Pharmaceutical formulations of GPR119 agonists and uses thereof

Abstract

The present disclosure relates to oral pharmaceutical formulations comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R, A and n are as described herein. The disclosure also relates to methods of their preparation and their use in the treatment of conditions, such as cardiovascular and metabolic conditions, including diabetes.

Description

[0001] This application claims the benefit of Indian Patent Application No. 202311054015, filed on August 11, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to oral pharmaceutical formulations comprising compounds of formula I or pharmaceutically acceptable salts thereof. Formula I, Wherein R, A, and n are as described herein. This invention also relates to methods of their preparation and their use in treating conditions, such as cardiovascular and metabolic disorders, including diabetes. Background Technology

[0003] Globally, approximately 415 million people have diabetes, with an estimated 193 million undiagnosed. Type 2 diabetes accounts for over 90% of all diabetes cases and can lead to microvascular and macrovascular complications, causing significant psychological and physical distress for patients and caregivers, and placing a heavy burden on healthcare systems. Type 2 diabetes is a chronic metabolic disease characterized by chronic hyperglycemia due to impaired insulin secretion and / or function (i.e., insulin resistance). Type 2 diabetes is known to be associated with reduced life expectancy and increased morbidity. Although cardiovascular disease is the most common cause of death and morbidity, type 2 diabetes is also associated with increased risk for other diseases, including cancer, chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), dyslipidemia and related conditions, cognitive decline, and accelerated arthritis, as well as microvascular and macrovascular complications.

[0004] After a long period of illness, most patients with type 2 diabetes eventually experience oral therapy failure and become insulin-dependent, requiring daily injections and frequent blood glucose monitoring. Oral antidiabetic drugs used in routine treatment (e.g., first-line or second-line therapy, and / or monotherapy or (initial or supplemental) combination therapy) include, for example, metformin, sulfonylureas, thiazolidinediones, meglitinides, and alpha-glucosidase inhibitors.

[0005] The high incidence of treatment failure is a major factor contributing to the high incidence of long-term hyperglycemia-related complications or chronic damage (including microvascular and macrovascular complications such as diabetic nephropathy, retinopathy or neuropathy, or cardiovascular complications) in patients with type 2 diabetes.

[0006] US Patent No. 10,208,030 describes a GPR119 agonist and its preparation method.

[0007] There remains a need for novel oral pharmaceutical formulations that can be used to treat conditions such as diabetes. This invention addresses this need. Summary of the Invention

[0008] In one aspect, the present invention relates to oral pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I. Formula I; Or its pharmaceutically acceptable salt, wherein Each R is independently selected from H, halogen, substituted or unsubstituted C. 1-4 Alkyl groups, and substituted or unsubstituted C groups 1-4 Alkoxy; Variable A is selected from hydrogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted (C 1-4 Alkyl)phenyl, substituted or unsubstituted 5-6 membered heteroaryl groups containing one or more heteroatoms selected from N, O, and S, substituted or unsubstituted heterocyclic groups containing one or more heteroatoms selected from N, O, and S, and substituted or unsubstituted C 1-4 alkoxycarbonyl; wherein the substituent is selected from halogens, substituted or unsubstituted C. 1-4 Alkyl groups and substituted or unsubstituted C groups 1-4 Alkoxy; n is 0, 1, 2, or 3; and * indicates the center of the solid; and one or more pharmaceutically acceptable excipients, The particle size D of the compound of formula I is arbitrarily selected. 90 Less than approximately 200 μm.

[0009] In any embodiment of any composition described herein, the compound of formula I is a compound of formula IA, IB, IC, ID, or IE: Formula IA; Formula IB; IC; Formula ID; Formula IE.

[0010] In one embodiment of any of the compositions described herein, the compound of formula I is formula IA (2-((S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)ethoxy)-6-(2-fluoro-4-(methanesulfonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole): Formula IA.

[0011] In one embodiment of any of the compositions described herein, the composition comprises a therapeutically effective amount of a compound of formula I.

[0012] In one embodiment of any of the compositions described herein, one or more pharmaceutically acceptable excipients are selected from diluents, disintegrants, binders, lubricants, flow aids, pH adjusters, surfactants, solubilizers, antioxidants, or any combination thereof.

[0013] In one embodiment of any of the compositions described herein, the compound of formula I (e.g., compounds of formula IA, IB, IC, ID, or IE) has a particle size D of less than about 200 μm. 90 .

[0014] In one embodiment of any of the compositions described herein, the compound of formula I (e.g., compounds of formula IA, IB, IC, ID, or IE) has a particle size D between about 60 µm and about 100 µm. 90 .

[0015] In one embodiment of any of the compositions described herein, the compound of formula I (e.g., compounds of formula IA, IB, IC, ID, or IE) has a particle size D between about 0.1 µm and about 200 µm. 90 .

[0016] In one embodiment of any of the compositions described herein, the compound of formula I (e.g., compounds of formula IA, IB, IC, ID, or IE) has a particle size D between about 2.0 µm and about 150 µm. 90 .

[0017] In one embodiment of any of the compositions described herein, the compound of formula I (e.g., compound of formula IA, IB, IC, ID, or IE) accounts for less than about 75% w / w of the total weight of the composition, for example less than about 60% w / w or less than about 50% w / w.

[0018] In one embodiment of any of the compositions described herein, the particle size D of the compound of formula I (e.g., compounds of formula IA, IB, IC, ID, or IE) 90The particle size is less than about 200 μm, and the compound constitutes about 75% w / w or less of the total weight of the composition.

[0019] In one embodiment of any of the compositions described herein, the composition is a solid, such as a tablet or capsule. In one embodiment, when tested according to USP II (paddle method) at 100 rpm and 37.0 °C ± 0.5 °C in 900 mL of (i) simulated gastric juice (without pepsin) at pH 1.2, (ii) an aqueous solution of 0.01 N HCl containing 1% sodium dodecyl sulfate, (iii) an aqueous solution of 0.1 N HCl containing 1% sodium dodecyl sulfate, (iv) an aqueous solution of acetate at pH 4.5 and 1% sodium dodecyl sulfate, or (v) an aqueous solution of phosphate at pH 6.8 and 1% sodium dodecyl sulfate, at least 90% of the compound of formula I in the composition is released within 30 minutes.

[0020] In one embodiment of any of the compositions described herein, the composition is a compressed tablet comprising a compound of formula IA or a pharmaceutically acceptable salt thereof. Formula IA The compound of formula IA or its pharmaceutically acceptable salt is dispersed in the following... (a) Nonionic water-dispersible surfactants (e.g., a mixture of lauroyl polyoxyethylene-32 glycerol ester and PEG 6000); (b) Colloidal silica; (c) Chloroprene; and (d) Spray-dried (i) D-mannitol, (ii) xylitol, (iii) microcrystalline cellulose, (iv) crosspovidone, and (v) calcium hydrogen phosphate or magnesium aluminosilicate. The particle size D of the compound of formula IA is described. 90 Less than approximately 200 μm.

[0021] In one embodiment of any of the compositions described herein, the composition is a compressed tablet comprising a compound of formula IA or a pharmaceutically acceptable salt thereof. Formula IA The compound of formula IA or its pharmaceutically acceptable salt is dispersed in the following... (a) Nonionic water-dispersible surfactants (e.g., a mixture of lauroyl polyoxyethylene-32 glycerol ester and PEG 6000); (b) Colloidal silica; (c) Chloroprene; and (d) Spray-dried (i) D-mannitol, (ii) xylitol, (iii) microcrystalline cellulose, (iv) crosspovidone and (v) dicalcium phosphate, The particle size D of the compound of formula IA is described. 90 Less than approximately 200 μm.

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

[0023] In another aspect, the present invention relates to a method for preparing an oral pharmaceutical composition comprising a compound of formula I (e.g., a compound of formula IA, IB, IC, ID, or IE), wherein the method comprises wet granulation, direct tableting, dry granulation, solid dispersion, melt granulation, or extrusion. In one embodiment, the composition comprises a therapeutically effective amount of a compound of formula I.

[0024] In another aspect, the present invention relates to a method for preparing an oral pharmaceutical composition comprising a compound of formula I (e.g., a compound of formula IA, IB, IC, ID, or IE) and one or more pharmaceutically acceptable excipients, the method comprising: (a) Preparation of blends or particles of a compound of formula I (e.g., compounds of formula IA, IB, IC, ID, or IE) with one or more pharmaceutically acceptable excipients; (b) Compress the product of step (a) into tablets or fill the product of step (a) into capsules.

