangeable and include, but are not limited to, solid and liquid dosage forms. Examples include, but are not limited to, tablets such as single-layer tablets, double-layer tablets, triple-layer tablets, and multi-layer tablets; caplets, mini-tablets, capsules, tablets within tablets, tablets within capsules, granules within capsules, pellets, pellets within capsules, powders, granules, solid dispersions, drug-coated inert cores, beads, spheroids, suspensions, solutions, and other dosage forms suitable for oral administration. Formulations described herein include, for example, immediate-release formulations, rapid-release formulations, orally disintegrating formulations, sustained-release formulations, modified-release formulations, delayed-release formulations, pulse-release formulations, and the like. These formulations may further be incorporated into drug carriers or drug delivery systems to improve stability and / or solubility, or to further enhance bioavailability. These formulations may be solid dispersions, lyophilized formulations, or spray-dried formulations.

[0039] As used herein, in certain embodiments, “stable” or “stable pharmaceutical formulation” means a pharmaceutical formulation containing a compound of Formula I according to any embodiment described herein, wherein the amount of impurities remains below the FDA-acceptable intake limit after exposure to 40°C ± 2°C and 75% ± 5% RH for 6 months, or to 25°C ± 2°C and 60% ± 5% RH for at least 12 months.

[0040] As used herein, the term “bioavailability” refers to the proportion of an administered active pharmaceutical ingredient (API) and / or active moiety, such as a compound of formula I as defined in any embodiment herein, that reaches the systemic circulation either unchanged or in another active form. By definition, when an active pharmaceutical ingredient (API) and / or active moiety is administered intravenously, its bioavailability is 100%. However, when administered by other routes of administration, such as oral administration, its bioavailability is reduced due to incomplete absorption and / or first-pass metabolism. Absolute oral bioavailability is calculated by comparing the relative exposure of the active pharmaceutical ingredient (API) and / or active moiety in systemic circulation after oral administration (estimated as the area under the plasma concentration-time curve) with the exposure of the active pharmaceutical ingredient (API) after intravenous administration.

[0041] As used herein, the terms “excipient” or “pharmaceutically acceptable excipient” mean a pharmacologically inert component. Suitable pharmaceutically acceptable excipients that may be used in any formulation described herein include, but are not limited to, diluents and / or fillers, binders, disintegrants, fluidizers, surfactants, solubilizers, sustained-release or delayed-release excipients, pH adjusters, antioxidants, preservatives, lubricants, flavoring agents, plasticizers, colorants, opacifiers, carriers, and any combination thereof. Excipients useful for preparing dosage forms are generally safe, non-toxic, and acceptable for both veterinary and human pharmaceutical applications. References to excipients include both one excipient and multiple excipients.

[0042] As used herein, the term “solid dispersion” means a dispersion of a compound of formula I (e.g., a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, in particular the compound of formula IA), in which the compound of formula I exists in a solubilized state, an amorphous state, or a mixture of amorphous and crystalline states.

[0043] All formulations described herein are stable and have oral bioavailability.

[0044] The compounds of formula I described herein have limited solubility in water.

[0045] The present invention relates to a stable and orally bioavailable pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I (for example, a compound selected from compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients.

[0046] In any additional embodiment of the formulations described herein, the compound of formula I (for example, a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, in particular the compound of formula IA) is present in the pharmaceutical formulation in an amount of about 50 mg to about 500 mg, for example, in an amount of about 50 mg to about 500 mg.

[0047] In any additional embodiment of the formulations described herein, the compound of formula I (for example, a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, in particular the compound of formula IA) is present in the pharmaceutical formulation in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg.

[0048] In any additional embodiment of the formulations described herein, the compound of formula I (e.g., a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, in particular the compound of formula IA) is amorphous, substantially crystalline (e.g., having greater than 90%, greater than 95%, or greater than 99% crystallinity), or crystalline.

[0049] In any additional embodiment of the formulations described herein, the compound of formula I (e.g., a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, in particular the compound of formula IA) is amorphous.

[0050] In any additional embodiment of the formulations described herein, the compound of formula I (e.g., a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, in particular the compound of formula IA) is substantially crystalline (e.g., having greater than 90%, greater than 95%, or greater than 99% crystallinity) or crystalline.

[0051] Suitable diluents / fillers for use in any of the formulations described herein include, but are not limited to, organic and inorganic diluents, such as cellulose and cellulose derivatives, starch and modified starch, polyols, carbohydrates, inorganic phosphates, carbonates, silicates, sulfates, and any combination thereof.

[0052] In certain embodiments, diluents / fillers include, but are not limited to, microcrystalline cellulose, silicic acid-treated microcrystalline cellulose, polyols and sugar alcohols (although not limited to these, such as algitol, mannitol, D-mannitol, meglumine, xylitol, isomalt, sorbitol, lactitol, pentitol, arabitol, ribitol, galactitol, erythritol, glycerol, etc.), carbohydrates (although not limited to these, such as monosaccharides, oligosaccharides, polysaccharides, dextrin, maltodextrin, pullulan, arabinose, dextrose, dextrate, lactose, sucrose, sucralose, saccharin, fructose, maltose, trehalose, psicose, tagatose, sorbose, cellulose derivatives, cellobiose, starch, modified starch, sucrose fatty acid esters, etc.), inorganic diluents (although not limited to these, such as calcium hydrogen phosphate, tricalcium phosphate, calcium carbonate, kaolin, calcium sulfate, etc.), and any combination of any of the above.

[0053] The diluent may contain co-processed excipients, such as D-mannitol and starch (Pearlitol® Flash), lactose and microcrystalline cellulose (Cellactose®), D-mannitol, xylitol, microcrystalline cellulose, crospovidone, and anhydrous calcium hydrogen phosphate (F-MELT® type C). F-MELT® is available in two grades: F-MELT® Type C and F-MELT® Type M. Type C contains anhydrous calcium hydrogen phosphate (Fujicalin®), and Type M contains magnesium aluminometasilicate (Neusilin®). If present, the filler may be used in an amount ranging from about 1% to about 80% by mass relative to the total weight of the pharmaceutical formulation, for example, in an amount ranging from about 1% to about 60% by mass relative to the total weight of the pharmaceutical formulation.

[0054] Suitable binders for use in any of the formulations described herein include, but are not limited to, natural or synthetic polymers, natural or synthetic gums, hydrocolloids, cellulose and cellulose derivatives, starch and modified starch, carbohydrates, vinyl polymers, and any combination of any of the foregoing. For example, in certain embodiments, binders include, but are not limited to, polyvinylpyrrolidone (PVP) (e.g., PVP K30 or PVP K90), polyvinyl acetate, polyvinyl alcohol, polyethylene glycol (PEG) (e.g., PEG400, PEG4000, PEG6000), PEG, copolymers of polyvinyl alcohol, polyvinyl acetate and PVP, hydroxypropyl methylcellulose, hydroxypropyl cellulose (in certain embodiments, both the hydroxypropyl methylcellulose and the hydroxypropyl cellulose are of medium to high viscosity, e.g., viscosity grade 3 or 6 cps), copovidone, maltodextrin, pre-gelatinized starch, microcrystalline cellulose, acacia, alginic acid, tragacanth, gelatin, liquid glucose, corn starch, sugars, ethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium alginate, and any combination of any of the above. If present, binders may be used in amounts ranging from about 0.1% to about 25% based on the weight of the pharmaceutical formulation.

