GLP1 Tablet Composition

Abstract

Disclosed herein is a tablet composition comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, and a pH adjuster. In one embodiment, the tablet composition comprises a spray-dried dispersion (SDD) of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, and the SDD also comprises a polymer for maintaining the amorphous state.

Description

[Technical Field]

[0001] The present invention relates to an oral tablet composition of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (referred to herein as GLP1RA), which is a GLP-1 receptor agonist, or a pharmaceutically acceptable salt thereof. The compositions disclosed herein may be useful for the treatment of type 2 diabetes mellitus (T2D) and weight management. [Background Art]

[0002] Diabetes is a chronic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. In T2D, the combined effects of impaired insulin secretion and insulin resistance are associated with elevated blood glucose levels. T2D is an increasingly prevalent disorder that often leads to impaired patient health and quality of life. Effective oral treatments for managing T2D and / or for use in weight management are desired.

[0003] GLP1RA, i.e., 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, is described and claimed in U.S. Pat. No. 10,858,356. U.S. Pat. No. 10,858,356 generally describes oral compositions.

[0004] GLP1RA can be prepared as a pharmaceutically acceptable salt. One salt of GLP1RA is a calcium hemihydrate, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate (hereinafter referred to as "GLP1RA-Ca"), which has the structure shown below.

[0005] [ka]

[0006] GLP1RA is a weak acid with low permeability and low solubility, and has a pKa of 5.1. GLP1RA has very low water solubility in the physiological pH range and in pseudo-physiological solutions. GLP1RA and its pharmaceutically acceptable salts have been observed to have strong pH-dependent solubility characteristics, which contribute to challenges such as absorption variability, and therefore pharmacokinetic performance and potential food influences. There is a need for a GLP1RA tablet composition containing, but not limited to, GLP1RA-Ca, that is easy for patients to swallow, provides reliable PK performance, minimizes the possibility of drug interactions, and reduces or eliminates the effects of food. GLP1RA compositions that enhance the solubility and dissolution rate of the active substance in tablet formulations may be desirable. A pharmaceutically sophisticated dosage form for delivering an effective amount of active GLP1RA to the target portion of the gastrointestinal tract is desirable, and a dosage form small enough to facilitate patient swallowing is desirable. [Overview of the project]

[0007] The compositions described herein provide desired properties. In some embodiments, the use of a spray-dried dispersion (SDD) of GLP1RA or a pharmaceutically acceptable salt thereof, together with a pH adjuster described herein, contributes to the desired properties. In some embodiments, SDDs of specific particle sizes and specific compositions described herein provide the desired properties. In some embodiments, the compositions disclosed herein provide desirable pharmacokinetic performance and deliver an effective amount of active GLP1RA to a target portion of the gastrointestinal tract. In some embodiments, disclosed herein are sophisticated dosage forms that are convenient for patients to take without dietary or fluid restrictions.

[0008] The solid oral formulations provided herein may be useful for patients requiring treatment for T2D. The solid oral formulations provided herein may be useful for patients requiring chronic weight management. [Modes for carrying out the invention]

[0009] One embodiment is, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, This is a tablet composition containing a pH adjuster.

[0010] In one embodiment, the tablet composition disclosed herein is an oral solid composition.

[0011] One embodiment is a composition in which the pH adjusting agent is selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and mixtures thereof.

[0012] One embodiment is, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, This is a solid oral tablet composition comprising a pH adjuster, wherein the pH adjuster is selected from the group consisting of calcium carbonate, anhydrous calcium carbonate, sodium bicarbonate, anhydrous sodium bicarbonate, sodium carbonate, anhydrous sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and anhydrous magnesium hydroxide.

[0013] In one embodiment, the pH adjuster is sodium carbonate. In another embodiment, the pH adjuster is anhydrous. In yet another embodiment, the pH adjuster is anhydrous sodium carbonate.

[0014] In one embodiment, the pH adjuster is sodium carbonate hydrate.

[0015] In one embodiment, the pH adjuster is sodium bicarbonate. In another embodiment, the pH adjuster is anhydrous. In yet another embodiment, the pH adjuster is anhydrous sodium bicarbonate.

[0016] One embodiment comprises 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, This is a tablet composition containing a pH adjuster, wherein the pH adjuster is anhydrous sodium carbonate.

[0017] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, pH adjuster, It contains a super-disintegrant.

[0018] In one embodiment, the super-disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof. In another embodiment, the super-disintegrant is selected from the group consisting of croscarmellose sodium and crospovidone.

[0019] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, pH adjuster, It includes a lubricant.

[0020] In one embodiment, the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and mixtures thereof. In one embodiment, the lubricant comprises magnesium stearate. In one embodiment, the lubricant is magnesium stearate.

[0021] One embodiment is a tablet composition, wherein the composition comprises 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, and a pH adjuster, and a superdisintegrant, and a lubricant.

[0022] One embodiment is a tablet composition, wherein the composition comprises 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, and a pH adjuster, and a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, and a lubricant that is magnesium stearate.

[0023] One embodiment is a tablet composition, wherein the composition comprises 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, pH adjuster, It contains crospovidone.

[0024] In some embodiments, the tablet composition includes an enteric coating. In some embodiments, the tablet composition includes an immediate-release coating. In some embodiments, the tablet composition includes both an immediate-release coating and an enteric coating.

[0025] In one embodiment, the tablet compositions include 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate and a pH adjuster.

[0026] In one embodiment, the tablet compositions contain 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one in an amount of about 0.5 to about 75 mg per tablet composition.

[0027] In one embodiment, the tablet composition contains 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one in an amount of about 0.5 to about 60 mg per tablet composition, or more specifically, about 0.5 to about 45 mg, or more specifically, about 0.5 to about 36 mg, or even more specifically, about 0.8 to about 36 mg.

[0028] In one embodiment, the tablet composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl Each tablet composition contains approximately 0.5 to 82 mg of ]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, or more specifically, approximately 0.5 to 75 mg, or more specifically, approximately 0.5 to 60 mg, or more specifically, approximately 0.5 to 45 mg, or more specifically, approximately 0.8 to 45 mg, or even more specifically, approximately 1 to 36 mg (all amounts are based on free acid).

[0029] As described herein, the conversion factor for GLP1RA / GLP1RA-Ca (i.e., hemicalcium salt hydrate of GLP1RA) is assumed to be approximately 0.91. As will be readily apparent to those skilled in the art, the exact conversion factor may vary slightly depending on the actual content of the hydrate.

[0030] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5 mg to about 75 mg (based on free acid), the above compound or a pharmaceutically acceptable salt thereof, A pH adjusting agent selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, in an amount of about 5 mg to about 15 mg of the pH adjusting agent, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of approximately 2 mg to approximately 25 mg of the super-disintegrant, The present invention comprises a lubricant selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and mixtures thereof, in an amount of about 0.5 mg to about 5 mg.

[0031] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.7 mg to about 60 mg (based on free acid), the above compound or a pharmaceutically acceptable salt thereof, A pH adjusting agent selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, in an amount of about 5 mg to about 15 mg of the pH adjusting agent, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of approximately 2 mg to approximately 25 mg of the super-disintegrant, The lubricant is magnesium stearate, and it contains an amount of approximately 0.5 mg to approximately 5 mg of the lubricant.

[0032] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.8 mg to about 45 mg (based on free acid), the above compound or a pharmaceutically acceptable salt thereof, A pH adjusting agent selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, in an amount of about 5 mg to about 15 mg of the pH adjusting agent, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of approximately 2 mg to approximately 17.5 mg, The lubricant is magnesium stearate, and the product contains a lubricant in an amount of approximately 1 mg to approximately 2.5 mg.

[0033] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 1 to about 36 mg (based on free acid), the above compound or a pharmaceutically acceptable salt thereof, A pH adjusting agent selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, and magnesium hydroxide, and mixtures thereof, in an amount of about 5 mg to about 10 mg of the pH adjusting agent, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of approximately 5 mg to approximately 20 mg of the super-disintegrant, The lubricant is magnesium stearate, and the product contains a lubricant in an amount of approximately 1 mg to approximately 2.5 mg.