[0025] In another aspect, the present invention relates to a method for preparing an oral pharmaceutical composition comprising a compound of formula I (e.g., a compound of formula IA, IB, IC, ID, or IE) and one or more pharmaceutically acceptable excipients, the method comprising: (a) Prepare a solution or suspension comprising a compound of formula I (e.g., a compound of formula IA, IB, IC, ID, or IE), a solvent, and optionally one or more pharmaceutically acceptable excipients; (b) Add the solution or suspension of step (a) to one or more pharmaceutically acceptable excipients to obtain particles, or coat the solution or suspension of step (a) onto an inert core to obtain a drug-coated core. (c) Optionally, the particle or drug coating core from step (b) is mixed with one or more pharmaceutically acceptable excipients; and (d) Compress the granules or drug coating core of step (b) or the mixture of step (c) into tablets, or fill the granules or drug coating core of step (b) or the mixture of step (c) into capsules.

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

[0027] As used herein, the singular forms “a,” “an,” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, references to “method” or “process” include one or more methods, one or more processes, and / or steps of the type described herein and / or steps that would become apparent to a person skilled in the art upon reading this disclosure.

[0028] As used herein, the term "compound of formula I," including "compounds of formulas IA-IE," "compounds of formulas IA, IB, IC, ID, and IE," and "active ingredient" refers to compounds as described herein, as well as their pharmaceutically acceptable or therapeutically active salts, esters, amides, prodrugs, metabolites, enantiomers, polymorphs, and analogs that can induce desired pharmacological or physiological effects. The terms "active," "active agent," "therapeutic agent," "therapeutic ingredient," "therapeutic substance," and "active substance" may be used synonymously with "active ingredient" and / or "compound of formula I," including "compounds of formulas IA-IE," "compounds of formulas IA, IB, IC, ID, and IE."

[0029] As used herein, the term "compound of formula I" refers to a compound having the following formula. I in Each R is independently selected from H, halogen, substituted or unsubstituted C. 1-4 Alkyl groups, and substituted or unsubstituted C groups 1-4 Alkoxy; A is selected from H, or C, whether substituted or unsubstituted. 1-4 Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted (C 1-4Alkyl)phenyl, substituted or unsubstituted 5-6 membered heteroaryl groups containing one or more heteroatoms selected from N, O, and S, substituted or unsubstituted heterocyclic groups containing one or more heteroatoms selected from N, O, and S, and substituted or unsubstituted C 1-4 alkoxycarbonyl; The substituents are selected from halogens, substituted or unsubstituted C. 1-4 Alkyl groups, and substituted or unsubstituted C groups 1-4 Alkoxy n = 0, 1, 2, 3; and * indicates the center of the solid.

[0030] The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when "substituted C..." 1-4 The substituent on the alkyl group is a substituted C 1-4 When "alkoxy" is used, "the substituted C" 1-4 The substituent on the alkoxy group cannot be a substituted C. 1-4 alkyl".

[0031] As used in this article, the term "C" 1-4 Unless otherwise stated, "alkyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any degree of unsaturation, having one to four carbon atoms, and connected to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl.

[0032] Term "C" 1-4 Unless otherwise specified, "alkoxy" refers to an alkyl group as defined above, which is attached to the remainder of the molecule by an oxygen-linking group. The term "substituted alkoxy" means that the alkyl component in an alkoxy group is substituted (i.e., -O-(substituted alkyl)), where "substituted alkyl" is defined as "alkyl" above. For example, "alkoxy" refers to a -O-alkyl group, including straight-chain or branched configurations and combinations thereof having 1 to 4 carbon atoms, attached to the parent structure by an oxygen group. 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, unless otherwise stated, the term "aryl" refers to an aromatic group having 6 to 20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0034] In certain embodiments of any formulation described herein, the compound of formula I is selected from compounds of formulas IA, IB, IC, ID, and IE: Formula IA; Formula IB; IC; Formula ID; Formula IE.

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

[0036] As used in this article, the term “about” when referring to a numerical value means that a variation of 10% above or below that value is within the range of the specified value.

[0037] As used herein, the term "therapeutic effective amount" refers to the amount or quantity of a compound of formula I (e.g., compounds selected from formulas IA, IB, IC, ID, and IE) sufficient to elicit the desired biological response when administered to a patient. It should be understood that the precise therapeutic effective amount will depend on the patient's age and condition, the nature of the condition to be treated, and will ultimately be determined by the attending physician.

[0038] As used herein, the terms “formulation,” “composition,” “oral formulation,” “oral composition,” “dosage form,” “pharmaceutical formulation,” and “pharmaceutical composition” are used interchangeably and include, but are not limited to, solid and liquid dosage forms, such as tablets, including single-layer tablets, double-layer tablets, triple-layer tablets, multilayer tablets, capsule-shaped tablets, microtablets, capsules, tablet-in-tablet, capsule-in-tablet, granules in capsules, microcapsules, microcapsules in capsules, powders, granules, solid dispersions, drug-coated inert cores, beads, spheres, suspensions, solutions, and any other suitable dosage forms for oral administration. Formulations described herein include immediate-release, rapid-release, orally disintegrating, sustained-release, modulated-release, delayed-release, pulsatile-release formulations, etc. These formulations may be further combined with drug carriers or drug delivery systems, for example, to improve stability and / or solubility or further improve bioavailability. These formulations may be solid dispersions or lyophilized or spray-dried formulations.

[0039] As used herein, in some embodiments, the term “stable” (as in “stable pharmaceutical formulation”) means a pharmaceutical formulation comprising a compound of formula I as defined in any of the embodiments described herein, wherein the impurity content remains below the FDA acceptable intake limit after the pharmaceutical formulation has been exposed to 40°C ± 2°C and 75% ± 5% relative humidity for six months or to 25°C ± 2°C and 60% ± 5% relative humidity for at least 12 months.

[0040] As used herein, the term "bioavailability" refers to the proportion of an administered dose of the active pharmaceutical ingredient (API) and / or active fraction (such as compounds of Formula I as defined in any embodiment herein) that reaches systemic circulation without alteration or in another active form. By definition, when the API and / or active fraction are administered intravenously, their bioavailability is 100%. However, when administered via other routes (e.g., oral), their bioavailability is reduced (due to incomplete absorption and / or first-pass metabolism). Absolute oral bioavailability is calculated as the ratio of the relative exposure of the API and / or active fraction in systemic circulation following oral administration (estimated by the area under the plasma concentration-time curve) to the API exposure following intravenous administration.

[0041] As used herein, the term "excipient" or "pharmaceuticalally acceptable excipient" refers to a pharmacologically inactive ingredient. Suitable pharmaceutically acceptable excipients applicable to any formulation described herein include, but are not limited to, diluents / fillers, binders, disintegrants, flow aids, surfactants, solubilizers, sustained-release or delayed-release excipients, pH adjusters, antioxidants, preservatives, lubricants, flavoring agents, plasticizers, colorants, opacifiers, carriers, and any combination thereof. Excipients used to prepare dosage forms are generally safe, non-toxic, and suitable for veterinary and human use. References to excipients include one excipient and multiple excipients.

[0042] As used herein, the term "solid dispersion" refers to a dispersion of a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID and IE, particularly a compound of formula IA), wherein the compound of formula I exists in a formulation in a dissolved, amorphous, or mixture of amorphous and crystalline states.

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

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

[0045] This invention relates to a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable, stable excipients having oral bioavailability.

[0046] In any further embodiments of any formulation described herein, a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID and IE, particularly a compound of formula IA) is present in the pharmaceutical formulation in an amount between about 50 mg and about 500 mg, for example, between about 50 mg and about 500 mg.

[0047] In any further embodiments of any formulation described herein, a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID and IE, particularly a 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 further embodiments of any formulation described herein, the compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly compounds of formula IA) is amorphous, substantially crystalline (e.g., greater than 90%, or greater than 95%, or greater than 99% crystalline), or crystalline.

[0049] In any further embodiments of any formulation described herein, the compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID and IE, particularly compounds of formula IA) is amorphous.

[0050] In any further embodiments of any formulation described herein, the compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly compounds of formula IA) is substantially crystalline (e.g., more than 90%, more than 95%, or more than 99% crystalline) or crystalline.