[0055] Suitable disintegrants for use in any of the formulations described herein include, but are not limited to, natural or synthetic polymers, natural or synthetic gums, cellulose and cellulose derivatives, starch and modified starch. For example, in certain embodiments, such disintegrants include, but are not limited to, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, corn starch, cross-linked sodium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium starch glycolate, cross-linked CMC (Ac-Di-Sol), sodium carboxymethyl starch, ion exchange resins, and formalin casein, which may be used alone or in combination thereof. If present, disintegrants may be used in an amount ranging from about 0.1% to about 20% based on the weight of the pharmaceutical formulation.

[0056] Suitable lubricants for use in any of the formulations described herein include, but are not limited to, zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silica, aluminum silicate or calcium silicate, cucurbita, PEG4000-8000, talc, and any combination of any of the above. If present, the lubricant may be used in an amount ranging from about 0.01% to about 10% based on the weight of the pharmaceutical formulation, preferably ranging from about 0.1% to about 5% based on the weight of the pharmaceutical formulation.

[0057] Suitable fluidizers for use in any of the formulations described herein include, but are not limited to, colloidal silicon dioxide (e.g., Aerosil200), mesoporous silica, stearate, magnesium trisilicate, powdered cellulose, starch, talc, and any combination of the foregoing. If present, the fluidizer may be used in an amount ranging from about 0.01% to about 10% based on the weight of the pharmaceutical formulation, for example, in an amount ranging from about 0.1% to about 5%.

[0058] Suitable solubilizers for use in any of the formulations described herein include, but are not limited to, surfactants, cyclic oligosaccharides / cyclodextrins, phospholipids, and any combination thereof. The solubilizer may be used in an amount ranging from about 0.01% to about 25% based on the weight of the pharmaceutical formulation, for example, in an amount ranging from about 1% to about 20% based on the weight of the pharmaceutical formulation.

[0059] Suitable surfactants for use in any of the formulations described herein include anionic, cationic, nonionic, and amphoteric surfactants known to those skilled in the art. Suitable surfactants include, but are not limited to, sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate, Tween® and Span (PEO-modified sorbitan monoesters and fatty acid sorbitan esters), poloxamers, polysorbates, alkylaryl polyethers, polyoxyethylene glycol alkyl ethers, polyoxyls, and any combination of any of the above. Poloxamers are nonionic triblock copolymers in which two hydrophilic polyoxyethylene (poly(ethylene oxide)) chains are positioned on either side of a central hydrophobic polyoxypropylene (poly(propylene oxide)) chain. Polysorbates are oily liquids derived from ethoxylated sorbitan esterified with fatty acids. Polyoxyls are mixtures of monoesters and diesters of stearates and polyoxyethylenediols.

[0060] In certain embodiments, suitable surfactants include, but are not limited to, poloxamer 188 (e.g., Pluronic® F-68), poloxamer 407 (e.g., Pluronic® F127), polysorbate 20, polysorbate 60, polysorbate 80, tyroxapole, Brij® 35, Brij® 78, Brij® 98, Brij® 700, Span® 20, Span® 40, Span® 60, Span® 80, polyoxyl 40 stearate, polyoxyl 30 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, hydrogenated castor oil (or PEG-40 hydrogenated castor oil) (HCO-40), Kolliphor EL (Cremophor EL), Cremophor RH 40, and Cremophor RH Examples of nonionic surfactants include, but are not limited to, 60, d-α-tocopherol polyethylene glycol 1000 succinate, Solutol HS 15, sorbitan monooleate, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, and mono- and di-fatty acid esters of PEG300, PEG400, or PEG1750, as well as any combination of the foregoing. If present, nonionic surfactants may be used in amounts ranging from about 0.01% to about 25% based on the weight of the pharmaceutical formulation.

[0061] Solubilizers that may be used in any of the formulations described herein include cyclic oligosaccharides / cyclodextrins, which include α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, cyclodextrin-2-HP25, ionic (e.g., anionic) β-cyclodextrin (Captisol®) with or without butylated salts, hydroxypropyl-γ-cyclodextrin, and γ-cyclodextrin. Furthermore, phospholipids, such as hydrogenated soybean phosphatidylcholine, distearoyl phosphatidylglycerol, L-α-dimiristoyl phosphatidylcholine, and L-α-dimiristoyl phosphatidylglycerol, polyethylene glycol (PEG), and any combination of any of the above. Where present, cyclodextrin may be used in an amount ranging from about 0.01% to about 25% based on the weight of the pharmaceutical formulation.

[0062] Suitable pH adjusters for use in any of the formulations described herein include acids selected from organic or inorganic acids, such as ascorbic acid, fumaric acid, citric acid, malic acid, succinic acid, adipic acid, maleic acid, lactic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, etc., or bases selected from organic bases, such as pyridine, alkanamines, such as methylamine, diisopropylamine, diisopropylethylamine, triethylamine, dimethylamine, trimethylamine, pyridine, imidazole, histidine, guanidine, polyethyleneimine, poly(vinylpyridine), diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane (Tris), sodium glycine, 1-methylimidazole, 2-methylimidazole, and 4(5)-methylimidazole Examples include, but are not limited to, 1,2-diaminoethane, 2-(bis(2-hydroxyethyl)amino)-2-(hydroxymethyl)propane-1,3-diol, sodium lysine, sodium histidine, and sodium arginine, polyvinylimidazole, and copolymers thereof (e.g., copolymers of polyethyleneimine with one or more of poly(vinylpyridine) and polyvinylimidazole, or copolymers of poly(vinylpyridine) and polyvinylimidazole), or inorganic bases, such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, sodium citrate, sodium hydroxide, potassium hydroxide, ammonium salts, and any combination of any of the above. In one embodiment, if present, pH adjusters may be used in amounts ranging from about 0.1% to about 10% based on the weight of the pharmaceutical formulation.

[0063] Suitable antioxidants for use in any of the formulations described herein include, but are not limited to, natural and synthetic compounds, organic acids and inorganic acids. In certain embodiments, the antioxidants include ascorbic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, citric acid, malic acid, lactic acid, benzenesulfonic acid, oxalic acid, triphenylacetic acid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, sodium ascorbate, α-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, gentisic acid (2,5-dihydroxybenzoic acid), acetylcysteine, ascorbyl palmitate, cysteine, dithiothreitol, thioglycerol, thiourea, caffeic acid, propyl gallate, ferulic acid, sodium pyrosulfite, edetic acid, edetate, 2,6-di-tert-butyl-p-cresol, gallic acid and its esters, nordihydroguaiaretic acid, and benzoic acid. Examples of antioxidants include, but are not limited to, benzoates, sorbic acid, sorbates, guaiacol esters, tea polyphenols, curcumin, chlorogenic acid, methionine, proline, dimeric flavonoids, superoxide dismutase, silymarin, grape skin / seed extract, melanin, rosemary extract, sodium sulfite, sodium thiosulfite, sodium bisulfite, sodium metasulfite, tert-butylhydroquinone, sodium citrate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, 3,4-dihydroxybenzoic acid, butylated hydroxybenzoic acid and its salts, erythorbic acid and its sodium salts, sorbic acid and its salts, formaldehyde sodium sulfite, glutathione, lipoic acid, dihydroxyfumaric acid, etc. In one embodiment, if present, antioxidants may be used in amounts ranging from about 0.1% to about 10% based on the weight of the pharmaceutical formulation.