[0034] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg to about 30 mg (based on free acid), the above compound or a pharmaceutically acceptable salt thereof, A pH adjusting agent selected from the group consisting of anhydrous calcium carbonate, anhydrous sodium bicarbonate, anhydrous sodium carbonate, sodium carbonate hydrate, and anhydrous magnesium hydroxide, in an amount of approximately 6 mg to approximately 8 mg of the pH adjusting agent, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of approximately 10 mg to approximately 18 mg of the super-disintegrant, The lubricant is magnesium stearate, and it contains an amount of approximately 1.5 mg to approximately 2 mg of the lubricant.

[0035] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, in an amount of approximately 0.8 mg to approximately 45 mg (based on free acid), the above compound and Anhydrous sodium carbonate is a pH adjuster, and approximately 8 mg of the pH adjuster is used. Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 17.5 mg. The lubricant is magnesium stearate, and it contains approximately 2 mg of this lubricant.

[0036] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, in an amount of approximately 1 mg to approximately 36 mg (based on free acid), and Anhydrous sodium carbonate is a pH adjuster, and approximately 8 mg of the pH adjuster is used. Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 17.5 mg. The lubricant is magnesium stearate, and it contains approximately 2 mg of this lubricant.

[0037] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, in an amount of approximately 45 mg to approximately 60 mg (based on free acid), the above compound, Anhydrous sodium carbonate is a pH adjuster, and approximately 8 mg of the pH adjuster is used. Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 17.5 mg. The lubricant is magnesium stearate, and it contains approximately 2 mg of this lubricant.

[0038] In one embodiment, GLP1RA or a pharmaceutically acceptable salt thereof is prepared as a spray-dried dispersion (SDD) for use as an active drug in a tablet composition. In one embodiment, the SDD of GLP1RA or a pharmaceutically acceptable salt thereof is prepared under the conditions described in Preparation 2 or Preparation 3 below.

[0039] In one embodiment, GLP1RA ("3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one") or GLP1RA-Ca ("3-[( "1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate" is present in the compositions described herein as an SDD preparation.

[0040] Generally, the SDD preparations disclosed herein comprise GLP1RA or a pharmaceutically acceptable salt thereof, and a polymer as a remaining component to maintain the amorphous state of GLP1RA or a pharmaceutically acceptable salt thereof. In some embodiments, the polymer is selected from the group consisting of polyvinylpyrrolidone (also known as "povidone" or "PVP") and polyvinylpyrrolidone vinyl acetate (also known as "copovidone" or "PVP-VA"). In some embodiments, the polymer is PVP-VA. In some embodiments, the polymer is PVP.

[0041] In embodiments where the weight percentage of GLP1RA or a pharmaceutically acceptable salt thereof in the SDD preparation is specified, the remaining components of the SDD are polymers selected from PVP and PVP-VA, i.e., the total weight percentage of GLP1RA or a pharmaceutically acceptable salt thereof and polymers is 100% by weight. In some embodiments, the polymer is PVP-VA. In some embodiments, the polymer is PVP.

[0042] In one embodiment, the SDD preparation comprises about 20% to about 40% by weight of GLP1RA or GLP1RA-Ca, with the remainder being PVP-VA. In another embodiment, the SDD preparation comprises about 30% to about 35% by weight of GLP1RA or GLP1RA-Ca, with the remainder being PVP-VA. In yet another embodiment, the SDD preparation comprises about 30% by weight of GLP1RA or GLP1RA-Ca, with the remainder being PVP-VA. In yet another embodiment, the SDD preparation comprises about 30% by weight of GLP1RA-Ca, with the remainder being PVP-VA.

[0043] In one embodiment, the average particle size of GLP1RA or GLP1RA-Ca SDD is approximately 5 μm to 150 μm in diameter. In another embodiment, the average particle size of SDD is approximately 5 μm to 113 μm in diameter. In yet another embodiment, the average particle size of SDD is approximately 40 μm to 65 μm in diameter. In yet another embodiment, the average particle size of SDD is approximately 40 μm to 50 μm in diameter. In yet another embodiment, the average particle size of SDD is approximately 5 μm to 25 μm in diameter.

[0044] One embodiment is, SDD comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, This is a tablet composition containing a pH adjuster.

[0045] In some embodiments, the pH adjuster is selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and mixtures thereof. In some embodiments, the pH adjuster is sodium bicarbonate. In some embodiments, the pH adjuster is sodium carbonate. In some embodiments, the pH adjuster is anhydrous sodium carbonate.

[0046] One embodiment is, Approximately 20% to 40% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, and This is a tablet composition comprising a pH adjuster selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and mixtures thereof.

[0047] One embodiment is, Approximately 30% to 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, and This is a tablet composition comprising a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0048] One embodiment is, SDD of approximately 30% to approximately 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, wherein the SDD has an average particle size of approximately 5 μm to approximately 113 μm in diameter, and This is a tablet composition comprising a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0049] One embodiment is, SDD is composed of approximately 30% to 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, and the remainder is a polymer selected from PVP-VA and PVP, wherein the SDD has an average particle size of approximately 5 μm to approximately 113 μm in diameter. This is a tablet composition comprising a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0050] One embodiment is, Approximately 30% to 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate is present in an amount of approximately 0.5 mg to 60 mg (based on free acid), and the remainder consists of a polymer selected from PVP-VA and PVP, comprising SDD, This is a tablet composition comprising a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0051] One embodiment is, SDD is composed of a polymer containing approximately 30% to 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate in an amount of approximately 0.8 mg to 45 mg (based on free acid), with the remainder being PVP-VA. This is a tablet composition comprising a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0052] One embodiment is, SDD is composed of a polymer in which approximately 30% to 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate is present in an amount of approximately 0.5 mg to 60 mg (based on free acid), and the remainder is PVP-VA. A tablet composition comprising a pH adjusting agent selected from the group consisting of sodium bicarbonate and sodium carbonate, in an amount of about 1 mg to about 100 mg.

[0053] In one embodiment of the above tablet composition, the SDD has an average particle size of approximately 5 μm to approximately 113 μm in diameter. The pH adjuster is sodium carbonate.

[0054] In one embodiment of the above tablet composition, the composition is A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, It also contains a lubricant.

[0055] In one embodiment of the above tablet composition, the superdisintegrant is crospovidone in an amount of about 2 mg to about 250 mg. The lubricant is magnesium stearate in an amount of approximately 0.1 mg to 10 mg.

[0056] In one embodiment, disclosed herein are tablet compositions selected from the group consisting of Composition 1 (Comp.1), Composition 2 (Comp.2), Composition 3 (Comp.3), Composition 4 (Comp.4), Composition 5 (Comp.5), Composition 6 (Comp.6), Composition 7 (Comp.7), and Composition 8 (Comp.8), as shown in the table below, where the amount of each component in a particular composition is indicated as the target amount of that composition. In one embodiment, GLP1RA-Ca is used as the active ingredient, and the amount of each GLP1RA in the composition is based on free acid.

[0057] [Table 1]

[0058] As those skilled in the art of pharmaceutical formulations can understand, the amounts of one or more components of a composition can be changed within certain limits while maintaining the desired properties of the composition. In addition, if the amount of one component is changed, the amounts of one or more other components can be adjusted accordingly within a certain range in order to keep the total weight of the composition constant and maintain the desired properties of the composition.

[0059] In the embodiments of the specific compositions shown in the table above, the amount of each component is within the respective variable A range shown in parentheses from the target amount, while the desired properties of the corresponding composition are maintained.

[0060] In the embodiments of the specific compositions shown in the table above, the amount of each component is within the respective variable B range shown in parentheses from the target amount, while the desired properties of the corresponding composition are maintained.

[0061] One embodiment is a process for preparing the claimed composition, comprising a spray-drying dispersion process.

[0062] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5 mg to about 75 mg based on free acid, the above compound or a pharmaceutically acceptable salt thereof, A pH adjusting agent selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, and an amount of approximately 1 mg to approximately 150 mg of the pH adjusting agent, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of approximately 1 mg to approximately 250 mg of the super-disintegrant, The lubricant is magnesium stearate, and it contains an amount of approximately 0.1 mg to approximately 10 mg of the lubricant.

[0063] One embodiment is a tablet composition claimed by claim 21, wherein the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.7 mg to about 60 mg based on free acid, the above compound or a pharmaceutically acceptable salt thereof, A pH adjusting agent selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, and an amount of approximately 2 mg to approximately 100 mg of the pH adjusting agent, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of approximately 2 mg to approximately 200 mg, The lubricant is magnesium stearate, and the product contains a lubricant in an amount of approximately 0.1 mg to approximately 2.5 mg.