[0051] Diluents / fillers applicable to any formulation 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 some embodiments, the diluent / filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, polyols, and sugar alcohols, wherein the sugar alcohols are selected from, but are not limited to, alditol, mannitol, D-mannitol, meglumine, xylitol, isomaltitol, sorbitol, lactitol, pentitol, arabinitol, ribitol, galactitol, erythritol, glycerol, etc.; the carbohydrates are selected from, but are not limited to, monosaccharides, oligosaccharides, polysaccharides, dextrin, maltodextrin, pullulan, arabinose, glucose, gluconate, lactose, sucrose, sucralose, saccharin, fructose, maltose, trehalose, allulose, tagatose, sorbitol, cellulose derivatives, cellobiose, starch, modified starch, sucrose fatty acid esters, etc.; the inorganic diluent is selected from, but is not limited to, dicalcium phosphate, tricalcium phosphate, calcium carbonate, kaolin, calcium sulfate, etc.; and any combination of the foregoing.

[0053] Diluents may include co-treated excipients, such as D-mannitol and starch (Pearlitol). ® Flash, lactose, and microcrystalline cellulose (Cellactose) ®D-mannitol, xylitol, microcrystalline cellulose, cropovidone, anhydrous calcium hydrogen phosphate (F-MELT) ® Type C). F-MELT ® There are two levels, F-MELT ® Type C and F-MELT ® Type M. Type C contains anhydrous dicalcium phosphate (Fujicalin). ® M type contains magnesium aluminum silicate (Neusilin) ® When present, the filler may be used in an amount of about 1% to about 80% of the weight of the pharmaceutical preparation, for example, about 1% to about 60% of the weight of the pharmaceutical preparation, for example, about 1%.

[0054] Binders suitable for use in any formulation described herein include, but are not limited to, natural and synthetic polymers, natural and synthetic gums, hydrocolloids, cellulose and cellulose derivatives, starch and modified starch, carbohydrates, vinyl polymers, and any combination thereof. For example, in some embodiments, the binder is selected from polyvinylpyrrolidone (PVP) (e.g., PVP K30 or PVP K90), polyvinyl acetate, polyvinyl alcohol, polyethylene glycol (PEG) (e.g., PEG 400, PEG 4000, PEG 6000), PEG copolymers, polyvinyl alcohol, polyvinyl acetate and PVP, hydroxypropyl methylcellulose, hydroxypropyl cellulose (in some embodiments, both hydroxypropyl methylcellulose and hydroxypropyl cellulose have medium to high viscosity, e.g., viscosity grade 3 or 6 cps), copovidone, maltodextrin, pregelatinized starch, microcrystalline cellulose, gum arabic, alginate, tragacanth gum, gelatin, liquid glucose, corn starch, sugars, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate, and any combination thereof. When present, the adhesive may be used in an amount of about 0.1% to about 25% of the weight of the pharmaceutical preparation.

[0055] Suitable disintegrants for any formulation described herein include, but are not limited to, natural and synthetic polymers, natural and synthetic gums, cellulose and its derivatives, starch and modified starch. For example, in some embodiments, the disintegrant is selected from low-substituted hydroxypropyl cellulose, croscarmellose, vinylpyrrolidone, corn starch, croscarmellose sodium, sodium carboxymethyl cellulose, microcrystalline cellulose, sodium carboxymethyl starch, croscarmellose sodium (Ac-Di-Sol), sodium carboxymethyl starch, ion exchange resins, and formaldehyde-casein, and may be used alone or in combination. When present, the disintegrant may be used in an amount from about 0.1% to about 20% of the weight of the pharmaceutical formulation.

[0056] Lubricants suitable for use in any formulation described herein include, but are not limited to, zinc stearate, magnesium stearate, sodium stearoyl fumarate, calcium stearate, stearic acid, colloidal silica, aluminum silicate or calcium silicate, stearic acid, Cutina, PEG 4000-8000, talc, and any combination thereof. When present, the lubricant may be used in an amount from about 0.01% to about 10%, preferably from about 0.1% to about 5% by weight of the pharmaceutical formulation.

[0057] Drifting agents suitable for use in any formulation described herein include, but are not limited to, colloidal silica (e.g., Aerosil 200), mesoporous silica, stearates, magnesium trisilicate, powdered cellulose, starch, talc, and any combination thereof. When present, the drifting agent may be used in an amount of about 0.01% to about 10% (e.g., about 0.1% to about 5%) of the weight of the pharmaceutical formulation.

[0058] Solubilizers suitable for use in any formulation described herein include, but are not limited to, surfactants, cyclic oligosaccharides / cyclodextrins, phospholipids, and any combination thereof. Solubilizers may be used in amounts from about 0.01% to about 25% of the pharmaceutical formulation by weight, for example, from about 1% to about 20% of the pharmaceutical formulation by weight.

[0059] Suitable surfactants for use in any formulation 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 stearoyl fumarate, and Tweens. ® And Spans (PEO-modified dehydrated sorbitan monoester and fatty acid dehydrated sorbitan ester), poloxamer, polysorbates, alkyl aryl polyethers, polyethylene glycol alkyl ethers, polyoxyethylene derivatives, and any combination thereof. Poloxamer is a nonionic triblock copolymer composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) and two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)) on both sides. Polysorbates are oily liquids formed by the esterification of ethoxylated dehydrated sorbitol with fatty acids. Polyoxyethylene esters are mixtures of monoesters and diesters of stearic acid and polyoxyethylene glycol. In some embodiments, suitable surfactants include, but are not limited to, poloxamer 188 (e.g., Pluronic). ® F-68) and Pluronic 407 (e.g., Pluronic) ® F127); Polysorbate 20, Polysorbate 60, Polysorbate 80, Tyrosine, Brij ® 35. Brij ® 78. Brij ® 98 and Brij ® 700, Span ® 20. Span ® 40. Span® 60. Span ® 80; and polyoxyethylene 40 stearate, polyoxyethylene 30 castor oil, polyoxyethylene 35 castor oil and polyoxyethylene 40 hydrogenated castor oil; hydrogenated castor oil (or PEG (40 hydrogenated castor oil) (HCO-40), Kolliphore EL (Cremophor EL), Cremophor RH 40, Cremophor RH 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 PEG 300, 400, or 1750, and any combination thereof. When present, the nonionic surfactant may be used in an amount from about 0.01% to about 25% by weight of the pharmaceutical formulation.

[0060] Suitable solubilizers for any formulation described herein include, but are not limited to: cyclic oligosaccharides / cyclodextrins, including but not limited to α-cyclodextrin, β-cyclodextrin, hydroxypropyl β-cyclodextrin and sulfobutyl ether-β-cyclodextrin, cyclodextrin-2-HP25, and ionicly charged (e.g., anionic) β-cyclodextrins (with or without butyrate (Captisol) ® Hydroxypropyl-γ-cyclodextrin, γ-cyclodextrin; phospholipids, including but not limited to hydrogenated soybean phosphatidylcholine, distearate phosphatidylglycerol, l-α-dimyristoyl phosphatidylcholine, l-α-dimyristoyl phosphatidylglycerol; polyethylene glycol (PEG); and any combination thereof. When present, cyclodextrin may be used in an amount from about 0.01% to about 25% by weight of the pharmaceutical preparation.

[0061] The pH adjusters applicable to any formulation described herein include, but are not limited to, 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, alkylamines (e.g., methylamine, diisopropylamine, diisopropylethylamine, triethylamine, dimethylamine, trimethylamine), pyridine, imidazole, histidine, guanidine, polyethyleneimine, poly(vinylpyridine), diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane (Tris), sodium glycine, 1-methylimidazole, 2-methyl Imidazole, 4(5)-methylimidazole, 1,2-diaminoethane, 2-(bis(2-hydroxyethyl)amino)-2-(hydroxymethyl)propane-1,3-diol, sodium lysine, sodium histidine, sodium arginine, polyvinylimidazole and its copolymers (e.g., copolymers of polyethyleneimine with poly(vinylpyridine) and / or polyvinylimidazole, or copolymers of poly(vinylpyridine) with 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 thereof. In one embodiment, when present, the pH adjuster may be used in an amount of about 0.1% to about 10% by weight of the pharmaceutical preparation.