[0064] Suitable sustained-release or delayed-release excipients for use in any of the formulations described herein include, but are not limited to, hydrophilic or hydrophobic agents, natural or synthetic polymers, and natural or synthetic gums. In certain embodiments, the sustained-release or delayed-release excipients include polyvinyl acetate, cellulose acetate, cellulose butyrate acetate, cellulose propionate acetate, ethylcellulose, fatty acids, fatty acid esters, alkyl alcohols, waxes, xanthan gum, gellan gum, shellac, rosin, zein (corn-derived prolamin), povidone, coridone SR (polyvinyl acetate and povidone), poly(meth)acrylate, poly(ethylene oxide), polyuronic acid, cellulose ether, tragacanth gum, karaya gum, guar gum, acacia, locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, polyethylene oxide, carbomer homopolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxyvinyl polymer, polymerized gelatin, methacrylate copolymer type C Examples include, but are not limited to, NF, cellulose acetate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydrogenated castor oil, stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers (Eudragit NE, Eudragit RL, Eudragit RS) containing methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate.If present, the polymer may be used in an amount ranging from about 0.1% to about 50% based on the weight of the formulation, for example, in an amount ranging from about 10% to about 50% or from about 10% to about 40% based on the weight of the formulation.

[0065] Suitable inert cores for use in any of the formulations described herein include, but are not limited to, sugars, sucrose, sorbitol, xylitol, mannitol, lactose, dicalcium phosphate, microcrystalline cellulose, maltodextrin, starch, hydrophilic cellulosic polymers, crosslinked hydrophilic synthetic polymers, fillers, diluents, and any combination of any of the foregoing.

[0066] The solvents that can be used to prepare solutions or dispersions (e.g., suspensions) of compounds of formula I (e.g., compounds selected from compounds of formulas IA, IB, IC, ID, and IE, in particular compounds of formula IA) may be aqueous solvents, non-aqueous solvents (e.g., organic solvents or inorganic solvents), or any combination thereof.

[0067] Suitable aqueous solvents include, for example, purified water, water for injection, bacteriostatic water for injection, sterile water, isotonic saline, and buffered aqueous solutions. Suitable non-aqueous solvents include organic solvents or inorganic solvents. Suitable organic solvents for use include, but are not limited to, acetic acid, methylene chloride, monohydric or polyhydric alcohols, isopropyl alcohol, ethanol, glycerin, propylene glycol, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, tert-butyl alcohol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, anhydrous alcohol, diethylene glycol, diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,2-dimethoxyethane (glyme, DME), dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). Examples include, but are not limited to, 1,4-dioxane, ethyl acetate, ethylene glycol, heptane, hexamethylphosphoramide (HMPA), hexamethylphosphorus triamide (HMPT), hexane, methanol, methyl tert-butyl ether (MTBE), N-methyl-2-pyrrolidone (NMP), nitromethane, pentane, petroleum ether (ligroin), 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethylamine, o-xylene, m-xylene, benzyl alcohol, glycoflore, solketal, glycerol formal, and any combination thereof. Suitable inorganic solvents include, but are not limited to, water, aqueous solutions containing special additives (surfactants, detergents, pH buffers, inhibitors), liquid anhydrous ammonia, concentrated sulfuric acid, fluorosulfonyl chloride, liquid sulfur dioxide, sulfuryl chloride, phosphorus oxychloride, nitrogen tetroxide, antimony trichloride, bromine pentafluoride, hydrogen fluoride, and any combination thereof.

[0068] Suitable coatings that may be used in any of the formulations described herein include, but are not limited to, immediate-release, sustained-release, and delayed-release coatings. Suitable examples include, but are not limited to, shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), acrylates, phthalates, zein (a protein derivative derived from corn), hydroxypropyl methylcellulose, methylhydroxyethylcellulose, ethylcellulose, povidone, polyvinyl acetate, polyvinyl alcohol, Opadry, and any combination of any of the above.

[0069] In any embodiment of the formulations described herein, the compound of formula I (for example, a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, in particular the compound of formula IA) has a particle size D of less than about 200 μm. 90 It has a size such as less than approximately 150 μm, less than approximately 100 μm, less than approximately 75 μm, less than approximately 50 μm, less than approximately 25 μm, or less than approximately 10 μm.

[0070] In any embodiment of the formulations described herein, the compound of formula I (for example, a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, particularly the compound of formula IA) has a particle size D of about 5 μm to about 20 μm. 50 It has.

[0071] In any embodiment of the formulations described herein, the compound of formula I (for example, a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, particularly the compound of formula IA) has a particle size D of about 1 μm to about 10 μm. 10 It has.

[0072] In one embodiment, the present invention relates to an oral pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I (for example, a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA), wherein the compound of formula I accounts for about 75% or less of the mass of the composition, for example, about 50% or less of the mass of the composition, or about 25% or less of the mass of the composition.

[0073] In any embodiment of the oral formulations described herein, the oral formulation is a tablet or a capsule. In any embodiment, the oral formulation is an immediate-release tablet. In any embodiment of the oral formulations described herein, the mass of the dosage form (e.g., an immediate-release tablet) is about 100 mg to about 2000 mg.

[0074] In one embodiment, the present invention relates to a process for preparing an oral pharmaceutical formulation comprising a compound of formula I (e.g., compounds of formula IA, formula IB, formula IC, formula ID, or formula IE, particularly a compound of formula IA), the process comprising dry granulation, wet granulation, direct compression, melt granulation, extrusion, or solid dispersion processes.

[0075] In one embodiment, the present invention relates to a process for preparing an oral pharmaceutical formulation comprising a compound of formula I (e.g., compounds of formula IA, formula IB, formula IC, formula ID, or formula IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients, wherein the process is: (1) Prepare a blend (mixture) or granule of a compound of formula I (e.g., compounds of formula IA, formula IB, formula IC, formula ID, or formula IE, especially a compound of formula IA) and one or more pharmaceutically acceptable excipients, and (2) Including compressing the blend or granules to form tablets, or filling the blend or granules into capsules.

[0076] In one embodiment, the present invention relates to a process for preparing an oral pharmaceutical formulation comprising a compound of formula I (e.g., a compound of formula IA, formula IB, formula IC, formula ID, or formula IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients, such as a direct compression process, wherein the process is: (1) Premix a compound of formula I (e.g., compounds of formulas IA, IB, IC, ID, and IE, especially the compound of formula IA) and a portion of one or more pharmaceutically acceptable excipients (e.g., a portion exceeding 50%) (e.g., in a mixer) to obtain a premixture. (2) Optionally, in order to separate agglomerating particles and improve content uniformity, the preliminary mixture obtained in (1) is dry-sieved through a screen. (3) Mix the pre-mixture obtained in (1) or (2) (for example, in a mixer), and optionally add one or more of the remaining pharmaceutically acceptable excipients to the mixture. (4) Compress the final mixture obtained in (3) (for example, by compressing it with a suitable tablet press) to produce a tablet core, and (5) Optionally, the tablet core obtained in step (4) is coated with a film coating.