[0064] One embodiment is a tablet composition, and the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, and Contains a pH adjuster.

[0065] One embodiment is a tablet composition, and the composition is SDD is composed of approximately 30% to 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of approximately 0.5 mg to 75 mg on a free acid basis, with the remainder of the SDD consisting of PVP-VA. The present invention contains a pH adjusting agent selected from the group consisting of sodium bicarbonate and sodium carbonate, in an amount of approximately 1 mg to approximately 150 mg.

[0066] One embodiment is a tablet composition, and the composition is SDD consists of approximately 30% to 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or its Ca0.5 hydrate, in an amount of approximately 0.7 mg to 60 mg based on free acid, and the remainder of the SDD is composed of PVP-VA, and The present invention contains a pH adjusting agent selected from the group consisting of sodium bicarbonate and sodium carbonate, in an amount of approximately 5 mg to approximately 100 mg.

[0067] One embodiment is a tablet composition, and the composition is SDD is composed of approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or its Ca0.5 hydrate, in an amount of approximately 1.7 mg to approximately 250 mg of SDD, with the remainder of SDD consisting of PVP-VA, and SDD making up approximately 2% to approximately 25% by weight of the total tablet weight. The material contains a pH adjuster, which is sodium carbonate, in an amount of approximately 6 mg to approximately 100 mg, and the pH adjuster makes up approximately 5% to approximately 15% by weight of the total tablet weight.

[0068] One embodiment is a tablet composition, and the composition is In SDD, approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate is present in an amount of approximately 1.7 mg to 14.3 mg of SDD, and the remainder of SDD consists of PVP-VA, with SDD accounting for approximately 2% to 16.9% by weight of the total tablet weight. The product contains a pH adjuster, which is sodium carbonate, in an amount of approximately 6.8 mg, and the pH adjuster constitutes approximately 8% by weight of the total tablet weight.

[0069] One embodiment is a tablet composition, and the composition is In SDD, approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate constitutes approximately 16.7 mg to 120 mg of SDD, and the remainder of SDD consists of PVP-VA, with SDD accounting for approximately 19.5% by weight of the total tablet weight. The product contains a pH adjuster, which is sodium carbonate, in an amount of approximately 6.8 mg to approximately 49.2 mg, with the pH adjuster making up approximately 8% by weight of the total tablet weight.

[0070] One embodiment is a tablet composition, and the composition is In SDD, approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate is present in an amount of approximately 150 mg to 250 mg of SDD, and the remainder of SDD consists of PVP-VA, with SDD accounting for approximately 21% to 25% by weight of the total tablet weight. The product contains a pH adjuster, which is sodium carbonate, in an amount of approximately 57.1 mg to approximately 80 mg, with the pH adjuster making up approximately 8% by weight of the total tablet weight.

[0071] In one embodiment of the above tablet composition, the SDD has an average particle size of approximately 5 μm to approximately 113 μm in diameter.

[0072] One embodiment is a tablet composition, which further comprises a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

[0073] One embodiment is a tablet composition, The super-disintegrant is crospovidone in an amount of approximately 8.5 mg to approximately 170 mg, and the super-disintegrant constitutes approximately 10% to approximately 17% by weight of the total tablet weight.

[0074] One embodiment is a tablet composition, and the composition is The tablet further contains a filler, which is MCC, in an amount of approximately 67 mg to approximately 495 mg, and the filler makes up approximately 49.5% to approximately 79.5% by weight of the total tablet weight.

[0075] One embodiment is a tablet composition, and the composition is The product further contains a lubricant, which is magnesium stearate, in an amount of approximately 0.4 mg to approximately 5 mg, with the lubricant making up approximately 0.1% to approximately 1% by weight of the total tablet weight.

[0076] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 19.5% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant makes up approximately 17% by weight of the total tablet weight. The tablet contains a filler, which is MCC, and the filler makes up about 55% by weight of the total tablet weight.

[0077] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 25% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant makes up approximately 17% by weight of the total tablet weight. The invention comprises a filler, which is MCC, and the filler constitutes approximately 49.5% by weight of the total tablet weight.

[0078] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 21% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant makes up approximately 17% by weight of the total tablet weight. The present invention comprises a filler, which is MCC, and the filler constitutes approximately 53.5% by weight of the total tablet weight.

[0079] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 16.9% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight. The present invention comprises a filler, which is MCC, and the filler constitutes approximately 64.6% by weight of the total tablet weight.

[0080] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 11.8% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight. The present invention comprises a filler, which is MCC, and the filler constitutes approximately 69.7% by weight of the total tablet weight.

[0081] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 9.8% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight. The invention comprises a filler, which is MCC, and the filler constitutes approximately 71.7% by weight of the total tablet weight.

[0082] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 3.9% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight. The invention comprises a filler, which is MCC, and the filler constitutes approximately 77.6% by weight of the total tablet weight.

[0083] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 3.2% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight. The present invention comprises a filler, which is MCC, and the filler constitutes approximately 78.3% by weight of the total tablet weight.

[0084] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 2.7% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight. The present invention comprises a filler, which is MCC, and the filler constitutes approximately 78.8% by weight of the total tablet weight.

[0085] One embodiment is a tablet composition, and the composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 2.0% by weight of the total tablet weight. A pH adjuster that is sodium carbonate, and the pH adjuster makes up about 8% by weight of the total tablet weight, Crospovidone is a super-disintegrant, and the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight. The present invention comprises a filler, which is MCC, and the filler constitutes approximately 79.5% by weight of the total tablet weight.

[0086] One embodiment is the above-described tablet composition, which further comprises a lubricant, which is magnesium stearate, wherein the lubricant is present in an amount of about 0.5% by weight of the total tablet weight.

[0087] One embodiment is the above-described composition, which further comprises an immediate-release coating.

[0088] One embodiment is the above-described tablet composition, the composition further comprising an enteric coating on top of an immediate-release coating.

[0089] Pharmaceutical compositions using amorphous forms of active substances are prepared using spray-dried dispersions (SDDs) to develop dosage forms for poorly soluble drugs. However, this SDD approach is complicated by the presence of polymeric functional excipients, which may be necessary to maintain the drug in an amorphous state. Compositions that provide acceptable pharmacokinetic performance and desired dietary influence properties can be particularly challenging for molecules with strongly pH-dependent solubility properties. GLP1RA and GLP1RA-Ca exhibit such pH-dependent solubility properties. Weak acids may present challenges in ensuring the dissolution of active substances in desired parts of the gastrointestinal tract, particularly the stomach, where the dissolution of weakly acidic drugs may be delayed by low pH. Certain excipients may become unstable when added to tablet compositions described herein. In some embodiments, the excipient is stable in a tablet composition containing a pH adjuster.

[0090] As used herein, pH adjusters mean inorganic basic salts, including but not limited to calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, and magnesium oxide, which are capable of raising the micro-pH during the disintegration and dissolution of the tablets, and which include both the anhydrous and hydrated forms of the respective salts.

[0091] In some embodiments, the GLP1RA or pharmaceutically acceptable salt composition contains a pH adjuster, which is sodium carbonate. In some embodiments, the GLP1RA or pharmaceutically acceptable salt composition contains a pH adjuster, which is sodium carbonate in anhydrous form.

[0092] One embodiment is a composition comprising GLP1RA or a pharmaceutically acceptable salt thereof, and a pH adjuster selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, and mixtures thereof.

[0093] One embodiment is a composition comprising GLP1RA or a pharmaceutically acceptable salt thereof, and a pH adjuster selected from the group consisting of calcium carbonate, anhydrous calcium carbonate, sodium bicarbonate, anhydrous sodium bicarbonate, sodium carbonate, anhydrous sodium carbonate, magnesium hydroxide, and anhydrous magnesium hydroxide.

[0094] In one embodiment, the tablet composition comprising GLP1RA or a pharmaceutically acceptable salt thereof and a pH adjuster is uncoated.

