GLP-1 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 a GLP-1 receptor agonist, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-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 (hereinafter referred to as GLP1RA in this specification), 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 disease characterized by hyperglycemia caused by 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 disease that often leads to a decline in the health and quality of life of patients. An effective oral treatment for managing T2D and / or for use in weight management is desired.

[0003] GLP1RA, namely 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-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, is described and claimed in U.S. Patent No. 10,858,356. U.S. Patent No. 10,858,356 generally describes oral compositions.

[0004] GLP1RA can be prepared as a pharmaceutically acceptable salt. One salt of GLP1RA is 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-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 Ca0.5 hydrate (hereinafter referred to as "GLP1RA-Ca" in this specification), and has the structure shown below.

[0005]

Chemical formula

[0006] GLP1RA is a weak acid with low permeability and low solubility, and its pKa is 5.1. GLP1RA has very low water solubility in the physiological pH range and in simulated physiological fluids. It has been observed that GLP1RA and its pharmaceutically acceptable salts have strong pH-dependent solubility characteristics, which are factors contributing to issues such as variability in absorption, thus pharmacokinetic performance and potential food effects. There is a desire for tablet compositions of GLP1RA, including but not limited to GLP1RA-Ca, that provide reliable PK performance in a dosage form that is easy for patients to take, with minimal potential for drug-drug interactions and reduced or no food effects. GLP1RA compositions may be desirable to increase the solubility and dissolution rate of the active substance in the tablet dosage form. A pharmaceutically refined dosage form for delivering an effective amount of active GLP1RA to the target portion of the gastrointestinal tract and in a dosage form small enough to facilitate patient swallowing is desired.

Summary of the Invention

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

[0008] The solid oral formulations provided herein may be useful for patients in need of treatment of T2D. The solid oral formulations provided herein may be useful for patients in need of chronic weight management.

DETAILED DESCRIPTION OF THE INVENTION

[0009] Certain embodiments are 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-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, and is a tablet composition.

[0010] In certain embodiments, the tablet compositions disclosed herein are oral solid compositions.

[0011] Certain embodiments are compositions wherein 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.

[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-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, a pH adjuster, and is a solid oral tablet composition, 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 one embodiment, the pH adjuster is anhydrous. In one 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 one embodiment, the pH adjuster is anhydrous. In one embodiment, the pH adjuster is anhydrous sodium bicarbonate.

[0016] 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-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, A tablet composition comprising a pH adjuster, wherein the pH adjuster is sodium anhydrous carbonate.

[0017] One embodiment is a tablet composition, and 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-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, a pH adjuster, and a superdisintegrant.

[0018] In certain embodiments, the superdisintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof. In certain embodiments, the superdisintegrant is selected from the group consisting of croscarmellose sodium and crospovidone.

[0019] One embodiment is a tablet composition, and 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-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, a pH adjuster, and a lubricant.

[0020] In certain embodiments, 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 certain embodiments, the lubricant comprises magnesium stearate. In certain embodiments, the lubricant is magnesium stearate.

[0021] Certain embodiments are tablet compositions, and the compositions 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-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, a pH adjuster, a superdisintegrant, and a lubricant.

[0022] Certain embodiments are tablet compositions, and the compositions 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-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, a pH adjuster, a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, and a lubricant that is magnesium stearate.

[0023] Certain embodiments are tablet compositions, and the compositions 3-[(1S,2S)-1-[5-[(4S)-2,2-Dimethyloxan-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, and crospovidone.

[0024] In certain embodiments, the tablet composition comprises an enteric coating. In certain embodiments, the tablet composition comprises an immediate release coating. In certain embodiments, the tablet composition comprises both an immediate release coating and an enteric coating.

[0025] In certain embodiments, the tablet 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-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 Ca0.5 hydrate and a pH adjuster.

[0026] In certain embodiments, the tablet 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-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 in an amount of from about 0.5 to about 75 mg per tablet composition.

[0027] In certain embodiments, the tablet 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-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 in an amount of from about 0.5 to about 60 mg, or more specifically from about 0.5 to about 45 mg, or more specifically from about 0.5 to about 36 mg, or even more specifically from about 0.8 to about 36 mg, per tablet composition.