[0077] In one embodiment, the present invention provides a process (e.g., a dry granulation process) for preparing an oral pharmaceutical formulation comprising a compound of formula I (e.g., a compound selected from compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients, the process comprising: (1) Mixing a compound of formula I (e.g., a compound selected from compounds of formulas IA, IB, IC, ID, and IE, in particular a compound of formula IA) with a portion (e.g., less than 100% or 100%) of one or more pharmaceutically acceptable excipients (e.g., mixing in a mixer), (2) Compress the mixture obtained in step (1) (for example, by compressing it on a suitable roller compactor) (for example, to obtain a ribbon), (3) The compressed mixture obtained in step (2) (e.g., ribbon) is crushed into granules (e.g., by an appropriate crushing and / or sieving process), (4) Optionally, mix the granules obtained in step (3) with one or more remaining pharmaceutically acceptable excipients to obtain a final mixture (e.g., by mixing in a mixer). (5) To manufacture a tablet core by compressing the granules obtained in step (3) or the final mixture obtained in step (4) (for example, by compressing it on a suitable tablet press), (6) Optionally, the tablet core obtained in step (5) is covered with a film coating.

[0078] In one embodiment, the present invention relates to a process (e.g., a wet granulation process) for preparing an oral pharmaceutical formulation comprising a compound of formula I (e.g., a compound selected from compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients, wherein the process is: (1) Premixing a compound of formula I (e.g., a compound selected from compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and a portion (e.g., more than 50%) of one or more pharmaceutically acceptable excipients to obtain a premixture (e.g., mixing in a mixer), (2) Granulate the premixture obtained in (1) (for example, by adding a granulation solution), (3) Dry the granules obtained in (2) (for example, by drying in a fluidized bed dryer or drying oven), (4) Optionally, the dried granules obtained in (3) are subjected to dry sieving. (5) Mix the dried granules obtained in (2) or (4) with the remaining one or more pharmaceutically acceptable excipients to obtain the final mixture (e.g., by mixing in a mixer). (6) Manufacturing a tablet core by compressing the final mixture obtained in (5) (for example, by compressing it on a suitable tablet press), or filling the final mixture obtained in (5) into capsules, and (7) Optionally, the tablet core obtained in (6) is covered with a film coating.

[0079] In one embodiment, the present invention relates to a process for preparing an oral pharmaceutical composition comprising a compound of formula I (for example, a compound selected from compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients, wherein the process is as follows: (1) Prepare a compound of formula I (for example, a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, particularly the compound of formula IA) in a suitable solvent with one or more pharmaceutically acceptable excipients as a solution or suspension. (2) Spray the solution or suspension obtained in (1) onto one or more pharmaceutically acceptable excipients to obtain granules, or coat an inert core with the solution or suspension obtained in (1) to obtain a drug-coated core. (3) Optionally, mix the granules or drug-coated cores obtained in (2) with one or more pharmaceutically acceptable excipients, and (4) The process involves compressing the granules or drug-coated core obtained in (2) or the mixture obtained in (3) to form a tablet, or filling the granules or drug-coated core obtained in (2) or the mixture obtained in (3) into a capsule.

[0080] In some embodiments, the formulations described herein may be granulated before compression. The formulation may comprise an intragranular portion and an extragranular portion, the intragranular portion being granulated and the extragranular portion being added after granulation. In some embodiments, the intragranular portion may comprise a compound of formula I (e.g., a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients. In some embodiments, the extragranular portion may comprise a compound of formula I (e.g., a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients. The extragranular portion may comprise a filler, a binder, a disintegrant, a lubricant, a fluidizer, or a combination thereof.

[0081] In one embodiment, the present invention provides a process for preparing an oral pharmaceutical composition comprising a compound of formula I (for example, a compound selected from compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA), the process comprising an extrusion process.

[0082] Extrusion may be wet extrusion or melt extrusion. Wet extrusion involves preparing a wet mass consisting of a compound of formula I (e.g., a compound selected from compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients, and then extruding the wet mass to form extruded pellets. Melt extrusion involves preparing a molten solid mass consisting of a compound of formula I (e.g., a compound selected from compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients, and then extruding the molten solid mass to form extruded pellets.

[0083] In another embodiment, the present invention relates to an amorphous solid dispersion comprising a compound of formula I (e.g., a compound selected from compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients.

[0084] In certain embodiments, the immediate-release dosage forms disclosed herein release more than 75% of the active ingredient contained therein, for example, compounds of formula I (e.g., compounds selected from compounds of formulas IA, IB, IC, ID, and IE, particularly compounds of formula IA) within a period selected from less than 1 hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, and less than 10 minutes after administration.

[0085] In any additional embodiment of the processes described herein, the process further includes purging the solution or suspension formulation with an inert gas to reduce the oxygen concentration.

[0086] In another embodiment, the present invention relates to a kit (e.g., a package or storage container) comprising a formulation according to any embodiment described herein. In certain embodiments, the package or container comprises an oxygen-blocking material or an oxygen-impermeable material. In certain embodiments, the package or container comprises an oxygen absorbent. In certain embodiments, the package or container comprises a desiccant or an oxygen absorbent.

[0087] In any other embodiment of a formulation comprising a compound of formula I described herein (e.g., a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA), the formulation is stable when stored for at least one month, at least three months, or at least six months under conditions of 40°C ± 2°C and 75% ± 5% relative humidity (RH).

[0088] In any other embodiment of a formulation comprising a compound of formula I described herein (e.g., a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, particularly a compound of formula IA), the formulation is stable when stored at 25°C ± 2°C and 60% ± 5% for at least 1 month, at least 3 months, at least 6 months, or at least 12 months.

[0089] In another embodiment of any formulation comprising a compound of formula I described herein (e.g., a compound selected from the compounds of formulas IA, IB, IC, ID, and IE, particularly the compound of formula IA), the formulation contains impurities below the FDA's permissible daily intake limit. Any formulation described herein, when stored for at least 6 months under conditions of 40°C ± 2°C and 75% ± 5% RH, or for at least 12 months under conditions of 25°C ± 2°C and 60% ± 5% RH, will have an impurity content of about 5%, about 4%, about 3%, about 2%, or about 1%.

[0090] In another aspect, the present invention relates to pharmaceutical uses of oral formulations according to any embodiment described herein, for example, in the treatment of cardiovascular and metabolic disorders, including but not limited to diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dyslipidemia, and related disorders.

[0091] In another embodiment, the present invention relates to a method for treating cardiovascular and metabolic disorders, including but not limited to diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dyslipidemia, and related disorders, the method comprising administering to a patient in need of such treatment an oral formulation according to any embodiment described herein.