[0095] In some embodiments, the tablet composition is prepared as an immediate-release (IR) dosage form that releases GLP1RA or a pharmaceutically acceptable salt thereof in the gastric compartment. Excessive amounts of pH modifiers in the tablet may affect the absorption of co-administered drugs whose absorption is pH-sensitive. In some embodiments, the amount of pH modifier is sufficiently low so as not to raise the overall gastric pH during dissolution, but to facilitate the dissolution of GLP1RA or a pharmaceutically acceptable salt thereof. Immediate-release dosage forms with sufficiently low amounts of pH modifiers may be desirable to minimize the increase in gastric pH and the potential for drug interactions (DDIs) with co-administered drugs.

[0096] In one embodiment, a tablet composition comprising GLP1RA or a pharmaceutically acceptable salt thereof and a pH adjuster is coated with an immediate-release coating.

[0097] As used herein, the term “immediate-release coating” means a coating intended primarily for aesthetic purposes and not intended to alter the disintegration and / or dissolution of the tablet. As used herein, a suitable immediate-release coating may be selected from known coatings, e.g., Opadry® Clear (03K19229) (Colorcon Inc.), but not limited to these. As is common in moisture-sensitive SDD formulations, protection from moisture may be desired to ensure the functionality and appearance of the product throughout its shelf life. This protection can be achieved through packaging and the use of coating materials to minimize moisture absorption by the tablet. One known immediate-release coating having this function is Opadry® ambII (Colorcon).

[0098] One embodiment is a composition comprising GLP1RA or a pharmaceutically acceptable salt thereof, a pH adjuster, and an immediate-release coating.

[0099] In one embodiment, a tablet composition comprising GLP1RA or its pharmaceutically acceptable salt and a pH adjuster is prepared as a delayed-release (DR) dosage form further comprising an enteric coating. The composition further comprising the enteric coating may be released in the intestine at a pH of 5.5 or higher. Intestinal release may be desirable for GLP1RA or its pharmaceutically acceptable salt to limit the risks potentially associated with the presence of the pH adjuster in the tablet. The DR composition may minimize the potential effects of food and may have other desirable effects on the pharmacokinetic profile, such as, but not limited to, the modulation of total exposure and Cmax.

[0100] As used herein, “enteric coating” means a functional coating intended to prevent the disintegration and / or dissolution of a tablet in the gastric environment but to dissolve in the intestinal environment.

[0101] One embodiment is a composition comprising GLP1RA or a pharmaceutically acceptable salt thereof, a pH adjuster, and an enteric coating.

[0102] One embodiment is a tablet composition comprising GLP1RA or a pharmaceutically active salt thereof, a pH adjuster, and a super-disintegrant.

[0103] One embodiment is a tablet composition comprising GLP1RA or a pharmaceutically active salt thereof, a pH adjuster, a super-disintegrant, and a lubricant.

[0104] One embodiment is a tablet composition comprising GLP1RA or a pharmaceutically acceptable salt thereof, a pH adjuster, a super-disintegrant, and an enteric coating on the tablet.

[0105] One embodiment is a tablet composition comprising GLP1RA or a pharmaceutically acceptable salt thereof, a pH adjuster, a superdisintegrant, and an immediate-release coating on the tablet.

[0106] As used herein, the terms “super-disintegrant” and “disintegrant” are interchangeable and mean excipients for facilitating the desired dissolution of GLP1RA or its pharmaceutically acceptable salt, including but not limited to croscarmellose sodium and crospovidone. The term “super-disintegrant” refers to an excipient that preferably promotes the dissolution of GLP1RA or its pharmaceutically acceptable salt within 30 to about 60 minutes. In some embodiments, the tablet composition comprises GLP1RA or its pharmaceutically acceptable salt, a pH adjuster, and a super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

[0107] One embodiment is a tablet composition comprising GLP1RA or a pharmaceutically active salt thereof, a pH adjuster, and crospovidone.

[0108] In one embodiment, the desired tablet composition provides reliable PK performance in a patient-friendly dosage form. The dosage form of the patient-friendly tablet composition should preferably have an acceptable size that facilitates swallowing during daily administration, minimizes the possibility of drug interactions (DDIs) with other concomitant medications, minimizes the influence of food, avoids limitations on administration time, and avoids limitations on the amount of liquid used to aid swallowing.

[0109] The tablet composition may be released in either the gastric compartment or the intestine (enteric coating) via an erosion mechanism. The dosage forms of the present invention offer the potential to improve absorption / PK performance. The dosage forms provided herein can reduce unwanted drug interactions.

[0110] Certain abbreviations are defined as follows: "cfm" refers to cubic feet / min, "Cmax" refers to the maximum plasma concentration the drug achieves in the test area after drug administration and before the second administration, "DDI" refers to drug interaction, "DR" refers to delayed release, "EtOH" refers to ethanol or ethyl alcohol, "FaSSiF" refers to fasted simulated intestinal fluid, "FaSSGF" refers to fasted simulated gastric fluid, "FeSSIF" refers to fed simulated intestinal fluid, "hr" refers to time, "hrs" refers to time, "IR" refers to immediate release, "PK" refers to pharmacokinetics, and "MeOH" refers to methanol or methyl alcohol. "Alcohol" refers to alcohol, "rpm" refers to revolutions per minute, "PVP-VA" refers to polyvinylpyrrolide / vinyl acetate copolymer, "SDD" refers to spray-dried dispersion, "SIF" refers to artificial intestinal fluid, "T2D" refers to type 2 diabetes, "THF" refers to tetrahydrofuran, "USP" refers to the United States Pharmacopeia, "Wt%" refers to the mass / total mass of the desired material, and "XRPD" refers to X-ray powder diffraction. As used herein, "prep" means preparation.

[0111] Those skilled in the art can prepare spray-dried dispersion (SDD) preparations of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one,0.5Ca using various apparatuses under various processing conditions to produce substances with suitable quality and important characteristics.

[0112] In one embodiment, the GLP1RA or GLP1RA-Ca in the SDD preparation is amorphous, with a desired weight percent of the drug (30%) and PVP-VA (70%) as measured by XRPD, has a particle size that allows for isolation and forward processing, and contains an acceptable amount of process-related impurities and excess residual solvent.

[0113] In one embodiment, an amorphous solid dispersion can be used in the preparation process. In one embodiment, the particle size is about 5 to about 113 μm for use in the preparation of tablet compositions.

[0114] The capsules are prepared for the assays described herein using conventional encapsulation methods.

[0115] Preparation 1 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate

[0116] [ka]

[0117] Example 1 can be prepared as described in International Publication No. 18 / 056453.

[0118] The title compound has other names. For example, it is also known as the hemicalcium salt hydrate of orfolglipron.

[0119] Another name for the title compound is 1,2,4-oxadiazole-5(2H)-one, 3-[(1S,2S)-1-[2-[[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazole-5-yl)-2,3-dihydro-2-oxo-1H-imidazole-1-yl]-2,4,6,7-tetrahydro-4-methyl-5H-pyrazolo[4,3-c]pyridine-5-yl]carbonyl]-5-[(4S)-tetrahydro-2,2-dimethyl-2H-pyran-4-yl]-1H-indole-1-yl]-2-methylcyclopropyl]-calcium salt (2:1) hydrate.

[0120] Preparation 2 SDD preparation of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate 30% of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5SDD is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]- The dispersions are prepared by dissolving 2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca 0.5 hydrate (8.7 g, potency 92%) and PVP-VA (also known as copovidone, CAS#25086-89-9) (18.7 g) in EtOH (200 mL) at room temperature. After dissolving the solids, the solution is spray-dried using a conventional spray dryer equipped with a pressure nozzle. The following parameters in Table 1 are used for preparing dispersions using a lab-scale spray dryer. Spray drying can be initiated when the spray dryer temperature exceeds 33°C. The material is collected and dried overnight under vacuum at 50°C to obtain the title compound (21.99 g, 7.0 g, titer 92%, recovery rate 80%), and the material is observed by optical microscope to be microscopically non-birefringent particles with a diameter of approximately 5–25 μm.

[0121] [Table 2]

[0122] Preparation 3 SDD preparation of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate is dissolved in MeOH-modified EtOH (5% v / v or w / w). A 20% w / w solid solution is prepared with a 30% w / w (based on free acid) solid fraction consisting of the title compound, with the remainder being PVP-VA. This is interpreted as 6% title compound (based on free acid), 14% PVP-VA, and 80% modified EtOH SDA-3A (all fractions are considered w / w). After spray drying, the resulting solid consists of 30% w / w (based on free acid) of the solid fraction made up of the title compound, with the remainder being PVP-VA. The percentage values ​​are shown in Table 2 below.