[0028] In certain embodiments, the tablet 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-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 Ca0.5 hydrate in an amount of about 0.5 to about 82 mg, or more specifically about 0.5 to about 75 mg, or more specifically about 0.5 to about 60 mg, or more specifically about 0.5 to about 45 mg, or more specifically about 0.8 to about 45 mg, or even more specifically about 1 to about 36 mg, per tablet composition (all amounts on a free acid basis).

[0029] As described herein, the conversion factor for GLP1RA / GLP1RA-Ca (i.e., the hemicalcium salt hydrate of GLP1RA) is assumed to be about 0.91. As will be readily appreciated by 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, the composition 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-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, in an amount of about 0.5 mg to about 75 mg (on a free acid basis), said compound or a pharmaceutically acceptable salt thereof, and A pH regulator 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, the pH regulator, and A superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of about 2 mg to about 25 mg, the superdisintegrant, and 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, the lubricant, and comprising.

[0031] One embodiment is a tablet composition, 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-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, in an amount of about 0.7 mg to about 60 mg (on a free acid basis), the above compound or a pharmaceutically acceptable salt thereof, and A pH regulator 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, the pH regulator, and A superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of about 2 mg to about 25 mg, the superdisintegrant, and Magnesium stearate, a lubricant, in an amount of about 0.5 mg to about 5 mg, the lubricant, and comprising.

[0032] One embodiment is a tablet composition, 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-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, in an amount of about 0.8 mg to about 45 mg (on a free acid basis), the above compound or a pharmaceutically acceptable salt thereof, and a pH adjuster 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, the pH adjuster, and a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of about 2 mg to about 17.5 mg, the superdisintegrant, and magnesium stearate as a lubricant, in an amount of about 1 mg to about 2.5 mg, the lubricant.

[0033] One embodiment is a tablet composition, and 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-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, in an amount of about 1 to about 36 mg (on a free acid basis), the above compound or a pharmaceutically acceptable salt thereof, and a pH adjuster 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, the pH adjuster, and A superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of about 5 mg to about 20 mg, the superdisintegrant, A lubricant which is magnesium stearate, in an amount of about 1 mg to about 2.5 mg, the lubricant, and comprising.

[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-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, in an amount of about 1 mg to about 30 mg (on a free acid basis), the above compound or a pharmaceutically acceptable salt thereof, A pH adjuster selected from the group consisting of calcium carbonate anhydrous, sodium bicarbonate anhydrous, sodium carbonate anhydrous, sodium carbonate hydrate, and magnesium hydroxide anhydrous, in an amount of about 6 mg to about 8 mg, the pH adjuster, A superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of about 10 mg to about 18 mg, the superdisintegrant, A lubricant which is magnesium stearate, in an amount of about 1.5 mg to about 2 mg, the lubricant, and comprising.

[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-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 Ca0.5 hydrate, in an amount of about 0.8 mg to about 45 mg (on a free acid basis), of the above compound, and Sodium carbonate anhydrous, as a pH adjuster, in an amount of about 8 mg, of the pH adjuster, and Crospovidone, as a superdisintegrant, in an amount of about 17.5 mg, of the superdisintegrant, and Magnesium stearate, as a lubricant, in an amount of about 2 mg, of the lubricant, and comprising.

[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-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 Ca0.5 hydrate, in an amount of about 1 mg to about 36 mg (on a free acid basis), of the above compound, and Sodium carbonate anhydrous, as a pH adjuster, in an amount of about 8 mg, of the pH adjuster, and Crospovidone, as a superdisintegrant, in an amount of about 17.5 mg, of the superdisintegrant, and Magnesium stearate, as a lubricant, in an amount of about 2 mg, of the lubricant, and comprising.

[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-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 Ca0.5 hydrate, in an amount of about 45 mg to about 60 mg (on a free acid basis) of said compound, and Sodium carbonate anhydrous, as a pH adjuster, in an amount of about 8 mg of said pH adjuster, and Crospovidone, as a superdisintegrant, in an amount of about 17.5 mg of said superdisintegrant, and Magnesium stearate, as a lubricant, in an amount of about 2 mg of said lubricant.