[0062] Suitable antioxidants applicable to any formulation described herein include, but are not limited to, natural and synthetic compounds, organic and inorganic acids, etc. In some embodiments, the antioxidant is selected from 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, gentianic acid (2,5-dihydroxybenzoic acid), acetylcysteine, ascorbyl palmitate, cysteine, dithiothreitol, thioglycerol, thiourea, caffeic acid, propyl gallate, ferulic acid, sodium metabisulfite, edetate, edetate salt, 2,6-di-tert-butyl-p-cresol, gallic acid and its esters. Antioxidants include, butadiene dihydroguaiac acid, benzoic acid, benzoates, sorbic acid, sorbates, guaiacol esters, tea polyphenols, curcumin, chlorogenic acid, methionine, proline, biflavonoids, superoxide dismutase, silymarin, grape skin / seed extract, melanin, rosemary extract, sodium sulfite, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, tert-butylhydroquinone, sodium citrate, magnesium ascorbate phosphate, sodium ascorbate phosphate, 3,4-dihydroxybenzoic acid, butylated hydroxybenzoic acid and its salts, isoascorbic acid and its sodium salt, sorbic acid and its salts, sodium formaldehyde sulfoxylate, glutathione, lipoic acid, dihydroxyfumaric acid, etc. In one embodiment, when present, the antioxidant may be used in an amount from about 0.1% to about 10% of the weight of the pharmaceutical preparation.

[0063] Sustained-release or delayed-release excipients suitable for use in any formulation described herein include, but are not limited to, hydrophilic or hydrophobic agents, natural and synthetic polymers, and natural and synthetic gums. In some embodiments, the sustained-release or delayed-release excipient is selected from polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids, fatty acid esters, alkyl alcohols, waxes, xanthan gum, gellan gum, shellac, rosin, zein (zein), povidone, kollidon SR (polyvinyl acetate and povidone), poly(meth)acrylate, polyethylene oxide, polyurethane, cellulose ethers, xanthan gum, tragacanth gum, guar gum, gum arabic, gellan gum, 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 methyl cellulose, carboxyvinyl polymers, polymeric gelatin, shellac, and methacrylic acid co-polymers. Polymer C-type NF, cellulose butyrate 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, dioxopropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic polymers and copolymers such as methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate copolymers with acrylic acid and methacrylate (Eudragit NE, Eudragit RL, Eudragit RS) and any combination thereof. When present, the polymer may be used in amounts of about 0.1% to about 50% of the formulation weight, for example, about 10% to about 50% or about 10% to about 40% of the formulation weight.

[0064] The inert nucleus suitable for use in any formulation described herein includes, but is not limited to, sugars, sucrose, sorbitol, xylitol, mannitol, lactose, dicalcium phosphate, microcrystalline cellulose, maltodextrin, starch, hydrophilic cellulose polymers or crosslinked hydrophilic synthetic polymers, or may be selected from any filler or diluent, or any combination thereof.

[0065] Solvents that can be used to prepare solutions or dispersions (e.g., suspensions) of compounds of formula I (e.g., compounds selected from compounds IA, IB, IC, ID, and IE, especially compounds of formula IA) can be aqueous solvents, non-aqueous solvents (e.g., organic solvents, inorganic solvents), or any combination thereof.

[0066] Suitable aqueous solvents include, for example, purified water, water for injection, antibacterial water for injection, sterile water, isotonic saline, and buffer solutions. Suitable non-aqueous solvents include organic or inorganic solvents. Suitable organic solvents include, but are not limited to, acetic acid, dichloromethane, mono- or polyols, isopropanol, ethanol, glycerol, propylene glycol, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, tert-butanol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, anhydrous ethanol, diethylene glycol, diethyl ether, diethylene glycol dimethyl ether, 1,2-dimethoxyethane (glycol dimethyl ether, DME), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1, 4-Dioxane, ethyl acetate, ethylene glycol, heptane, hexamethylphosphoramide (HMPA), hexamethylphosphoric triamine (HMPT), hexane, methanol, methyl tert-butyl ether (MTBE), N-methyl-2-pyrrolidone (NMP), nitromethane, pentane, petroleum ether, 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethylamine, o-xylene, m-xylene, benzyl alcohol, glycine-furan, acetone glycerol, glycerol formaldehyde, 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, sulfuryl chloride fluoride, liquid sulfur dioxide, sulfuryl chloride, phosphorus oxychloride, nitrogen tetroxide, antimony trichloride, bromine pentafluoride, hydrogen fluoride, and any combination thereof.

[0067] Coating agents suitable for use in any formulation described herein include, but are not limited to, immediate-release coatings, sustained-release coatings, 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, and zein (a corn protein derivative), hydroxypropyl methylcellulose, methyl hydroxyethyl cellulose, ethyl cellulose, povidone, polyvinyl acetate, polyvinyl alcohol, Opadry, and any combination thereof.

[0068] In one embodiment of any formulation described in this disclosure, the D of a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA) 90 Particle size less than about 200 μm, for example less than about 150 μm, less than about 100 μm, less than about 75 μm, less than about 50 μm, less than about 25 μm or less than about 10 μm.

[0069] In one embodiment of any formulation described herein, the compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA) has a D-value of about 5 µm to about 20 µm. 50Particle size.

[0070] In one embodiment of any formulation described herein, the compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA) has a D-value of about 1 µm to about 10 µm. 10 Particle size.

[0071] In one embodiment, the present invention relates to an oral pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA), wherein the compound of formula I constitutes about 75% or less of the composition by weight, for example, about 50% or less of the composition by weight, or about 25% or less of the composition by weight. In one embodiment of any oral formulation described herein, the oral formulation is a tablet or capsule. In one embodiment, the oral formulation is an immediate-release tablet. In certain embodiments of any oral formulation described herein, the dosage form (e.g., a tablet, such as an immediate-release tablet) weighs from about 100 mg to about 2000 mg.

[0072] In one embodiment, the present invention relates to a method for preparing an oral pharmaceutical formulation comprising a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA), wherein the method includes dry granulation, wet granulation, direct tableting, melt granulation, extrusion, or solid dispersion processes.

[0073] In one embodiment, the present invention relates to a method for preparing an oral pharmaceutical formulation of a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients, the method comprising: (1) Preparation of blends (mixtures) or granules of compounds of formula I (e.g., compounds selected from compounds IA, IB, IC, ID, and IE, especially compounds of formula IA) with one or more pharmaceutically acceptable excipients; and (2) Compress the blend or granules into tablets or fill the blend or granules into capsules.

[0074] In one embodiment, the present invention relates to a method for preparing an oral pharmaceutical formulation (e.g., direct compression), the oral pharmaceutical formulation comprising a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients, the method comprising: (1) A compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID and IE, especially a compound of formula IA) is premixed with a portion (e.g., >50%) of one or more pharmaceutically acceptable excipients (e.g., in a mixer) to obtain a premix; (2) Optionally, the premix is ​​dry-sieved through a screen (e.g., to separate sticky particles and improve content uniformity); (3) Mix the premix of step (1) or (2) (e.g., in a mixer), and optionally add the remaining one or more pharmaceutically acceptable excipients to the mixture; (4) Compress the final mixture from step (3) into tablets (e.g., by pressing on a suitable tablet press) to produce tablet cores; (5) Optionally, the tablet core from step (4) is coated with a film coating.

[0075] In one embodiment, the present invention provides a method (e.g., a dry granulation method) for preparing an oral pharmaceutical formulation comprising a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly compounds of formula IA) and one or more pharmaceutically acceptable excipients, the method comprising: (1) A compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID and IE, especially a compound of formula IA) is mixed with a portion (e.g., less than 100% or 100%) of one or more pharmaceutically acceptable excipients (e.g., in a mixer). (2) Compact the mixture from step (1) (e.g., on a suitable roller press) (e.g., to obtain a strip); (3) Reduce the compacted mixture (e.g., strip) obtained in step (2) into particles (e.g., by appropriate grinding and / or sieving steps); (4) Optionally, the particles from step (3) are mixed with one or more remaining pharmaceutically acceptable excipients (e.g., in a mixer) to obtain a final mixture; (5) Compress the granules from step (3) or the final mixture from step (4) into tablets (e.g., by pressing on a suitable tablet press) to prepare tablet cores; (6) Optionally, the tablet core from step (5) is coated with a film coating.

[0076] In one embodiment, the present invention relates to a method (e.g., a wet granulation method for preparing an oral pharmaceutical formulation comprising a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly compounds of formula IA) and one or more pharmaceutically acceptable excipients), the method comprising: (1) A compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID and IE, especially a compound of formula IA) is premixed with a portion (e.g., >50%) of one or more pharmaceutically acceptable excipients (e.g., in a mixer) to obtain a premix; (2) Granulate the premix from step (1) (e.g., by adding granulation liquid); (3) Dry the particles from step (2) (e.g., in a fluidized bed dryer or drying oven); (4) Optionally, the dried particles from step (3) are dry-sieved; (5) The dried granules from step (2) or step (4) are mixed with one or more remaining pharmaceutically acceptable excipients (e.g. in a mixer) to obtain a final mixture; (6) Compress the final mixture of step (5) into tablets (e.g., by pressing on a suitable tablet press) to produce tablet cores or fill the final mixture of step (5) into capsules; (7) Optionally, the tablet core from step (6) is coated with a film coating.