[0123] [Table 3]

[0124] A solution is prepared and pumped into a spray dryer, where it is atomized. Heated drying gas is introduced in parallel to the atomized liquid at the top of the spray drying chamber at a ratio of approximately 0.044 kg / kg of spray solution to drying gas. The inlet temperature is adjusted to provide an outlet temperature of 35-45°C. The solid formed in the spray dryer is recovered through a cyclone and a filter housing above the gas flow. The gas is passed through a condenser maintained at -3°C to remove the solvent (dew point -3°C). The gas is then heated to the inlet temperature and returned to the spray dryer.

[0125] Preparation 4 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3hou5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate Capsule formulation First, sodium bicarbonate (600 mg) is added to a hypromellose capsule (size 0), followed by the addition of SDD (54 mg) from preparation 3 to prepare the capsule.

[0126] [Table 4]

[0127] Preparation 5 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, tablet formulation Preparation of core tablet composition To prepare the core tablets, the SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate (13.3% w / w) and the excipients (described in Examples 1-7), excluding magnesium stearate, are sieved through a 600 μm sieve before use. The materials are added to a container (1000 mL) and mixed using a mixer at 32 rpm for approximately 10 minutes. Sift the mixture through a sieve (600 μm) and mix using a mixer at 32 rpm for approximately 10 minutes twice. Mixing. Add magnesium stearate and mix the mixture at 32 rpm for approximately 3 minutes. Compress the mixture blend on a single-station tablet press using a 14.10 × 7.75 mm oval tablet tool to produce tablets (400.0 mg) with a hardness of 30 kP.

[0128] Tablet compositions are prepared using the parameters in Tables 4 to 10 below, as substantially described above in this specification, to prepare the corresponding Examples 1 to 7 (compositions T1, T2, A, B, C, D, and E). Each of Examples 1 to 7 contains an IR coating as substantially described herein, and the tablets of Examples 1 to 6 may further contain an enteric coating. The tablet of Example 7 contains only the IR coating.

[0129] Example 1: Tablet composition T1

[0130] [Table 5]

[0131] Example 2: Tablet composition T2

[0132] [Table 6]

[0133] Example 3: Tablet composition A

[0134] [Table 7]

[0135] Example 4: Tablet Composition B

[0136] [Table 8]

[0137] Example 5: Tablet Composition C

[0138] [Table 9]

[0139] Example 6: Tablet Composition D

[0140] [Table 10]

[0141] Example 7 Tablet composition E

[0142] [Table 11] * The numbers in parentheses indicate the theoretical target of GLP1RA.

[0143] Immediate-release coatings of Examples 1 to 7 Immediate-release tablets coating Core tablet compositions prepared substantially as described in each of Examples 1-7 are film-coated with an immediate-release coating such as Opadry® Clear (03K19229) (Colorcon Inc.) up to a target increase of 3% by weight (tolerance range 2.5-3.5%). The tablets are coated using conventional pan-coating equipment and vendor-recommended coating conditions, with water as the base for the spray suspension. Compositions Examples 1-7 are coated using this immediate-release coating.

[0144] Example 8 Delayed-release tablet composition coating (enteric coating) The tablet compositions of Examples 1 to 6 are coated with Opadry® Clear substantially as described above. The tablets coated with Opadry® Clear are further enterically coated with Acryl-EZE® (93A18597) (Colorcon Inc) and PEG8000 as a plasticizer at an increase of 8% by weight relative to Acryl-EZE, up to a target increase of 6.75% by weight (tolerance range of 6.25 to 7.25 percent). The tablets are coated using conventional pan coating equipment and coating conditions recommended by the distributor, with water as the base for the spray suspension.

[0145] Example 9 Enteric-coated tablet compositions - Enteric-coated tablets are prepared using tablet compositions substantially as described in Examples 1-6, except that the weight % of sodium carbonate is adjusted and the microcrystalline cellulose content is adjusted. The tablets are coated with Opadry® 03K19229 (Colorcon Inc.) using 8 wt% solid in a spray suspension to a target weight increase of 3%. The tablets are coated using a benchtop pan coater with a 0.8 mm orifice spray nozzle spray gun with an anti-bearding cap, an inlet airflow of 30 cfm, an inlet air temperature of 70°C, a spray suspension rate of 2.3 g / min, a spray pressure of 1.5 bar, a pattern air pressure of 0.25 bar, and a pan speed of 32 rpm. The tablets are then enterically coated with Acryl-EZE 93A18597 (Colorcon Inc.) using the same apparatus to a target weight increase of approximately 6.5%. An aqueous suspension is prepared using 20% ​​by weight Acryl-EZE powder containing 8% by weight PEG-8000 as a plasticizer relative to Acryl-EZE. The coating conditions are as follows: a spray gun with a 0.8 mm orifice spray nozzle equipped with an anti-bearding cap, an inlet airflow of 25 cfm, an inlet air temperature of 60°C, a spray suspension rate of 4.1 g / min, a spray pressure of 1.5 bar, a pattern air pressure of 0.25 bar, and a pan speed of 35 rpm.

[0146] Example 10 Quantitative IR tablet composition

[0147] [Table 12]

[0148] Example 11 Superdisintegrant alternative tablet composition containing croscarmellose sodium

[0149] [Table 13]

[0150] Example 12 Crospovidone-containing alternative tablet composition super-disintegrating agent

[0151] [Table 14]

[0152] Tablet compositions are prepared using these superdisintegrants in formulations as shown in Tables 11 and 12. All materials except magnesium stearate are added to a brown glass bottle and mixed for 10 minutes at 22 rpm using a rotary diffusion mixer. The blend is passed through a #35 mesh screen and then mixed for a further 10 minutes. Magnesium stearate is passed through a #35 mesh and added to the bottle, and mixed for 5 minutes. The blend is compressed using a modified elliptical tool with a compression force of 6 kN using a single-station tablet press. The core tablets are coated with Opadry® 03K19229 (Colorcon Inc.) using 8 wt% solid in a spray suspension until a target weight increase of 3% is reached. The tablets are coated using a benchtop pan coater with a spray gun featuring a 0.8 mm orifice spray nozzle with an anti-bearding cap, an inlet airflow of 30 cfm, an inlet air temperature of 70°C, a spray suspension rate of 2.3 g / min, a spray pressure of 1.5 bar, a pattern air pressure of 0.25 bar, and a pan speed of 32 rpm. The tablets are then enterically coated with Acryl-Eze 93A18597 (Colorcon Inc.) using the same apparatus to a target increase of 6.5% by weight. An aqueous suspension is prepared with 20% by weight Acryl-Eze powder containing 8% by weight of PEG-8000 as a plasticizer relative to Acryl-EZE. The coating conditions are as follows: A spray gun with an anti-bearding cap, 0.8mm orifice spray nozzle, 25cfm inlet airflow, 60°C inlet air temperature, 4.1g / min atomization suspension rate, 1.5 bar spray pressure, 0.25 bar pattern air pressure, and 35 rpm panning speed.

[0153] Example 13 Tablets with a total weight of 400 mg of tablet composition Tablets (400 mg total weight) are prepared using the proportions in Table 14. The tablets are prepared and coated with an immediate-release coating, and then with an enteric coating, substantially as described in Example 9.

[0154] [Table 15]

[0155] Example 14 Tablet composition 9-30 Core tablet compositions 9 to 30 (Comp.9 to Comp.30) are prepared using the proportions shown in the table below and the methods described above. The core tablets are prepared, coated with an immediate-release coating, and then further coated with an enteric coating, substantially as described in Example 9.

[0156] [Table 16-1]

[0157] [Table 16-2]

[0158] Particle size measurement The particle size of SDDs was determined by laser diffraction using wet dispersion with a Malvern Mastersizer 3000 (Malvern Instruments Ltd. UK) equipped with a Hydro MV (medium volume) liquid disperser. Optical model: Mie model, obscuration limit: 5-30%, general-purpose model. Volume-based distribution was measured and (D10, D50, D90) quantiles were reported.

[0159] The SDD of preparations 2 and 3 has an average particle size of approximately 40 to 65 μm, or more specifically, approximately 40 to 50 μm, as measured by the method described above.