[0092] The present invention also relates to the pharmaceutical use of oral formulations according to any embodiment described herein. In particular embodiments of any use and method described herein, the formulations may be used for the following medical treatments (e.g., those related to diabetes): (i) Prevention and / or treatment of all forms of diabetes, including hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (young-onset adult-onset diabetes), gestational diabetes, and / or reduction of HbA1c. (ii) Delay or prevention of the progression of diabetic disease, including progression in type 2 diabetes, progression from impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or progression from non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes. (iii) Improvement of β-cell function, including reduction of β-cell apoptosis, increase of β-cell function and / or β-cell mass, and / or restoration of glucose sensitivity of β-cells. (iv) Prevention and / or treatment of cognitive impairment, (v) Prevention and / or treatment of obesity by reducing food intake, weight loss, appetite suppression, or induction of satiety; treatment or prevention of obesity induced by bulimia nervosa, bulimia nervosa, and / or antipsychotic drugs or steroids; reduction of gastric motility and / or delay of gastric emptying; (vi) Prevention and / or treatment of diabetic complications, including neuropathy, nephropathy, or retinopathy, (vii) Prevention and / or treatment of dyslipidemia, including improvement of lipid parameters such as a decrease in total serum lipids, a decrease in HDL, a decrease in small, high-density LDL, a decrease in VLDL, a decrease in triglycerides, a decrease in cholesterol, an increase in HDL, a decrease in plasma levels of lipoprotein a (Lp(a)) in humans, and / or inhibition of apolipoprotein a (apo(a)) production in vitro and / or in vivo. (viii) Prevention and / or treatment of cardiovascular diseases, including syndrome X, arteriosclerosis, myocardial infarction, coronary heart disease, stroke, cerebral ischemia, early heart disease or early cardiovascular disease including left ventricular hypertrophy, coronary artery disease, essential hypertension, hypertensive emergency, cardiomyopathy, heart failure, impaired exercise tolerance, chronic heart failure, arrhythmia, dysregulation, syncope, mild chronic heart failure, angina pectoris, cardiac bypass reocclusion, intermittent claudication, diastolic dysfunction, and / or systolic dysfunction. (ix) Prevention and / or treatment of gastrointestinal diseases, including inflammatory bowel syndrome, small bowel syndrome, or Crohn's disease, dyspepsia, and / or gastric ulcers. (x) Treatment of critically ill patients, patients with critically ill polyneuropathy (CIPNP), and / or patients at risk of developing CIPNP; prevention of the development of critical illness or CIPNP; prevention, treatment, and / or cure of systemic inflammatory response syndrome (SIRS); and prevention or reduction of the likelihood of developing bacteremia, sepsis, and / or septic shock during hospitalization, (xi) Prevention and / or treatment of non-alcoholic fatty liver disease (NAFLD), such as non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and / or (xii) Prevention and / or treatment of polycystic ovary syndrome (PCOS).

[0093] In one embodiment, the present invention relates to a method for treating diabetes or obesity, the method comprising administering an oral formulation according to any embodiment described herein to a patient in need of such treatment. In a particular embodiment, the formulation is an orally administered tablet, for example, an orally administered immediate-release tablet.

[0094] In another embodiment, any of the formulations described herein may further comprise one or more additional therapeutic agents. In another embodiment, any of the formulations described herein may be administered to a patient in need of such treatment in combination with (sequentially or simultaneously) one or more other additional agents.

[0095] For example, one or more additional medications include, but are not limited to, SGLT2 inhibitors, DPP IV inhibitors, biguanides, thiazolidinediones, sulfonylureas, GLP-1 agonists, angiotensin receptor blockers, antianginal drugs, antiarrhythmic drugs, antihypertensive drugs, β-adrenergic agonists, calcium channel blockers, diuretics, and other cardiovascular medications, as well as any combination of any of the above.

[0096] One or more additional medications may include: biguanides (e.g., metformin), thiazolidinediones selected from pioglitazone, rosiglitazone, troglitazone, englitazone, or dalglitazone, sulfonylureas selected from glimepiride, gliclazide, glipizide, tolbutamide, glubornelide, glikidone, or glibenclamide, glinides selected from nateglinide or repaglinide, α-glucosidase inhibitors selected from acarbose, miglitol, or voglibose, dapagliflozin, empagliflozin, sotagliflozin, canagliflozin Examples of SGLT-2 inhibitors include, but are not limited to, szin, luseogliflozin, tofogliflozin, ipragliflozin, ertugliflozin, atigliflozin, or remogliflozin; DPP-4 inhibitors selected from sitagliptin, vildagliptin, saxagliptin, carmegliptin, gosogliptin, alogliptin, linagliptin, melogliptin, gemigliptin, anagliptin, teneligliptin, trelagliptin, dutogliptin, evogliptin, or omaligliptin; and any pharmaceutically acceptable salts of any of the above.

[0097] While selected embodiments of the present invention are shown and described herein, it will be apparent to those skilled in the art that these embodiments are merely illustrative. A number of modifications, changes, and substitutions can be conceived by those skilled in the art without departing from the scope of the present invention.

[0098] It is understood that various alternative embodiments may be employed in carrying out the present invention in place of the embodiments described herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention pertains. All patents and publications referenced herein are incorporated herein by reference. [Examples]

[0099] The present invention will be specifically described using the following examples. However, the scope of the present invention is not intended to be limited to, nor is it intended to be limited to, the embodiments illustrated below. Particle size analysis was performed using a Malvern particle size distribution analyzer (Mastersizer 3000, Malvern Instrument Ltd.).

[0100] Sample preparation Accurately weigh 100 mg of the sample into a 100 mL beaker. Add 3 drops of Tween80 and 1 mL of water, and mix into a paste using a glass rod. Then, add 10 mL of water and sonicate externally for 10 seconds while continuing to shake. [Table 1]

[0101] procedure

[0102] After cleaning, initialize the system and perform background measurements. Add the sample so that the shielding rate is 10-20%, and wait until the shielding rate stabilizes. Start the analysis according to the set instrument conditions, or perform the standard operating procedure. Analyze the sample repeatedly, and D 10 , D 50 and D 90 In this report, we will present the average results (instrument average) of the two preparations.

[0103] Chemical purity was measured by high-performance liquid chromatography (HPLC). [Table 2] [Table 3]

[0104] process

[0105] 1. The compound of formula I and microcrystalline cellulose are sieved through a 40-mesh sieve. 2. The mixture obtained in step (1) is sieved together with colloidal silicon dioxide through a 40-mesh sieve. 3. Blend the mixture obtained in step (2) in a blender for 10-20 minutes. 4. Fluid the mixture from step 3 in a blender with magnesium stearate for 3 to 7 minutes. 5. The mixture obtained in step (4) is compressed on a tablet press to obtain compressed tablets. 6. The tablets are coated with OpaDryWhite in a coating machine, with a weight increase rate of 2-4%. [Table 4]

[0106] process

[0107] 1. Each component was sieved separately using an appropriate sieve to ensure that the entire amount (100%) passed through the sieve (for example, a 24-mesh sieve). 2. The compound of formula I, microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide, which had been sieved beforehand, were dry-mixed in a suitable blender. 3. The dry-mixed components from step 2 in the blender were lubricated with approximately 50% sodium stearyl fumarate. 4. The mixture from step 3 was passed through a roller compactor to obtain a compressed / ribbon-like material. 5. The compressed / ribbon-like material from step 4 was passed through a suitable mesh screen (e.g., 18-30 mesh) and then through a required sieve (e.g., 18-30 mesh) to obtain granules. 6. The granules obtained from step 5 were mixed in a suitable blender and lubricated with the remaining sodium stearyl fumarate. 7. The mixture from step 6 was compressed into tablets. 8. The tablets from step 7 were film-coated. [Table 5]