[0077] In one embodiment, the present invention relates to a method for preparing an oral pharmaceutical composition comprising a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly compounds of formula IA) and one or more pharmaceutically acceptable excipients, the method comprising: (1) Prepare a solution or suspension of a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID and IE, especially a compound of formula IA) in a suitable solvent, optionally with one or more pharmaceutically acceptable excipients; (2) Spray the solution or suspension of step (1) onto one or more pharmaceutically acceptable excipients to obtain particles, or coat the solution or suspension of step (1) onto an inert core to obtain a drug-coated core. (3) Optionally, the particle or drug coating core of step (2) is mixed with one or more pharmaceutically acceptable excipients; (4) Compress the granules or drug coating core of step (2) or the mixture of step (3) into tablets, or fill the granules or drug coating core of step (2) or the mixture of step (3) into capsules.

[0078] In some embodiments, the formulations described herein may be granulated prior to compaction. These formulations may comprise an intragranular portion and an extragranular portion, wherein the intragranular portion has been granulated and the extragranular portion is added after granulation. In some embodiments, the intragranular portion may comprise a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly compounds 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 compounds IA, IB, IC, ID, and IE, particularly compounds of formula IA) and one or more pharmaceutically acceptable excipients. The extragranular portion may comprise a filler, binder, disintegrant, lubricant, gliding agent, or any combination thereof.

[0079] In one embodiment, the present invention provides a method for preparing an oral pharmaceutical composition comprising a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA). Extrusion can be wet extrusion or melt extrusion. Wet extrusion involves preparing a wet mass of a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA) with one or more pharmaceutically acceptable excipients, and then extruding the wet mass to form extruded granules. Melt extrusion involves preparing a melt-solidified agglomerate of a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA) with one or more pharmaceutically acceptable excipients, and then extruding the melt-solidified agglomerate to form extruded granules.

[0080] Another embodiment of the invention relates to an amorphous solid dispersion comprising a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA) and one or more pharmaceutically acceptable excipients.

[0081] In some embodiments, the immediate-release formulations disclosed herein release more than about 75% of the active ingredient contained herein, such as a compound of formula I (e.g., compounds selected from compounds IA, IB, IC, ID and IE, particularly compounds of formula IA), within a time period selected from less than one hour, less than 45 minutes, less than 30 minutes, less than 15 minutes and less than 10 minutes after administration.

[0082] In another embodiment of any of the methods described herein, the method further comprises purging the solution or suspension formulation with an inert gas to reduce the oxygen concentration.

[0083] In another aspect, the present invention relates to kits (e.g., packaging or storage containers) comprising formulations according to any of the embodiments described herein. In some embodiments, the packaging or container comprises an oxygen-barrier or oxygen-impermeable material. In some embodiments, the packaging or container comprises an oxygen scavenger. In some embodiments, the packaging or container comprises a desiccant or an oxygen absorbent.

[0084] In another embodiment of any formulation comprising a compound of formula I described herein (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly a compound of formula IA), the formulation is stable when stored at 40 ± 2 °C and 75% ± 5% relative humidity (RH) for at least one month, at least three months, or at least six months.

[0085] In another embodiment of any formulation described herein that comprises a compound of formula I (e.g., a compound selected from compounds 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 one month, at least three months, at least six months, or at least 12 months.

[0086] In another embodiment of any formulation described herein that comprises a compound of formula I (e.g., a compound selected from compounds IA, IB, IC, ID, and IE, particularly compounds of formula IA), the formulation contains impurities below the FDA acceptable daily intake limit. For any formulation described herein, when stored at 40±2°C and 75%±5% relative humidity for at least six months or at 25±2°C and 60%±5% relative humidity for at least twelve months, the impurities are less than about 5%, about 4%, about 3%, about 2%, or about 1%.

[0087] In another aspect, the present invention relates to oral formulations according to any embodiment described herein for medicinal use, such as 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 conditions.

[0088] In another aspect, the present invention relates to a method for treating cardiovascular and metabolic diseases, including but not limited to diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dyslipidemia and related diseases, the method comprising administering to a patient in need an oral formulation according to any embodiment described herein. The present invention also relates to the use of an oral formulation according to any embodiment described herein as a medicine. In some embodiments of any use and method described herein, the formulation may be used for medical treatments such as those related to diabetes: (i) Prevention and / or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (adult-onset diabetes), gestational diabetes, and / or for lowering HbA1C. (ii) Delay or prevent the progression of diabetes, such as the progression of type 2 diabetes, delaying the progression from impaired glucose tolerance (IGT) to insulin-dependent type 2 diabetes, and / or delaying the progression from non-insulin-dependent type 2 diabetes to insulin-dependent type 2 diabetes. (iii) Improve β-cell function, such as reducing β-cell apoptosis, increasing β-cell function and / or β-cell number, and / or restoring β-cell sensitivity to glucose; (iv) Prevention and / or treatment of cognitive impairment; (v) Prevention and / or treatment of eating disorders, such as obesity, such as by reducing food intake, reducing weight, suppressing appetite, inducing satiety; treatment or prevention of bulimia, bulimia nervosa and / or obesity caused by antipsychotic or steroid administration; decreased gastric motility; and / or delayed gastric emptying; (vi) Prevention and / or treatment of diabetic complications, such as neuropathy, including peripheral neuropathy; nephropathy; or retinopathy; (vii) Improve lipid parameters, such as preventing and / or treating dyslipidemia, reducing total serum lipids; reducing high-density lipoprotein; reducing small dense low-density lipoprotein; reducing very low-density lipoprotein; reducing triglycerides; reducing cholesterol; increasing high-density lipoprotein; reducing plasma levels of lipoprotein a (Lp(a)) in the human body; inhibiting the production of apolipoprotein an (apo(a)) in vitro and / or in vivo; (viii) Prevention and / or treatment of cardiovascular diseases, such as syndrome X; atherosclerosis; myocardial infarction; coronary artery disease; stroke, cerebral ischemia; early cardiac or early cardiovascular diseases, such as left ventricular hypertrophy; coronary artery disease; essential hypertension; acute hypertensive emergencies; cardiomyopathy; heart failure; exercise tolerance; chronic heart failure; arrhythmias; cardiac rhythm abnormalities; syncope; atherosclerosis; mild chronic heart failure; angina pectoris; re-occlusion after coronary artery bypass grafting; intermittent claudication (occlusive atherosclerosis); diastolic dysfunction; and / or systolic dysfunction; (ix) Prevention and / or treatment of gastrointestinal disorders, such as inflammatory bowel syndrome; short bowel syndrome or Crohn's disease; dyspepsia; and / or gastric ulcers; (x) Prevention and / or treatment of critical illness, such as treatment of critically ill patients, patients with critical illness polyneuropathy (CIPNP) and / or potential CIPNP patients; prevention of critical illness or CIPNP development; prevention, treatment and / or cure of systemic inflammatory response syndrome (SIRS) in patients; and / or for the prevention or reduction of the likelihood of bacteremia, sepsis and / or septic shock in patients during hospitalization; and / or (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).

[0089] In one aspect, the present invention relates to a method for treating diabetes or obesity, the method comprising administering to a patient in need an oral formulation according to any of the embodiments described herein. In some embodiments, the formulation is an oral tablet, such as an oral immediate-release tablet.

[0090] According to another embodiment, any formulation described herein may further comprise one or more additional therapeutic agents. Alternatively, any formulation described herein may be administered to a patient in need in combination with one or more other adjuvants (sequentially or simultaneously).

[0091] For example, the one or more other adjuvants may be antidiabetic drugs, such as, but not limited to, SGLT2 inhibitors, DPP IV inhibitors, biguanides, thiazolidinediones, sulfonylureas, GLP-1 agonists, angiotensin receptor blockers, antianginal agents, antiarrhythmic agents, antihypertensive drugs, beta-adrenergic drugs, calcium channel blockers, diuretics, and other cardiovascular drugs, as well as any combination of the foregoing.