[0160] Solubility test 24-hour water solubility of crystalline GLP1RA-Ca at 25°C

[0161] [Table 17] * Not measured

[0162] Embodiments of the present invention are oral tablet formulations containing amorphous SDD of GLP1RA-Ca. Crystalline GLP1RA-Ca has low water solubility, as shown in Table 15. Amorphous SDD of GLP1RA-Ca using PVP-VA as a carrier polymer has been shown to provide improved hydrophilicity and solubility compared to crystalline GLP1RA-Ca (Table 16).

[0163] [Table 18]

[0164] [Table 19]

[0165] As shown in Tables 16 and 17, preparation 3 exhibits pH-dependent solubility. When the pKa is 5.1, the drug solubility is expected to begin increasing at pH values ​​near the pKa, and the dissolution performance is expected to improve at pH values ​​above the pKa. To test this, capsules containing SDD and a sufficient amount of sodium bicarbonate to raise the pH of the acidic dissolution medium to near the pKa were evaluated in dissolution experiments compared to tablets containing much less pH adjuster. Quantitative formulations are shown in Table 11 for tablets and Table 3 for capsules.

[0166] Formulation dissolution test The formulation will be evaluated in a two-step dissolution test consisting of a 1-hour acid step (500 mL 0.0133 N HCl / 8.12 mM NaCl) followed by the addition of concentrated FaSSIF (400 mL) to convert the medium to the same pH and composition as conventional fasted intestinal fluid. To prepare each 1 L of concentrated FaSSIF, add anhydrous disodium phosphate (5.714 g), anhydrous monosodium phosphate (2.906 g), and NaCl (12.354 g) with water to make 1 L and mix well. The pH should be approximately 7.0. Add SIF powder (5.6 g) (FaSSIF / FeSSIF / FaSSGF powder (Biorelevant)).

[0167] The test is performed using a USP II elution device at 100 rpm. A portion is taken, filtered through a 0.22 micrometer filter, diluted 1:1 with MeOH to prevent drug precipitation, and analyzed by HPLC.

[0168] Surprisingly, even though the capsule formulation raised the pH of the medium to above 5 with a large amount of sodium bicarbonate, and the tablet formulation did not affect the pH of the medium and remained at pH 2, the IR tablet was found to function better in the stomach than the capsule formulation.

[0169] [Table 20] StDev refers to the standard deviation.

[0170] Capsule preparation 4 and the IR tablet composition of Example 7 were also compared using alternative dissolution conditions. The conditions used were a 100 rpm USP II paddle with 50 mM pH 6.8 phosphate buffer containing 2% sodium lauryl sulfate as the elution medium. The samples were analyzed by HPLC.

[0171] Surprisingly, despite the presence of a substantial amount of sodium bicarbonate, which should facilitate the dissolution of SDD from the capsules, the IR tablets released faster than the capsules, achieving 100% release within 30 minutes, while the capsules only achieved 35% release in 30 minutes and did not reach over 90% release until approximately 75 minutes.

[0172] [Table 21]

[0173] [Table 22]

[0174] pH adjusters in both IR and DR tablets promote the dissolution of weakly acidic drugs by increasing the local, or microscopic, pH of the tablet during disintegration. Enteric-coated tablets are used to determine the required level of pH adjuster in the enteric-coated tablet composition. Example 9, an enteric-coated tablet, is tested in a two-step dissolution test using a USP II apparatus at a paddle speed of 100 rpm. First, the acid challenge step is performed for 2 hours in pH 4.5 sodium acetate buffer (500 mL), after which the tablet is removed and placed in FaSSiF (Biorelevant) (500 mL). A portion is taken out, filtered through a 0.22 micrometer filter, diluted 1:1 with MeOH to prevent drug precipitation, and analyzed by HPLC.

[0175] Unexpectedly, very high levels of pH adjusters (20% by weight in the tablet) resulted in DR tablets with poorer dissolution behavior compared to lower levels. Furthermore, optimal peak and more sustained dissolution levels were achieved with approximately 10% by weight of sodium carbonate.

[0176] [Table 23] nm=not measured

[0177] The tablets from Examples 11 and 12 were tested in a two-step dissolution test using a USP II apparatus with a paddle speed of 100 rpm. The acid challenge stage was performed in pH 4.5 sodium acetate buffer (500 mL) for 2 hours, after which the tablets were removed and placed in FaSSiF (Biorelevant) (500 mL). A portion was taken out, filtered through a 0.22 micrometer filter, diluted 1:1 with MeOH to prevent drug precipitation, and analyzed by HPLC.

[0178] Surprisingly, it was found that croscarmellose sodium used in Example 11 did not provide the desired release characteristics, while crospovidone used in Example 12 did.

[0179] [Table 24]

[0180] In further embodiments, the release rate from enteric-coated tablets can be controlled to affect specific aspects of the PK profile, such as Cmax or peak-to-trough plasma concentration, as these may be beneficial to the patient in order to aid tolerability and / or efficacy.

[0181] Controlled release from tablets is often achieved using rate-controlled polymers such as hypromellose, as in hydrophilic sustained-release matrix tablets. The challenge with hypromellose or similar polymers is that they tend to act over several hours by diffusion and / or erosion mechanisms. This period can be too long for low-permeability molecules, and if the drug concentration in the intestinal lumen is not maximized, the gradual release of the drug over a long period can reduce the flow rate across the intestinal epithelium, leading to decreased absorption.

[0182] Surprisingly, it was found that by controlling the amount of superdisintegrant in the enteric-coated dosage form, it is possible to control the release rate to a considerable extent over the desired complete release time of 30 minutes or less.

[0183] Tablets T1 and T2 were evaluated in a two-step dissolution test substantially similar to that previously described, except that the pH 4.5 sodium acetate step was set to 1 hour, followed by transferring the tablets to FaSSiF (Biorelevant). The results are shown in Table 23.

[0184] Surprisingly, controlled levels of release in FaSSiF can be achieved simply by adjusting the concentration of the disintegrant.

[0185] [Table 25]

[0186] Another means of regulating drug release from enteric-coated tablets is to change the amount of sodium carbonate. The tablets are subjected to dissolution in pH 6.8 phosphate buffer containing 2% sodium lauryl sulfate, as described herein. The results of this study demonstrate a synergistic effect between the level of disintegrant and the amount of pH modifier that can be used to control drug release from tablets. Furthermore, the release is controlled within a desired range of less than 30 minutes to less than 3 hours to model the approximate in vivo transit time through the small intestine where most drug absorption is expected to occur. The results are shown in Table 24.

[0187] [Table 26]

[0188] Clinical trials Repeated dose-escalation studies were conducted to characterize and compare the pharmacokinetics (PK) of prototype formulations of Preparation 4 (capsule), Example 1 (DR tablet composition T1 with enteric coating prepared in the same manner as Example 9, hereinafter referred to as T1 DR tablet), and Example 7 (IR tablet composition E with immediate-release coating, hereinafter referred to as E IR tablet). The studies were conducted in two parts, A and B.

[0189] Part A evaluated the safety, tolerability, and pharmacokinetics of repeated oral administration of GLP1RA prototype formulations T1 and E in healthy participants compared to reference capsule formulation 4. The dose escalation period was from day 1 to day 18, during which participants received increasing amounts of GLP1RA in capsules. Intratherapeutic dose escalations were every 6 days, reaching a maximum dose of 16 mg of GLP1RA once daily (QD) on day 19. From days 19 to 24, participants were administered reference capsule formulation 4 (16 mg QD), and then entered the study phase from days 25 to 36. During study period 1, participants were randomly administered the GLP1RA prototype tablet formulation (16 mg QD). Subsequently, participants crossed over to the second prototype tablet (16 mg QD) on day 31 of period 2 and received it until day 36.

[0190] [Table 27] Abbreviations: AUC(0-24) = Area under the curve 0-24 hours after administration; Cmax = Maximum observed concentration; Frel AUC(0-24) = Relative bioavailability based on AUC(0-24); Frel Cmax = Relative bioavailability based on Cmax; h = Time; N / A = Not applicable

[0191] The results from Part A show that the mean peak and total exposure levels (measured by Cmax and AUC(0-24)) for 16 mg DR tablet T1 were approximately 67% and 50% higher, respectively, than for 4 capsules of the 16 mg reference preparation. These increases were statistically significant at the 10% significance level (p<.001 for both Cmax and AUC(0-24)).