[0108] process

[0109] 1. All components were sieved separately using appropriate sieves. 2. The compound of formula I and the dried components were mixed in a rapid mixer granulator (RMG). 3. Hypromellose and sodium lauryl sulfate were dissolved in purified water and added to the product from step 2, and mixed until a homogeneous dispersion (binder) was obtained. 4. The components dry-mixed in step 2 were granulated in an RMG (Rapid Mixing Granulator) using the binder from step 3. 5. The wet granules from step 4 were dried in a fluidized bed dryer (FBD) until the required loss on drying (LOD) was achieved. 6. The dried granules were passed through an appropriate mesh (for example, 18-30 mesh), and any excess granules were ground using a multi-mill. 7. The granules from step 6 were mixed in a suitable blender. 8. The granules from step 7 were mixed in a suitable blender with the pre-sieved microcrystalline cellulose, crospovidone, and colloidal silicon dioxide. 9. The mixture from step 8 was lubricated in a blender with pre-sieved magnesium stearate. 10. The mixture from step 9 was compressed into tablets. 11. The tablets were packaged as required. [Table 6]

[0110] process

[0111] 1. All components were sieved separately using an appropriate sieve (e.g., 24-40 mesh). 2. The dried components (microcrystalline cellulose and crospovidone) were mixed in RMG. 3. The compound of formula IA was added to the methylene chloride and mixed until a clear solution was formed. Then, hypromellose was added to the methylene chloride and mixed until a homogeneous dispersion (binder) was obtained. 4. The components dry-mixed in step 2 were mixed together with the binder from step 3 in RMG. 5. The wet granules from step 4 were dried in a fluidized bed dryer (FBD) until the required level of discharge (LOD) was achieved. 6. The dried granules from step 5 were passed through an appropriate mesh (for example, 18-30 mesh), and any excess granules were ground using a multi-mill. 7. The granules from step 6 were mixed in a suitable blender. 8. The granules from step 7 were mixed in a suitable blender with the pre-sieved microcrystalline cellulose, crospovidone, and colloidal silicon dioxide. 9. The mixture from step 8 was mixed in a blender with the pre-sieved magnesium stearate. 10. The mixture from step 9 was compressed into tablets. 11. The tablets were packaged as required. [Table 7]

[0112] process

[0113] 1,2-Hydroxypropyl-β-cyclodextrin and the compound of formula IA were weighed. 2. Water for injection was added to 2-hydroxypropyl-β-cyclodextrin to obtain a 5% w / v solution. 3. A 5% solution of 2-hydroxypropyl-β-cyclodextrin from step 2 was added to the compound of formula IA while stirring to obtain a suspension. [Table 8]

[0114] process

[0115] 1. All components were sieved separately using an appropriate sieve (e.g., 24-40 mesh). 2. The dried components (peritol flush, crospovidone, and 2-hydroxypropyl-β-cyclodextrin) were mixed in RMG. 3. The compound of formula IA was added to the methylene chloride and mixed until a clear solution was formed. Then, hypromellose was added to the methylene chloride and mixed until a homogeneous dispersion (binder) was obtained. 4. The components dry-mixed in step 2 were granulated in RMG using the binder from step 3. 5. The wet granules from step 4 were dried in a fluidized bed dryer (FBD) until the required level of discharge (LOD) was achieved. 6. The dried granules from step 8 were passed through an appropriate mesh (for example, 18-30 mesh), and any excess granules were ground using a multi-mill. 7. The granules from step 6 were mixed in a suitable blender. 8. The granules from step 7 were mixed in a suitable blender with the pre-sieved sodium starch glycolate, crospovidone, peritol flush, and colloidal silicon dioxide. 9. The mixture from step 8 was lubricated in a blender with pre-sieved magnesium stearate. 10. The mixture from step 9 was compressed into tablets. 11. The tablets were packaged as required. [Table 9]

[0116] process

[0117] 1. All components were sieved separately using an appropriate sieve (e.g., 24-40 mesh). 2. The dry components (F-melt and crospovidone) were mixed in RMG. 3. The compound of formula IA was added to the methylene chloride and mixed until a clear solution was formed. Then, hypromellose was added to the methylene chloride and mixed until a homogeneous dispersion (binder) was obtained. 4. The components dry-mixed in step 2 were granulated in RMG using the binder from step 3. 5. The wet granules from step 4 were dried in a fluidized bed dryer (FBD) until the required level of discharge (LOD) was achieved. 6. The dried granules from step 5 were passed through an appropriate mesh, and any excess granules were ground using a multi-mill. 7. The granules from step 6 were mixed in a suitable blender. 8. The granules from step 7 were mixed in a suitable blender with the pre-sieved F-melt, crospovidone, aspartame, strawberry flavor, and colloidal silicon dioxide. 9. The mixture from step 8 was mixed in a blender with the pre-sieved magnesium stearate. 10. The mixture from step 9 was compressed into tablets. 11. The tablets were packaged as required. [Table 10]

[0118] process

[0119] 1. sieving F-Melt (D-mannitol, xylitol, microcrystalline cellulose, crospovidone, and fusicalin), Aeroperl 300, Polyplasdone XL 10, and Gelucire 59 / 14 (Gattefose) were sieved through a 40-mesh sieve and mixed.

[0120] 2. Binder preparation 300 grams of methylene chloride was divided into three portions (200g, 50g, and 50g) and each portion was added to a separate glass beaker. The compound of formula IA was gradually added while continuously stirring until it dissolved in 200 g of MDC, and this process was continued until a clear, light brown solution was formed. PVPK 29 / 32 was dissolved in 50 g of MDC in a separate beaker to obtain a clear solution. Then, while stirring, this solution was added to the compound solution of formula IA to obtain a light brown solution (binder / API solution).

[0121] 3. Addition of binder The binder / API solution was gradually added to the pre-mixed components that had been sieved in step 1, while continuously mixing. The addition rate was kept slow and constant to prevent clumping. After the complete addition of the binder / API solution, the beaker was washed with 50 g of MDC, and the washing solution was added and mixed to form a homogeneous wet material.

[0122] 4. dry The wet material was dried in a fluidized bed dryer at 50°C for 20 minutes with an air flow rate of 20-25 cfm. The resulting LOD was 1.0-1.5.

[0123] 5. Mixing and lubrication The dried granules were sieved through a 30# mesh and then mixed with Polyplasdone XL 10 for 2-3 minutes. Pre-sieved (60 mesh) magnesium stearate was added and mixed for 2 minutes.

[0124] 6. Tablet compression The mixture was compressed using the following parameters. Punch details: Oval punch, 19.00 x 9.90 mm Average tablet weight: 1120 mg DT: 2~3 minutes Hardness: 12kg Thickness: 6.80~6.90mm

[0125] Dissolution test

[0126] Dissolution tests were conducted on formulation 8A under the following conditions.

[0127] Eluate

[0128] 1.0.01N HCl+1%SLS eluate

[0129] Number of tablets: 12

[0130] The sampling time intervals were set to 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, and 60 minutes.