[0038] In certain embodiments, the GLP1RA or a pharmaceutically acceptable salt thereof is formulated into a spray dried dispersion (SDD) for use as an active drug in a tablet composition. In certain embodiments, the SDD of the 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-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 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-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 Ca0.5 hydrate) is present as an SDD preparation in the compositions described herein.

[0040] Generally, the SDD preparations disclosed herein comprise a GLP1RA or a pharmaceutically acceptable salt thereof, and a polymer as the remaining component for maintaining the amorphous state of the GLP1RA or a pharmaceutically acceptable salt thereof. In one embodiment, 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 one embodiment, the polymer is PVP-VA. In one embodiment, the polymer is PVP.

[0041] In embodiments where the weight percentage of the 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, that is, the total weight percentage of the GLP1RA or a pharmaceutically acceptable salt thereof and the polymer is 100% by weight. In certain embodiments, the polymer is PVP-VA. In certain embodiments, the polymer is PVP.

[0042] In certain embodiments, the SDD preparation comprises from about 20% to about 40% by weight of the GLP1RA or GLP1RA-Ca, the remainder being composed of PVP-VA. In certain embodiments, the SDD preparation comprises from about 30% to about 35% by weight of the GLP1RA or GLP1RA-Ca, the remainder being composed of PVP-VA. In certain embodiments, the SDD preparation comprises about 30% by weight of the GLP1RA or GLP1RA-Ca, the remainder being composed of PVP-VA. In certain embodiments, the SDD preparation comprises about 30% by weight of the GLP1RA-Ca, the remainder being composed of PVP-VA.

[0043] In certain embodiments, the average particle size of the GLP1RA or GLP1RA-Ca SDD is from about 5 μm to about 150 μm in diameter. In certain embodiments, the average particle size of the SDD is from about 5 μm to about 113 μm in diameter. In certain embodiments, the average particle size of the SDD is from about 40 μm to about 65 μm in diameter. In certain embodiments, the average particle size of the SDD is from about 40 μm to about 50 μm in diameter. In certain embodiments, the average particle size of the SDD is from about 5 μm to about 25 μm in diameter.

[0044] Certain embodiments are 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-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, and is a tablet composition.

[0045] In certain 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 certain embodiments, the pH adjuster is sodium bicarbonate. In certain embodiments, the pH adjuster is sodium carbonate. In certain embodiments, the pH adjuster is anhydrous sodium carbonate.

[0046] Certain embodiments about 20% to about 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-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 of SDD, and 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, and is a tablet composition.

[0047] Certain embodiments The SDD of about 30% to about 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-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 selected from the group consisting of sodium bicarbonate and sodium carbonate, and is a tablet composition.

[0048] One embodiment is the SDD of about 30% to about 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-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, wherein the SDD has an average particle size of about 5 μm to about 113 μm, the SDD, and a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate, and is a tablet composition.

[0049] One embodiment is An SDD comprising about 30% to about 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-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 Ca0.5 hydrate, and the balance being composed of a polymer selected from PVP-VA and PVP, the SDD having an average particle size of about 5 μm to about 113 μm, and a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate, and is a tablet composition.

[0050] One embodiment is an SDD in which about 30% to about 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-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 Ca0.5 hydrate is in an amount of about 0.5 mg to about 60 mg (on a free acid basis), and the balance is composed of a polymer selected from PVP-VA and PVP, and a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate, and is a tablet composition.

[0051] One embodiment is About 30% to about 35% by weight 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 Ca0.5 hydrate is in an amount of about 0.8 mg to about 45 mg (on a free acid basis), and the balance is composed of a polymer that is PVP-VA, SDD, and a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate, and a tablet composition.

[0052] One embodiment is About 30% to about 35% by weight 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 Ca0.5 hydrate is in an amount of about 0.5 mg to about 60 mg (on a free acid basis), and the balance is composed of a polymer that is PVP-VA, SDD, and a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate, the pH adjuster being in an amount of about 1 mg to about 100 mg, and a tablet composition.