[0192] Similarly, for the 16 mg E IR tablets, the mean peak and total exposure levels (measured by Cmax and AUC(0-24)) were approximately 47% and 41%, respectively, higher than those of the 16 mg reference capsule. These increases were statistically significant at the 10% significance level (p=.007 and p<.001 for Cmax and AUC(0-24), respectively).

[0193] Part B further evaluated the E IR tablet in terms of the effect of food and the DDI effect with co-administered proton pump inhibitors (PPIs). Similar to Part A, dose escalation was performed every 6 days during the escalation period, reaching the maximum dose of 16 mg QD on day 19. Treatment was then advanced with GLP-1RA in fasted or fed conditions, and in a fasted state with co-administration of PPIs. Each option began with a 6-day reference period (16 mg QD) using the E IR tablet as a reference, followed by two 6-day trial periods (16 mg QD).

[0194] [Table 28] Abbreviations: AUC(0-24) = Area under the curve 0-24 hours after administration; Cmax = Maximum observed concentration; Frel AUC(0-24) = Relative bioavailability based on AUC(0-24); Frel Cmax = Relative bioavailability based on Cmax; h = Time; N / A = Not applicable The results from Part B show that the mean peak and total exposure levels (measured by Cmax and AUC(0-24)) of the 16 mg E IR tablet in a fed state were comparable to the mean peak and total exposure levels of the 16 mg E IR tablet in a fasted state (i.e., fed exposure was within 11% and 4% of the fasted exposure in Cmax and AUC(0-24) respectively) (p=.39 and p=.66 for Cmax and AUC(0-24), respectively).

[0195] The mean peak and total exposure levels (measured by Cmax and AUC(0-24)) for the 16 mg Tablet E IR Tablet and PPI were also comparable to those of the 16 mg Tablet E composition (i.e., 6% lower and 6% higher, respectively, for Cmax and AUC(0-24)) (p=.65 and p=.57, respectively, for Cmax and AUC(0-24)).

[0196] Although the present invention has been described in considerable detail with reference to certain specific embodiments thereof, other variations are possible. The embodiments disclosed herein are for illustrative purposes only, and various modifications to the embodiments and further embodiments in addition to those shown and described herein will be apparent to those skilled in the art from the entire content of the present specification. The invention described in the original claims of this application is listed below. [1] A tablet composition, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, A tablet composition containing a pH adjuster. [2] The composition according to [1], wherein the pH adjusting agent is selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and mixtures thereof. [3] The composition according to [2], wherein the pH adjusting agent is selected from the group consisting of calcium carbonate, anhydrous calcium carbonate, sodium bicarbonate, anhydrous sodium bicarbonate, sodium carbonate, anhydrous sodium carbonate, magnesium hydroxide, and anhydrous magnesium hydroxide. [4] The composition according to [3], wherein the pH adjusting agent is anhydrous. [5] The composition according to [3], wherein the pH adjusting agent is sodium carbonate. [6] The composition according to [5], wherein the pH adjusting agent is anhydrous sodium carbonate. [7] The composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, pH adjuster, A composition according to any one of [1] to [6], comprising a super-disintegrant. [8] The composition according to [7], wherein the super-disintegrant is selected from the group consisting of croscarmellose sodium and crospovidone. [9] The composition according to [8], wherein the super-disintegrant is crospovidone.

[10] The composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, pH adjuster, Super-disintegrant and A composition according to any one of [1] to [9], comprising a lubricant.

[11] The composition according to

[10] , wherein the lubricant is magnesium stearate.

[12] The composition according to any one of [1] to

[11] , further comprising an immediate-release coating.

[13] The composition according to any one of [1] to

[12] , further comprising an enteric coating.

[14] The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one salt, The composition is one of the following [1] to

[13] , which is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate.

[15] The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, The composition according to any one of [1] to

[14] , wherein the compound is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, and the amount of the compound is about 0.7 to about 50 mg per tablet composition based on free acid.

[16] The composition according to

[15] , wherein the amount of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate is approximately 48 mg per tablet.

[17] A composition according to any one of [1] to

[16] for use in the treatment of type 2 diabetes.

[18] A composition according to any one of [1] to

[16] for use in weight management.

[19] A process for preparing a tablet composition according to any one of [1] to

[16] , comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a spray-dried dispersion of a pharmaceutically acceptable salt thereof.

[20] The process according to

[19] , wherein the spray-dried dispersion of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, further comprises a PVP-VA polymer.

[21] A tablet composition, wherein the composition is Approximately 0.5 mg to 75 mg of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, A pH adjusting agent selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, in an amount of approximately 1 mg to approximately 150 mg, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of approximately 1 mg to approximately 250 mg, A lubricant consisting of approximately 0.1 mg to 10 mg of magnesium stearate, A tablet composition containing the following:

[22] The composition is Approximately 0.7 mg to 60 mg of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, A pH adjusting agent selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, in an amount of approximately 2 mg to approximately 100 mg, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of approximately 2 mg to approximately 200 mg, A lubricant consisting of approximately 0.1 mg to 2.5 mg of magnesium stearate, The tablet composition according to

[21] , comprising:

[23] A tablet composition, wherein the composition 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, and A tablet composition containing a pH adjuster.

[24] The composition is SDD comprising approximately 30% to 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of approximately 0.5 mg to 75 mg on a free acid basis, wherein the remainder of the SDD is composed of PVP-VA, and A pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate in an amount of approximately 1 mg to approximately 150 mg, The tablet composition according to

[23] , comprising:

[25] The composition is SDD comprising approximately 30% to 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or its Ca0.5 hydrate, in an amount of approximately 0.7 mg to 60 mg based on free acid, with the remainder of the SDD consisting of PVP-VA, A pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate in an amount of approximately 5 mg to approximately 100 mg, A tablet composition according to any one of

[23] to

[24] , comprising the above.

[26] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one or its Ca0.5 hydrate, in an amount of approximately 1.7 mg to approximately 250 mg, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 2% to approximately 25% by weight of the total tablet weight, and The tablet composition according to

[24] , comprising the pH adjusting agent, which is sodium carbonate, in an amount of about 6 mg to about 100 mg, and the pH adjusting agent is about 5% to about 15% by weight of the total tablet weight.

[27] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, with an amount of approximately 1.7 mg to approximately 14.3 mg of the SDD, the remainder of the SDD being composed of PVP-VA, and the SDD making up approximately 2% to approximately 16.9% by weight of the total tablet weight, and A pH adjusting agent comprising approximately 6.8 mg of sodium carbonate, wherein the pH adjusting agent constitutes approximately 8% by weight of the total tablet weight, and the pH adjusting agent is... The tablet composition according to

[26] , comprising:

[28] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, with an amount of approximately 16.7 mg to approximately 120 mg of the SDD, the remainder of the SDD being composed of PVP-VA, and the SDD is approximately 19.5% by weight of the total tablet weight, and the SDD is A pH adjusting agent, which is sodium carbonate, in an amount of approximately 6.8 mg to approximately 49.2 mg, wherein the pH adjusting agent constitutes approximately 8% by weight of the total tablet weight, and the pH adjusting agent is... The tablet composition according to

[26] , comprising:

[29] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, with an amount of approximately 150 mg to approximately 250 mg of the SDD, the remainder of the SDD being composed of PVP-VA, and the SDD making up approximately 21% to approximately 25% by weight of the total tablet weight, and the SDD, A pH adjusting agent comprising approximately 57.1 mg to approximately 80 mg of sodium carbonate, wherein the pH adjusting agent constitutes approximately 8% by weight of the total tablet weight, and The tablet composition according to

[26] , comprising:

[30] The SDD has an average particle size of approximately 5 μm to approximately 113 μm in diameter, The tablet composition according to any one of

[21] to

[29] , wherein the pH adjusting agent is sodium carbonate.

[31] The composition is The tablet composition according to

[30] , further comprising a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

[32] The tablet composition according to

[31] , wherein the super-disintegrant is crospovidone in an amount of about 8.5 mg to about 170 mg, and the super-disintegrant is about 10% to about 17% by weight of the total tablet weight.

[33] The composition is The tablet composition according to

[32] , further comprising a filler which is MCC, in an amount of about 67 mg to about 495 mg, wherein the filler constitutes about 49.5% to about 79.5% by weight of the total tablet weight.