[0131] Device: USPII (paddle)

[0132] Capacity: 900mL

[0133] Rotation speed: 100 rpm

[0134] Temperature: 37.0 ± 0.5℃ [Table 11] [Table 12]

[0135] *F-Melt is available from Fuji Chemical Industries USA in Burlington Township, New Jersey, USA; Aeroperl 300 is colloidal silicon dioxide; Polyplasdone XL10 (available from Ashland in Rotterdam, Netherlands) is crospovidone; and Gelucire 59 / 14 (available from Gatefose in Saint-Prieste, France) is a mixture of lauroyl polyoxyl-32 glyceride and PEG6000.

[0136] process

[0137] Step 1: Sieving and dry mixing F-Melt (D-mannitol, xylitol, microcrystalline cellulose, crospovidone, fusicalin), Aeroperl 300, Polyplasdone XL10, and Gelucire 59 / 14 (Gattefose) were sieved (#40 mesh) and mixed for 5 minutes.

[0138] Step 2: Binder preparation PVP29 / 32 was added to 100 grams of methylene chloride while stirring to obtain a clear solution. The compound of formula IA was gradually added while stirring to obtain a light brown solution.

[0139] Step 3: Adding binder The binder preparation prepared in step 2 was added to the dry-mixed components in step 1 while continuously mixing. The wet material was mixed uniformly before adding any further additions of the binder preparation. The binder preparation was added completely and mixed thoroughly. The container for the binder preparation was washed with 50 grams of methylene chloride, and the washing solution was gradually added to the wet material while continuously mixing.

[0140] Step 4: Drying The wet material from step 4 was dried using a fluidized bed dryer (FBD). Initial drying was performed at 40°C (inlet temperature) for 20 minutes. The semi-dried material was then passed through a sieve (#20 mesh) and further dried in the fluidized bed dryer (FBD) at 50-55°C for 20-30 minutes. The final LOD of the granules was 2.0-2.5% (measured with an infrared moisture meter at 105°C).

[0141] Process 5: Sizing The dried granules obtained in step 4 were passed through a #30 sieve. The granules after sorting were transferred to a double-lined polyethylene bag (2.0 kg capacity).

[0142] Step 6: Mixing Polyplasdone XL10 was passed through a #40 sieve and added to the dry granules from step 5, and mixed for 5 minutes. Magnesium stearate was passed through a #60 sieve and added to the dry granules from step 5, and mixed for 5 minutes.

[0143] Step 7: Tablet compression The mixture was compressed using the following parameters. [Table 13]

[0144] Dissolution test Dissolution tests were conducted on formulations 9A, 9B, and 9C under the following conditions.

[0145] Formulations 9A and 9B

[0146] Eluate: 1. Artificial gastric fluid (pepsin-free): Add 2.0 g of NaCl and 7.0 mL of HCl, make up with purified water to 1000 mL, and adjust the pH to 1.2. 2.0.01NHCl + 1% SLS (sodium lauryl sulfate) eluate.

[0147] Formulation 9C

[0148] Eluate: 1.0.01NHCl + 1% SLS eluate. 2.0.1NHCl+1%SLS eluate. 3. pH 4.5 acetate buffer + 1% SLS eluate. 4. pH 6.8 phosphate buffer + 1% SLS eluate. Test conditions common to all eluents: Number of tablets: 12 Sampling time intervals: 30 minutes, 45 minutes, and 60 minutes Device: USPII (paddle) Capacity: 900mL Rotation speed: 100 rpm Temperature: 37.0±0.5℃ Average weight of tablets for formulation 9A: 300 mg Average weight of tablets for formulation 9B: 310 mg Average weight of formulation 9C tablets: 310 mg result [Table 14] [Table 15]

[0149] Stability testing

[0150] Stability and dissolution tests were conducted on formulations 9A, 9B, and 9C at 40°C and 75% relative humidity (RH). The results are shown below. [Table 16] [Table 17] [Table 18] [Table 19]

[0151] process

[0152] Step 1: Sieving and dry mixing F-Melt (D-mannitol, xylitol, microcrystalline cellulose, crospovidone, fusicalin), Aeroperl 300, Polyplasdone XL10, and Gelucire 59 / 14 (Gattefose) were sieved (#40 mesh) and mixed for 5 minutes.

[0153] Step 2: Binder preparation PVP29 / 32 was added to 150 grams of methylene chloride while stirring to obtain a clear solution. The compound of formula IA was gradually added while stirring to obtain a light brown solution.

[0154] Step 3: Adding binder The binder preparation prepared in step 2 was added to the dry-mixed components in step 1 while continuously mixing. The wet material was mixed uniformly before adding any further additions of the binder preparation. The binder preparation was added completely and mixed thoroughly. The container for the binder preparation was washed with 50 grams of methylene chloride, and the washing solution was gradually added to the wet material while continuously mixing.

[0155] Step 4: Drying The wet material from step 4 was dried using an FBD. Initial drying was performed at 40°C (inlet temperature) for 20 minutes. The semi-dried material was then passed through a sieve (#20 mesh) and further dried in the FBD at 50-55°C for 20-30 minutes. The final LOD of the granules was 2.0-2.5% (infrared moisture meter at 105°C).

[0156] Process 5: Sizing The dried granules obtained in step 4 were passed through a #30 sieve. The granules after sorting were transferred to a double-lined polyethylene bag (2.0 kg capacity).

[0157] Step 6: Mixing Polyplasdone XL10 was passed through a #40 sieve and added to the dry granules from step 5, and mixed for 5 minutes. Magnesium stearate was passed through a #60 sieve and added to the dry granules from step 5, and mixed for 5 minutes.

[0158] Step 7: Tablet compression The mixture was compressed using the following parameters. [Table 20]

[0159] Dissolution test

[0160] Dissolution tests were conducted on formulations 10A and 10B under the following conditions.

[0161] Formulation 10A Eluate: 1. 0.01N HCl + 1% SLS dissolution solution. 2. 0.1N HCl + 1% SLS dissolution solution. 3. pH 4.5 acetate buffer + 1% SLS dissolution solution. 4. pH 6.8 phosphate buffer + 1% SLS dissolution solution.

[0162] Formulation 10B Dissolution solution: 1. 0.01N HCl + 1% SLS dissolution solution. Test conditions common to all dissolution solutions: Number of tablets: 12 Sampling time intervals: 30 minutes, 45 minutes, and 60 minutes (Formulation 10A) Sampling time intervals: 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, and 60 minutes (Formulation 10B) Apparatus: USP II (paddle) Volume: 900 mL Rotation speed: 100 rpm Temperature: 37.0 ± 0.5 °C Average weight of tablets of Formulation 10A: 520 mg Average weight of tablets of Formulation 10B: 520 mg

Table 21

Table 22

[0163] Stability test For Formulation 10A, stability tests and dissolution tests were carried out at 40 °C and relative humidity 75% (RH). The results are shown below.

Table 23

Table 24

[0164] Process

[0165] Step 1: Sifting of ingredients F-Melt (D-mannitol, xylitol, microcrystalline cellulose, crospovidone, fusicalin), Aeroperl 300, Polyplasdone XL10, and Gelucire 59 / 14 (Gattefose) were sieved (#40 mesh) and mixed for 2-3 minutes.