[0053] In certain embodiments of the above tablet composition, the SDD has an average particle size of about 5 μm to about 113 μm, the pH adjuster is sodium carbonate.

[0054] In certain embodiments of the above tablet composition, the composition A super-disintegrant selected from the group consisting of croscarmellose sodium and crospovidone, and a lubricant.

[0055] In certain embodiments of the tablet composition, the super-disintegrant is crospovidone in an amount of about 2 mg to about 250 mg, and the lubricant is magnesium stearate in an amount of about 0.1 mg to about 10 mg.

[0056] In certain embodiments, disclosed herein is a tablet composition 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 following table, and the amount of each component of a particular composition is shown as the target amount for that composition. In one embodiment, GLP1RA-Ca is used as the active ingredient, and the amount of each GLP1RA in the composition is on a free acid basis.

[0057]

Table 1

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

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

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

[0061] One embodiment is a process for preparing a composition claimed herein, including a spray drying dispersion process.

[0062] One embodiment is a tablet composition, the composition 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-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, in an amount of about 0.5 mg to about 75 mg on a free acid basis, the above compound or a pharmaceutically acceptable salt thereof, and a pH regulator 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 1 mg to about 150 mg, the pH regulator, and a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of about 1 mg to about 250 mg, the superdisintegrant, and magnesium stearate, a lubricant, in an amount of about 0.1 mg to about 10 mg, the lubricant.

[0063] One embodiment is a tablet composition claimed according to claim 21, the 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, in an amount of about 0.7 mg to about 60 mg on a free acid basis, the above compound or a pharmaceutically acceptable salt thereof, and a pH adjuster selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, and in an amount of about 2 mg to about 100 mg, the pH adjuster, and a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, and in an amount of about 2 mg to about 200 mg, the superdisintegrant, and magnesium stearate as a lubricant, and in an amount of about 0.1 mg to about 2.5 mg, the lubricant, and is included.

[0064] One embodiment is a tablet composition, and the composition the 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 a pH adjuster, and is included.

[0065] One embodiment is a tablet composition, and the composition SDD, 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-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 in an amount of about 30 wt% to about 35 wt%, or a pharmaceutically acceptable salt thereof, is in an amount of about 0.5 mg to about 75 mg on a free acid basis, and the balance of the SDD is composed of PVP-VA, and the SDD, a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate, in an amount of about 1 mg to about 150 mg,

[0066] One embodiment is a tablet composition, and the composition SDD, 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-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 in an amount of about 30 wt% to about 35 wt%, or its Ca0.5 hydrate, is in an amount of about 0.7 mg to about 60 mg on a free acid basis, and the balance of the SDD is composed of PVP-VA, and the SDD, a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate, in an amount of about 5 mg to about 100 mg,

[0067] One embodiment is a tablet composition, and the composition SDD, which is about 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-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 its Ca0.5 hydrate, is in an amount of about 1.7 mg to about 250 mg of SDD, the balance of the SDD is composed of PVP-VA, and the SDD is about 2% to about 25% by weight of the total tablet weight, SDD, A pH adjuster, which is sodium carbonate, is in an amount of about 6 mg to about 100 mg, and the pH adjuster is about 5% to about 15% by weight of the total tablet weight, the pH adjuster, and

[0068] One embodiment is a tablet composition, and the composition SDD, which is about 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-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 Ca0.5 hydrate, is in an amount of about 1.7 mg to about 14.3 mg of SDD, the balance of the SDD is composed of PVP-VA, and the SDD is about 2% to about 16.9% by weight of the total tablet weight, SDD, A pH adjuster, which is sodium carbonate, is in an amount of about 6.8 mg, and the pH adjuster is about 8% by weight of the total tablet weight, the pH adjuster, and

[0069] One embodiment is a tablet composition, and the composition SDD, which is about 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-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 Ca0.5 hydrate, is in an amount of about 16.7 mg to about 120 mg of SDD, the balance of the SDD is composed of PVP-VA, and the SDD is about 19.5% by weight of the total tablet weight, SDD, and Sodium carbonate, which is a pH adjuster and is in an amount of about 6.8 mg to about 49.2 mg, and the pH adjuster is about 8% by weight of the total tablet weight, a pH adjuster, and.