[34] The composition is The tablet composition according to

[33] , further comprising a lubricant, which is magnesium stearate, in an amount of about 0.4 mg to about 5 mg, wherein the lubricant is about 0.1% to about 1% by weight of the total tablet weight.

[35] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 19.5% by weight of the total tablet weight, and A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is approximately 17% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 55% by weight of the total tablet weight, The tablet composition according to

[26] , comprising:

[36] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 25% by weight of the total tablet weight, and the SDD is A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is approximately 17% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 49.5% by weight of the total tablet weight, and The tablet composition according to

[26] , comprising:

[37] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 21% by weight of the total tablet weight, and the SDD is A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is approximately 17% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 53.5% by weight of the total tablet weight, The tablet composition according to

[26] , comprising:

[38] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 16.9% by weight of the total tablet weight, and A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 64.6% by weight of the total tablet weight, and The tablet composition according to

[26] , comprising:

[39] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 11.8% by weight of the total tablet weight, and A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 69.7% by weight of the total tablet weight, The tablet composition according to

[26] , comprising:

[40] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 9.8% by weight of the total tablet weight, and A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 71.7% by weight of the total tablet weight, The tablet composition according to

[26] , comprising:

[41] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 3.9% by weight of the total tablet weight, and A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 77.6% by weight of the total tablet weight, The tablet composition according to

[26] , comprising:

[42] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 3.2% by weight of the total tablet weight, and A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 78.3% by weight of the total tablet weight, The tablet composition according to

[26] , comprising:

[43] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 2.7% by weight of the total tablet weight, and A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 78.8% by weight of the total tablet weight, The tablet composition according to

[26] , comprising:

[44] The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 2.0% by weight of the total tablet weight, and A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight, A filler that is MCC, wherein the filler is approximately 79.5% by weight of the total tablet weight, The tablet composition according to

[26] , comprising:

[45] The tablet composition according to any one of

[35] to

[44] , wherein the SDD has an average particle size of approximately 5 μm to approximately 113 μm in diameter.

[46] The tablet composition according to any one of

[44] , wherein the SDD has an average particle size of about 40 μm to about 65 μm in diameter.

[47] The tablet composition according to any one of

[21] to

[46] , wherein the composition further comprises a lubricant which is magnesium stearate, the lubricant which is about 0.5% by weight of the total tablet weight.

[48] ​​The tablet composition according to

[47] , further comprising an immediate-release coating.

[49] The tablet composition according to

[48] , further comprising an enteric coating on the immediate-release coating.

[50] A composition according to any one of

[21] to

[49] for use in the treatment of type 2 diabetes.

[51] A composition according to any one of

[21] to

[49] for use in weight management.

Claims

1. A tablet composition, A spray-dried dispersion (SDD) of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one or a pharmaceutically acceptable salt thereof, A tablet composition comprising a pH adjuster.

2. The composition according to claim 1, wherein the pH adjusting agent is selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and mixtures thereof.

3. The composition according to claim 2, wherein the pH adjusting agent is selected from the group consisting of calcium carbonate, anhydrous calcium carbonate, sodium bicarbonate, anhydrous sodium bicarbonate, sodium carbonate, anhydrous sodium carbonate, magnesium hydroxide, and anhydrous magnesium hydroxide.

4. The composition according to claim 3, wherein the pH adjusting agent is sodium carbonate.

5. The composition is A spray-dried dispersion (SDD) of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one or a pharmaceutically acceptable salt thereof, pH adjuster, The composition according to claim 1, comprising a super-disintegrant.

6. The composition according to claim 5, wherein the super-disintegrant is selected from the group consisting of croscarmellose sodium and crospovidone.

7. The composition is A spray-dried dispersion (SDD) of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one or a pharmaceutically acceptable salt thereof, pH adjuster, Super-disintegrant and The composition according to claim 1, comprising a lubricant.

8. The composition according to claim 1, further comprising an immediate-release coating.

9. The pharmaceutically acceptable salts of the aforementioned 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one are, The composition according to claim 1, wherein the Ca0.5 hydrate is present in an amount of about 0.7 to about 50 mg per tablet composition based on free acid.

10. The composition according to claim 1 for use in the treatment of type 2 diabetes.

11. The composition according to claim 1 for use in weight management.

12. A tablet composition, wherein the composition is A spray-dried dispersion (SDD) of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one or a pharmaceutically acceptable salt thereof in an amount of approximately 0.7 mg to approximately 60 mg based on free acid, A pH adjusting agent selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, in an amount of approximately 2 mg to approximately 100 mg, A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of approximately 2 mg to approximately 200 mg, A lubricant consisting of approximately 0.1 mg to approximately 2.5 mg of magnesium stearate, A tablet composition containing the following:

13. The composition is An SDD comprising approximately 30% to approximately 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or a pharmaceutically acceptable salt thereof, in an amount of approximately 0.5 mg to approximately 75 mg based on free acid, wherein the remainder of the SDD is composed of PVP-VA, A pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate in an amount of approximately 1 mg to approximately 150 mg, A tablet composition according to claim 1, comprising:

14. The composition is An SDD comprising approximately 30% to approximately 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one, or its Ca0.5 hydrate, in an amount of approximately 0.7 mg to approximately 60 mg based on free acid, wherein the remainder of the SDD is composed of PVP-VA, and A pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate in an amount of approximately 5 mg to approximately 100 mg, The tablet composition according to claim 13, comprising:

15. The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one or its Ca0.5 hydrate, in an amount of approximately 1.7 mg to approximately 250 mg, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 2% to approximately 25% by weight of the total tablet weight, The tablet composition according to claim 13, comprising the pH adjusting agent, which is sodium carbonate, in an amount of about 6 mg to about 100 mg, and the pH adjusting agent is about 5% to about 15% by weight of the total tablet weight.

16. The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, in an amount of approximately 150 mg to approximately 250 mg, the remainder of the SDD is composed of PVP-VA, and the SDD is approximately 21% to approximately 25% by weight of the total tablet weight, and the SDD is A pH adjusting agent comprising approximately 57.1 mg to approximately 80 mg of sodium carbonate, wherein the pH adjusting agent constitutes approximately 8% by weight of the total tablet weight, and the pH adjusting agent is... The tablet composition according to claim 15, comprising:

17. The SDD has an average particle size of approximately 5 μm to approximately 113 μm in diameter. The tablet composition according to claim 12, wherein the pH adjusting agent is sodium carbonate.

18. The composition is The tablet composition according to claim 17, further comprising a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

19. The tablet composition according to claim 18, wherein the super-disintegrant is crospovidone in an amount of about 8.5 mg to about 170 mg, and the super-disintegrant is about 10% to about 17% by weight of the total tablet weight.

20. The composition is The tablet composition according to claim 19, further comprising a filler which is MCC, in an amount of about 67 mg to about 495 mg, wherein the filler constitutes about 49.5% to about 79.5% by weight of the total tablet weight.

21. The composition is The tablet composition according to claim 20, further comprising a lubricant, which is magnesium stearate, in an amount of about 0.4 mg to about 5 mg, wherein the lubricant is about 0.1% to about 1% by weight of the total tablet weight.

22. The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the amount of the SDD is approximately 19.5% to approximately 25% by weight of the total tablet weight, A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is approximately 17% by weight of the total tablet weight, A filler that is MCC, wherein the amount of the filler is approximately 49.5% to approximately 55% by weight of the total tablet weight, The tablet composition according to claim 15, comprising:

23. The composition is The SDD is approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5-one Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the amount of the SDD is approximately 2.0% to approximately 16.9% by weight of the total tablet weight, A pH adjusting agent which is sodium carbonate, wherein the pH adjusting agent is present in an amount of approximately 8% by weight of the total tablet weight, A super-disintegrant which is crospovidone, wherein the super-disintegrant is present in an amount of approximately 10% by weight of the total tablet weight, A filler which is MCC, wherein the amount of the filler is approximately 64.6% to approximately 79.5% by weight of the total tablet weight, The tablet composition according to claim 15, comprising:

24. The tablet composition according to claim 22, wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter.

25. The tablet composition according to claim 12, wherein the composition further comprises a lubricant which is magnesium stearate, and the lubricant is in an amount of about 0.5% by weight of the total tablet weight.

26. The tablet composition according to claim 25, wherein the composition further comprises an immediate-release coating.

Images