[0092] The one or more other adjuvants may be biguanides, such as metformin; thiazolidinediones, selected from the group including but not limited to pioglitazone, rosiglitazone, troglitazone, empaglitazone, or dapaglitazone; sulfonylureas, selected from the group including but not limited to glimepiride, gliclazide, glipizide, tolbutamide, glibenclamide, gliquidone, and glibenclamide; glinides, selected from the group including but not limited to nateglinide and repaglinide; and α-glucosidase inhibitors, selected from the group including but not limited to acarbose, miglitol, and voglibose. Sugars; SGLT-2 inhibitors selected from, but not limited to, dapagliflozin, empagliflozin, soragliflozin, canagliflozin, luggliflozin, toggliflozin, ioggliflozin, erggliflozin, aloggliflozin, or repaggliflozin; DPP-4 inhibitors selected from, but not limited to, sitagliptin, vildagliptin, saxagliptin, canagliflozin, gogliptin, alogliptin, linagliptin, megliptin, giagliptin, alagliptin, ticagliptin, tregliptin, dugliptin, iogliptin, ocagliptin, or pharmaceutically acceptable salts thereof.

[0093] While selected embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in carrying out the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications cited herein are incorporated by reference.

[0094] Example This disclosure is now specifically illustrated through the following illustrative embodiments. However, the scope of the invention is not intended to be, and should not be limited to, the following exemplary embodiments: Particle size analysis was performed using a Malvern Mastersizer 3000 particle size analyzer (Malvern Instrument Ltd).

[0095] Sample preparation Accurately weigh 100 mg of sample into a 100 mL beaker. Add 3 drops of Tween-80 and 1 mL of water, and use a glass rod to help form a paste. Then add 10 mL of water and sonicate externally for 10 seconds with continuous shaking.

[0096] Instrument parameters

[0097] program After cleaning, initialize the system and measure the background value. Add sample to bring the turbidity to between 10% and 20%, and wait for the turbidity to stabilize. Begin analysis according to the given instrument parameters or run the standard operating procedure. Analyze the sample in duplicate and report the results for both preparations at D... 10 D 50 and D 90 The average result at the location (instrument average).

[0098] Chemical purity was determined by high performance liquid chromatography (HPLC).

[0099] Example 1

[0100] Example 2

[0101] method 1. The compound of Formula 1 and microcrystalline cellulose are sieved through a 40-mesh sieve.

[0102] 2. Sieve the mixture from step 1 and colloidal silica through a 40-mesh sieve.

[0103] 3. Mix the mixture from step 2 in a mixer for 10-20 minutes.

[0104] 4. Lubricate the mixture from step 3 with magnesium stearate in a mixer for 3-7 minutes.

[0105] 5. Compress the mixture from step 4 on a tablet press to obtain compressed tablets.

[0106] 6. Coat tablets with Opadry white coating in a coating machine (weight gain 2%-4%).

[0107] Example 3

[0108] method 1. Sieve all ingredients separately through an appropriate sieve (100% should be able to pass through the sieve, e.g., 24 mesh).

[0109] 2. The pre-sieved compound of Formula 1, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and colloidal silica are dry-mixed in a suitable mixer.

[0110] 3. Lubricate the dry mixture in the mixer from step 2 with approximately 50% sodium stearoyl fumarate.

[0111] 4. Pass the mixture from step 3 through a roller press to obtain compacted blocks / strips.

[0112] 5. Pass the compacted blocks / strips from step 4 through a suitable sieve (e.g., 18 to 30 mesh), and pass the mixture through the desired sieve (e.g., 18 to 30 mesh) to obtain granules.

[0113] 6. Mix the particles obtained in step 5 in a suitable mixer and lubricate with the remaining sodium stearoyl fumarate.

[0114] 7. Compress the mixture from step 6 into tablets.

[0115] 8. Coat the tablets from step 7 with a film.

[0116] Example 4

[0117] method: 1. Sieve all ingredients separately through an appropriate sieve.

[0118] 2. The compound of Formula I is mixed with the dried components in a rapid mixing granulator (RMG).

[0119] 3. Add hydroxypropyl methylcellulose and sodium dodecyl sulfate to the product of step 2 in purified water and mix until a homogeneous dispersion (binder) is obtained.

[0120] 4. Granulate the dry mixture from step 2 in an RMG (Rapid Mix Granulator) using the binder from step 3.

[0121] 5. Dry the wet particles from step 4 in a fluidized bed dryer (FBD) until the desired loss on drying (LOD) is achieved.

[0122] 6. Sieve the dried granules through a suitable sieve (e.g., 18 to 30 mesh) and grind any oversized granules using a multi-grind mill.

[0123] 7. Mix the particles from step 6 in a suitable mixer.

[0124] 8. Mix the particles from step 7 with the pre-sieved microcrystalline cellulose, cross-povidone, and colloidal silica in a suitable mixer.

[0125] 9. Lubricate the mixture from step 8 in a mixer with pre-sieved magnesium stearate.

[0126] 10. Compress the mixture from step 9 into tablets.

[0127] 11. The tablets are packaged as required.

[0128] Example 5

[0129] method 1. Sieve all ingredients separately through an appropriate sieve (e.g., 24 to 40 mesh).

[0130] 2. Mix the dried components [microcrystalline cellulose and crosspovidone] in RMG.

[0131] 3. Add the compound of formula IA to a solution in dichloromethane and mix until a clear solution is formed. Then add the hydroxypropyl methylcellulose solution in dichloromethane and mix until a homogeneous dispersion (binder) is obtained.

[0132] 4. Mix the dried mixture from step 2 with the adhesive from step 3 in RMG.

[0133] 5. Dry the wet granules from step 4 in FBD until the desired LOD is achieved.

[0134] 6. Sieve the dried particles from step 5 through a suitable sieve (e.g., 18 to 30 mesh), and grind any oversized particles using a multi-grind mill.

[0135] 7. Mix the particles from step 6 in a suitable mixer.

[0136] 8. Mix the particles from step 7 with the pre-sieved microcrystalline cellulose, cross-povidone, and colloidal silica in a suitable mixer.

[0137] 9. Mix the mixture from step 8 with the pre-sieved magnesium stearate in a mixer.

[0138] 10. Compress the mixture from step 9 into tablets.

[0139] 11. The tablets are packaged as required.

[0140] Example 6

[0141] method 1. Weigh out 2-hydroxypropyl β-cyclodextrin and the compound of formula 1A.

[0142] 2. Add water for injection to 2-hydroxypropyl β-cyclodextrin to obtain a 5% w / v solution.

[0143] 3. Add the 5% solution of 2-hydroxypropyl β-cyclodextrin from step 2 to the compound of formula 1A under stirring to obtain a suspension.

[0144] Example 7

[0145] method 1. Sieve all ingredients separately through an appropriate sieve (e.g., 24 to 40 mesh).

[0146] 2. Mix the dried components (Pearlitol-Flash, cropovidone, and 2-hydroxypropyl β-cyclodextrin) in RMG.

[0147] 3. Add the compound of formula IA to a solution in dichloromethane and mix until a clear solution is formed. Then add the hydroxypropyl methylcellulose solution in dichloromethane and mix until a homogeneous dispersion (binder) is obtained.

[0148] 4. Granulate the dried mixture from step 2 in RMG using the binder from step 3.

[0149] 5. Dry the wet granules from step 4 in FBD until the desired LOD is achieved.

[0150] 6. Sieve the dried particles from step 8 through a suitable sieve (e.g., 18 to 30 mesh) and grind any oversized particles using a multi-grind mill.

[0151] 7. Mix the particles from step 6 in a suitable mixer.

[0152] 8. Mix the granules from step 7 with the pre-sieved sodium glycolate starch, crospovidone, Pearlitol Flash, and colloidal silica in a suitable mixer. 9. Lubricate the mixture from step 8 in a mixer with pre-sieved magnesium stearate.

[0153] 10. Compress the mixture from step 9 into tablets.

[0154] 11. The tablets are packaged as required.

[0155] Example 8

[0156] method 1. Sieve all ingredients separately through an appropriate sieve (e.g., 24 to 40 mesh).

[0157] 2. Mix the dry components (F-melt and crosspovidone) in RMG.

[0158] 3. Add the compound of formula IA to dichloromethane solution and mix until a clear solution is formed. Mix hydroxypropyl methylcellulose in dichloromethane until a homogeneous dispersion (binder) is obtained.

[0159] 4. Granulate the dried mixture from step 2 in RMG using the binder from step 3.

[0160] 5. Dry the wet granules from step 4 in FBD until the desired LOD is achieved.