[0166] Step 2: Binder preparation 250g of methylene chloride was divided into three portions (150g, 50g, and 50g), and each portion was added to a separate glass beaker. A clear, light brown solution was obtained by gradually adding the compound of formula IA to 150 g of methylene chloride in a flask and continuously stirring. In a separate flask, 50 grams of PVPK29 / 32 were dissolved in 50 g of methylene chloride to obtain a clear solution.

[0167] The PVPK29 / 32 solution was gradually added to the compound solution of formula IA while stirring to obtain a clear, light brown solution (binder / API solution).

[0168] Step 3: Adding binder The binder / API solution from step 2 was sieved in step 1 and gradually added to the pre-mixed components while continuously mixing. The addition rate was kept slow and constant to prevent clumping. After adding the entire amount of binder / API solution, the flask was washed with 50 g of methylene chloride, and the washing solution was added to the remaining mixture and mixed thoroughly to form a homogeneous wet material.

[0169] Step 4: Drying the wet material The wet material from step 3 was dried in an FBD at 50°C with an airflow of 20-25 cfm for 20 minutes. The LOD was 1.5-2.0%.

[0170] Step 5: Mixing and Lubrication The dried granules were passed through a #30 mesh and mixed with Polyplasdone XL10 in a plastic bag for 2-3 minutes. Magnesium stearate, which had been previously sieved (#60 sieve), was added to the above mixture and mixed in the plastic bag for 2 minutes.

[0171] Step 6: Tablet compression The mixture was compressed using the following parameters.

Table 25

[0172] Dissolution test

[0173] For Formulation 11A, the dissolution test was carried out under the following conditions.

[0174] Formulation 11A

[0175] Dissolution medium:

[0176] 1. 0.01N HCl + 1% SLS dissolution medium. 2. 0.1N HCl + 1% SLS dissolution medium. 3. pH 4.5 acetate buffer + 1% SLS dissolution medium. 4. pH 6.8 phosphate buffer + 1% SLS dissolution medium. Test conditions common to all dissolution media: Number of tablets: 12 Sampling time intervals: 30 minutes, 45 minutes and 60 minutes Apparatus: USP II (paddle) Volume: 900 mL Rotation speed: 100 rpm Temperature: 37.0 ± 0.5 °C Average weight of tablets of Formulation 11A: 720 mg

Table 26

[0177] Stability test

[0178] For Formulation 10A, stability tests and dissolution tests were carried out at 40 °C and 75% relative humidity (RH). The results are shown below.

Table 27

[0179] process

[0180] Step 1: Dispensing The required amounts of the compound of formula IA and (2-hydroxypropyl)β-cyclodextrin (HPPCD) were weighed.

[0181] Step 2: Mixing and ultrasonic treatment Sterile water for injection was added to (2-hydroxypropyl)β-cyclodextrin to obtain a 5% w / v solution. Half of the obtained 5% HPPCD solution was added to the compound of formula I while mixing. The resulting mixture was sonicated for 15 minutes. Then, the remaining half of the 5% HPPCD solution was added, and the resulting suspension was sonicated for a further 15 minutes.

[0182] Step 3: Stirring The suspension prepared in step 2 was stirred at 900-1200 rpm for 60 minutes to obtain a white to off-white suspension. Maintain a temperature of 20-25°C throughout all processes. The final suspension should be stored at 20-25°C for up to 24 hours.

[0183] Stability testing [Table 29] [Table 30] [Table 31]

[0184] All references and patent documents cited herein are incorporated herein by reference.

Claims

1. An oral pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, Each R can independently be H, halogen, substituted or unsubstituted C １～４ Alkyl, and substituted or unsubstituted C １～４ Selected from alkoxy, A is H, substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted (C １～４ A substituted or unsubstituted 5-6 membered heteroaryl containing one or more heteroatoms selected from alkyl)phenyl, N, O, and S; a substituted or unsubstituted heterocyclyl containing one or more heteroatoms selected from N, O, and S; and a substituted or unsubstituted C １～４ Selected from alkoxycarbonyls, the substituents are halogens, substituted or unsubstituted C １～４ Alkyl, and substituted or unsubstituted C １～４ Selected from alkoxy, n is 0, 1, 2, or 3. * indicates the center of the solid. It also contains one or more pharmaceutically acceptable excipients, Here, the compound of formula I has a particle size D of less than approximately 200 μm. ９０ The oral pharmaceutical composition having the following characteristics.

2. The compound of formula I is 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 The oral pharmaceutical composition according to claim 1, wherein the compound is [the compound].

3. The compound of formula I is 【Transformation 7】 An oral pharmaceutical composition according to claim 1 or 2, wherein the compound is [the compound].

4. The compound of formula I has a particle diameter D of about 60 μm to about 100 μm ９０ The oral pharmaceutical composition according to any one of claims 1 to 3, which has the above characteristics.

5. The compound of formula I has a particle size D of approximately 2.0 μm to approximately 150 μm. ９０ An oral pharmaceutical composition according to any one of claims 1 to 3, comprising:

6. The oral pharmaceutical composition according to any one of claims 1 to 5, wherein the compound of formula I accounts for less than about 75% by mass (w / w) of the total weight of the composition.

7. The oral pharmaceutical composition according to any one of claims 1 to 5, wherein the composition is a tablet or a capsule.

8. The oral pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is a solid and, when tested by USP II (paddle method) at 100 rpm and 37.0 ± 0.5°C in 900 mL of (i) pH 1.2 simulated gastric juice (pepsin-free), (ii) 0.01 N HCl aqueous solution containing 1% sodium lauryl sulfate, (iii) 0.1 N HCl aqueous solution containing 1% sodium lauryl sulfate, (iv) pH 4.5 aqueous acetic acid solution and 1% sodium lauryl sulfate, or (v) pH 6.8 aqueous phosphoric acid solution and 1% sodium lauryl sulfate, at least 90% of the compound of formula I in the composition is released within 30 minutes.

9. The oral pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is a solution or a suspension.

10. A compressible tablet comprising a compound of formula IA or a pharmaceutically acceptable salt thereof, wherein the compressible tablet is 【Transformation 8】 (a) Nonionic water-dispersible surfactant, (b) Colloidal silicon dioxide, (c) Crospovidone, and (d) The compound of formula IA is dispersed in spray-dried (i) D-mannitol, (ii) xylitol, (iii) microcrystalline cellulose, (iv) crospovidone, and (v) calcium hydrogen phosphate, with a particle size D of less than approximately 200 μm. ９０ The compression tablet having the following features.

11. The tablet according to claim 10, wherein the nonionic water-dispersible surfactant is a mixture of lauroyl polyoxyl-32 glyceride and PEG6000.

12. (a) Compounds of formula IA or pharmaceutically acceptable salts thereof 【Chemistry 9】 And, (b) An oral aqueous suspension containing 2-hydroxypropyl β-cyclodextrin.

13. The oral aqueous suspension according to claim 12, wherein the ratio of the compound of formula IA to 2-hydroxypropyl β-cyclodextrin is about 1:5 to about 1:

10.

14. A method for treating diabetes or obesity, comprising orally administering an oral pharmaceutical composition according to any one of claims 1 to 13 to a patient who requires treatment for diabetes or obesity.

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