[0161] 6. Pass the dried particles from step 5 through a suitable sieve, and grind any oversized particles using a multi-grind mill.

[0162] 7. Mix the particles from step 6 in a suitable mixer.

[0163] 8. Mix the granules from step 7 with the pre-sieved F-melt, cropovidone, aspartame, strawberry flavoring, and colloidal silica in a suitable mixer.

[0164] 9. Mix the mixture from step 8 with the pre-sieved magnesium stearate in a mixer.

[0165] 10. Compress the mixture from step 9 into tablets.

[0166] 11. The tablets are packaged as required.

[0167] Example 8A

[0168] method 1. Screening F Melt (D-mannitol, xylitol, MCC, fujicalin), Aeroperl 300, Polyplasdone XL 10, and Gelucire 59 / 14 (Gattefose) were sieved through a 40-mesh sieve and mixed.

[0169] 2. Adhesive preparation Divide 300 grams of dichloromethane into three portions (200 g, 50 g, and 50 g) and add them to different glass beakers.

[0170] The compound of formula IA was dissolved in 200 g of MDC by slow addition and continuous stirring until a clear, light brown solution was formed.

[0171] PVPK 29 / 32 was dissolved in 50 g of MDC in a separate beaker to obtain a clear solution. This solution was then added to the compound solution of formula IA with stirring to obtain a light brown solution (adhesive / API solution).

[0172] 3. Adhesive Additives Slowly add the binder / API solution to the sieved and premixed components from step 1 while continuously stirring. The addition rate should be slow and uniform to avoid clumping. After the binder / API solution has been completely added, rinse the beaker with 50 g of MDC and add the rinse solution, mixing to form a homogeneous wet mass.

[0173] 4. dry The wet blocks were dried in a fluidized bed dryer at 50°C with an air flow rate of 20 to 25 cfm for 20 minutes. The obtained LOD was 1.0 to 1.5.

[0174] 5. Mixing and Lubrication Pass the dried granules through a 30-mesh sieve and mix with povidone XL 10 for 2 to 3 minutes. Add the pre-sieved (60-mesh) magnesium stearate to the mixture and mix for 2 minutes.

[0175] 6. Tableting The mixture was compressed into tablets using the following parameters.

[0176] Punching details: Oval die, 19.00 x 9.90 mm Average tablet weight: 1120 mg DT: 2 to 3 minutes Hardness: 12 kg Thickness: 6.80 to 6.90 mm Dissolution test Dissolution testing of formulation 8A was performed under the following conditions: Dissolution medium 1. 0.01N HCl + 1% SLS medium Number of tablets: 12 Sampling time intervals were 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min.

[0177] Instrument: USP II (paddle method) Volume: 900 ml Speed: 100 rpm Temperature: 37.0℃ ± 0.5℃ result

[0178] Example 9

[0179] * - F-Melt was purchased from Fuji Chemical Industries USA, Inc., Burlington, New Jersey, USA. Aeroperl 300 is colloidal silica. Polyplasdone XL 10 (purchased from Ashland, Rotterdam, Netherlands) is cyclopovidone. Gelucire 59 / 14 (purchased from Gattefossé, Saint-Presse, France) is a mixture of lauroyl polyoxyethylene-32 glycerol ester and PEG 6000.

[0180] method Step 1 - Sieving and Dry Mixing Sieve F Melt (D-mannitol, xylitol, microcrystalline cellulose, cropovidone Fujiicalin), Aeroperl 300, Polyplasdone XL 10 and Gelucire 59 / 14 (Gattefose) through a 40-mesh sieve and mix for 5 minutes.

[0181] Step 2 - Adhesive Preparation PVP 29 / 32 was added to 100 g of dichloromethane and stirred to obtain a clear solution. The compound of formula IA was slowly added and stirred to obtain a light brown solution.

[0182] Step 3 - Adding Adhesive Add the adhesive preparation from step 2 to the dry mix from step 1 while continuously stirring. Mix the wet block thoroughly before adding any further incremental adhesive preparation. Add the adhesive formulation completely and mix thoroughly. Rinse the adhesive formulation container with 50 g of dichloromethane and slowly add it to the wet block while continuously stirring.

[0183] Step 4 - Drying The wet lumps from step 4 were dried using an air-drying filter (FBD). Initial drying was carried out 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°C–55°C for 20–30 minutes. The final LOD of the granules was 2.0% to 2.5%. (IR moisture analyzer, 105°C) Step 5 - Sieving Pass the dried granules from step 4 through a 30-mesh sieve. Transfer the sieved granules into double-layered polyethylene bags (capacity 2.0 kg).

[0184] Step 6 - Mixing Sieve Polyplasdone XL 10 through a 40-mesh sieve, add it to the dried granules from step 5, and mix for 5 minutes. Sieve magnesium stearate through a 60-mesh sieve, add it to the dried granules from step 5, and mix for 5 minutes.

[0185] Step 7 - Tableting The mixture was compressed into tablets using the following parameters.

[0186] Dissolution test Dissolution tests were performed on formulations 9A, 9B, and 9C under the following conditions: Formulations 9A and 9B Dissolution medium: 1. Simulated gastric juice (without pepsin): 2.0 mg NaCl + 7.0 ml HCl, diluted to 1000 ml with purified water, pH 1.2 2. 0.01N HCl + 1% SLS (sodium dodecyl sulfate) medium.

[0187] Formulation 9C Dissolution medium: 1. 0.01N HCl + 1% SLS medium 2. 0.1N HCl + 1% SLS medium 3. pH 4.5 acetate + 1% SLS medium 4. pH 6.8 phosphate + 1% SLS medium Test conditions for all media: Number of tablets: 12 Sampling time intervals: 30, 45, and 60 minutes Instrument: USP II (paddle method) Volume: 900 mL Speed: 100 rpm Temperature: 37.0℃ ± 0.5℃ Average weight of Formulation 9A tablets: 300 mg Average weight of Formulation 9B tablets: 310 mg Average weight of 9C tablets: 310 mg result Formulations 9A and 9B

[0188] Formulation 9C Stability test Stability and dissolution of formulations 9A, 9B, and 9C were tested at 40°C and 75% relative humidity (RH). The results are shown below.

[0189] 1 0.01 N HCl + 1% SLS, 900 mL, 100 RPM, USP II (paddle method)

[0190] 1 0.01 N HCl + 1% SLS, 900 mL, 100 RPM, USP II (paddle method)

[0191] 1 0.01 N HCl + 1% SLS, 900 mL, 100 RPM, USP II (paddle method) Example 10

[0192] method Step 1 - Sieving and Dry Mixing Sieve F Melt (D-mannitol, xylitol, microcrystalline cellulose, cropovidone Fujiicalin), Aeroperl 300, Polyplasdone XL 10 and Gelucire 59 / 14 (Gattefose) through a 40-mesh sieve and mix for 5 minutes.

[0193] Step 2 - Adhesive Preparation PVP 29 / 32 was added to 150 g of dichloromethane and stirred to obtain a clear solution. The compound of formula IA was slowly added and stirred to obtain a light brown solution.

[0194] Step 3 - Adding Adhesive Add the adhesive preparation from step 2 to the dry mix from step 1 while continuously stirring. Mix the wet block thoroughly before adding any further incremental adhesive preparation. Add the adhesive formulation completely and mix thoroughly. Rinse the adhesive formulation container with 50 g of dichloromethane and slowly add it to the wet block while continuously stirring.

[0195] Step 4 - Drying The wet lumps from step 4 were dried using an air-drying filter (FBD). Initial drying was carried out 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°C–55°C for 20–30 minutes. The final LOD of the granules was 2.0% to 2.5%. (IR moisture analyzer, 105°C) Step 5 - Sieving Pass the dried granules from step 4 through a 30-mesh sieve. Transfer the sieved granules into double-layered polyethylene bags (capacity 2.0 kg).

[0196] Step 6 - Mixing Sieve Polyplasdone XL 10 through a 40-mesh sieve, add it to the dried granules from step 5, and mix for 5 minutes. Sieve magnesium stearate through a 60-mesh sieve, add it to the dried granules from step 5, and mix for 5 minutes.

[0197] Step 7 - Tableting The mixture was compressed into tablets using the following parameters.

[0198] Dissolution test Dissolution tests were performed on formulations 10A and 10B under the following conditions: Formulation 10A Dissolution medium: 1. 0.01N HCl + 1% SLS medium.

[0199] 2. 0.1N HCl + 1% SLS medium 3. pH 4.5 acetate + 1% SLS medium 4. pH 6.8 phosphate + 1% SLS medium Formulation 10B Dissolution medium: 1. 0.01N HCl + 1% SLS medium.

[0200] Test conditions for all media: Number of tablets: 12 Sampling time intervals: 30, 45, and 60 minutes (Formulation 10A) Sampling time intervals: 5, 10, 15, 20, 30, 45, and 60 minutes (Formulation 10B) Instrument: USP II (paddle method) Volume: 900 mL Speed: 100 rpm Temperature: 37.0℃ ± 0.5℃ Average weight of Formulation 10A tablets: 520 mg Average weight of Formulation 10B tablets: 520 mg Formulation 10A Formulation 10B

[0201] Stability test Stability and dissolution of formulation 10A were tested at 40°C and 75% relative humidity (RH). The results are shown below.

[0202] 1 0.01 N HCl + 1% SLS, 900 mL, 100 RPM, USP II (paddle method) Example 11

[0203] method Step 1 - Ingredient sieving Sift the F melt (D-mannitol, xylitol, microcrystalline cellulose, fujicalin), Aeroperl 300, Polyplasdone XL 10, and Gelucire 59 / 14 (Gattefose) through a 40-mesh sieve and mix for 2-3 minutes.

[0204] Step 2 - Adhesive Preparation Divide 250 g of dichloromethane into three portions (150 g, 50 g, and 50 g) and add them to different glass beakers.

[0205] In a flask, the compound of formula IA was dissolved in 150 g of dichloromethane by slow addition and continuous stirring, resulting in a clear, slightly brown solution.

[0206] In another flask, 50 g of PVPK 29 / 32 was dissolved in 50 g of dichloromethane to obtain a clear solution.

[0207] The PVPK 29 / 32 solution was slowly added to the compound solution of formula IA while stirring, resulting in a clear, slightly brown solution (adhesive / API solution). Step 3 - Adding Adhesive Slowly add the binder / API solution from step 2 to the sieved and premixed components from step 1 while continuously stirring. The addition rate should be slow and uniform to avoid clumping. After the binder / API solution has been completely added, rinse the flask with 50 g of dichloromethane and add the rinse solution to the remaining contents, mixing thoroughly to form a homogeneous wet mass.

[0208] Step 4 - Dry the wet block The wet block from step 3 is dried in an FBD at 50°C for 20 minutes (air flow rate 20 to 25 cfm). LOD is 1.5% to 2.0%.

[0209] Step 5 - Mixing and Lubrication Pass the dried granules through a 30-mesh sieve and mix with Polyplasdone XL 10 in a polyethylene bag for 2 to 3 minutes. Add magnesium stearate, which has been pre-sieved through a 60-mesh sieve, to the above mixture and mix in a polyethylene bag for 2 minutes.

[0210] Step 6 - Tableting The mixture was compressed into tablets using the following parameters.

[0211] Dissolution test Dissolution testing of formulation 11A was performed under the following conditions: Formulation 11A Dissolution medium: 1. 0.01N HCl + 1% SLS medium.

[0212] 2. 0.1N HCl + 1% SLS medium 3. pH 4.5 acetate + 1% SLS medium 4. pH 6.8 phosphate + 1% SLS medium Test conditions for all media: Number of tablets: 12 Sampling time intervals: 30, 45, and 60 minutes Instrument: USP II (paddle method) Volume: 900 mL Speed: 100 rpm Temperature: 37.0℃ ± 0.5℃ Average weight of Formulation 11A tablets: 720 mg Formulation 11A Stability test Stability and dissolution of formulation 10A were tested at 40°C and 75% relative humidity (RH). The results are shown below.

[0213] 1 0.01 N HCl + 1% SLS, 900 mL, 100 RPM, USP II (paddle method) Example 12

[0214] method Step 1 – Dispensing Weigh out the required amounts of the compound of formula IA and (2-hydroxypropyl)β-cyclodextrin (HPPCD).

[0215] Step 2 – Mixing and Ultrasonic Treatment Add sterile water for injection to (2-hydroxypropyl)-β-cyclodextrin to obtain a 5% w / v solution. Add half the volume of the 5% HPPCD solution to the compound of formula I with stirring. Sonicate the resulting material for 15 minutes. Then add the remaining half volume of the 5% HPPCD solution, and sonicate the resulting suspension again for 15 minutes. Step 3 - Stir The suspension prepared in step 2 was stirred at 900-1200 RPM for 60 minutes to obtain a white to grayish-white suspension.

[0216] Maintain a temperature of 20°C–25°C throughout all process steps.

[0217] The final suspension should be stored at 20°C-25°C for no more than 24 hours.

[0218] Stability Study Formulation 12A

[0219] Average particle size parameter: D 10 = 3.29 μm, D 50 = 13.2 μm, D 90 = 48.4 μm Formulation 12B

[0220] Average particle size parameter: D 10 = 3.00 μm, D 50= 10.9 μm, D 90 = 31.5 μm Formulation 12C

[0221] Average particle size parameter: D 10 = 2.91 μm, D 50 = 12.2 μm, D 90 = 44.3 μm.

[0222] All references and patent publications cited in this article are hereby incorporated by way of citation.

Claims

1. An oral pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof: Equation I; in Each R is independently selected from H, halogen, substituted or unsubstituted C. 1-4 Alkyl groups, and substituted or unsubstituted C groups 1-4 Alkoxy; A is selected from H, or C, whether substituted or unsubstituted. 1-4 Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted (C 1-4 Alkyl)phenyl, substituted or unsubstituted 5-6 membered heteroaryl groups containing one or more heteroatoms selected from N, O, and S, substituted or unsubstituted heterocyclic groups containing one or more heteroatoms selected from N, O, and S, and substituted or unsubstituted C 1-4 alkoxycarbonyl; wherein the substituent is selected from halogens, substituted or unsubstituted C. 1-4 Alkyl groups and substituted or unsubstituted C groups 1-4 Alkoxy; n is 0, 1, 2, or 3; and * indicates the center of the solid; and one or more pharmaceutically acceptable excipients, The particle size D of the compound of formula I is described. 90 Less than approximately 200 μm.

2. The oral pharmaceutical composition of claim 1, wherein the compound of formula I is a compound of formula IA, IB, IC, ID, or IE: Formula IA; Formula IB; IC; Formula ID; Formula IE.

3. The oral pharmaceutical composition of claim 1 or claim 2, wherein the compound of formula I is a compound of formula IA: Formula IA.

4. The oral pharmaceutical composition according to any one of claims 1-3, wherein the particle size D of the compound of formula I is... 90 Between approximately 60 µm and approximately 100 µm.

5. The oral pharmaceutical composition according to any one of claims 1-3, wherein the particle size D of the compound of formula I is... 90 It ranges from approximately 2.0 µm to approximately 150 µm.

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

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

8. The oral pharmaceutical composition of any one of claims 1-7, wherein the composition is a solid and, when tested according to USP II (paddle method) at 100 rpm and 37.0 °C ± 0.5 °C in 900 mL of (i) simulated gastric juice (without pepsin) at pH 1.2, (ii) an aqueous solution of 0.01 N HCl containing 1% sodium dodecyl sulfate, (iii) an aqueous solution of 0.1 N HCl containing 1% sodium dodecyl sulfate, (iv) an aqueous solution of acetate at pH 4.5 and 1% sodium dodecyl sulfate, or (v) an aqueous solution of phosphate at pH 6.8 and 1% sodium dodecyl 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 1-6, wherein the composition is a solution or suspension.

10. A compressed tablet comprising a compound of formula IA or a pharmaceutically acceptable salt thereof. Formula IA The compound of formula IA or its pharmaceutically acceptable salt is dispersed in the following... (a) Nonionic water-dispersible surfactants; (b) Colloidal silica; (c) Chloroprene; and (d) Spray-dried (i) D-mannitol, (ii) xylitol, (iii) microcrystalline cellulose, (iv) crosspovidone and (v) dicalcium phosphate; The particle size D of the compound of formula IA is described. 90 Less than approximately 200 μm.

11. The tablet of claim 10, wherein the nonionic water-dispersible surfactant is a mixture of lauroyl polyoxyethylene-32 glycerol ester and PEG 6000.

12. An oral aqueous suspension comprising: (a) A compound of formula IA or a pharmaceutically acceptable salt thereof Formula IA; and (b) 2-Hydroxypropylβ-cyclodextrin.

13. The oral aqueous suspension of 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, the method comprising orally administering to a patient in need an oral pharmaceutical composition as described in any one of claims 1-13.

Images