[0070] One embodiment is a tablet composition, and the composition is SDD, which is about 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-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 Ca0.5 hydrate, is in an amount of about 150 mg to about 250 mg of SDD, the balance of the SDD is composed of PVP-VA, and the SDD is about 21% to about 25% by weight of the total tablet weight, SDD, and Sodium carbonate, which is a pH adjuster and is in an amount of about 57.1 mg to about 80 mg, and the pH adjuster is about 8% by weight of the total tablet weight, a pH adjuster, and.

[0071] In certain embodiments of the above tablet composition, the SDD has an average particle size of about 5 μm to about 113 μm.

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

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

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

[0075] One embodiment is a tablet composition, and the composition further comprises a lubricant which is magnesium stearate and is in an amount of about 0.4 mg to about 5 mg, and the lubricant is about 0.1% to about 1% by weight of the total tablet weight.

[0076] One embodiment is a tablet composition, and the composition about 30% by weight of 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-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 Ca0.5 hydrate, the balance of the SDD being composed of PVP-VA, and the SDD being about 19.5% by weight of the total tablet weight, an SDD, a pH adjuster which is sodium carbonate, and the pH adjuster is about 8% by weight of the total tablet weight, a pH adjuster, a superdisintegrant which is crospovidone, and the superdisintegrant is about 17% by weight of the total tablet weight, a superdisintegrant, An MCC, which is a filler, and the filler is about 55% by weight of the total tablet weight, including the filler.

[0077] One embodiment is a tablet composition, and the composition is An SDD of about 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-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 Ca0.5 hydrate, the balance of the SDD is composed of PVP-VA, and the SDD is about 25% by weight of the total tablet weight, including the SDD and A pH adjuster which is sodium carbonate, and the pH adjuster is about 8% by weight of the total tablet weight, including the pH adjuster and A superdisintegrant which is crospovidone, and the superdisintegrant is about 17% by weight of the total tablet weight, including the superdisintegrant and An MCC, which is a filler, and the filler is about 49.5% by weight of the total tablet weight, including the filler.

[0078] One embodiment is a tablet composition, and the composition is An SDD of about 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-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 Ca0.5 hydrate, the balance of the SDD is composed of PVP-VA, and the SDD is about 21% by weight of the total tablet weight, including the SDD and A pH adjuster which is sodium carbonate, and the pH adjuster is about 8% by weight of the total tablet weight, including the pH adjuster and Crospovidone, a superdisintegrant, wherein the superdisintegrant is about 17% by weight of the total tablet weight, and the superdisintegrant, MCC, a filler, wherein the filler is about 53.5% by weight of the total tablet weight, and the filler.

[0079] One embodiment is a tablet composition, and the composition is, About 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-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 Ca0.5 hydrate SDD, wherein the balance of the SDD is composed of PVP-VA, and the SDD is about 16.9% by weight of the total tablet weight, and the SDD, Sodium carbonate, a pH adjuster, wherein the pH adjuster is about 8% by weight of the total tablet weight, and the pH adjuster, Crospovidone, a superdisintegrant, wherein the superdisintegrant is about 10% by weight of the total tablet weight, and the superdisintegrant, MCC, a filler, wherein the filler is about 64.6% by weight of the total tablet weight, and the filler.

[0080] One embodiment is a tablet composition, and the composition is, The SDD of about 30% by weight 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 Ca0.5 hydrate, the remainder of the SDD being composed of PVP-VA, and the SDD being about 11.8% by weight of the total tablet weight, the SDD, and Sodium carbonate as a pH adjuster, the pH adjuster being about 8% by weight of the total tablet weight, the pH adjuster, and Crospovidone as a superdisintegrant, the superdisintegrant being about 10% by weight of the total tablet weight, the superdisintegrant, and MCC as a filler, the filler being about 69.7% by weight of the total tablet weight, the filler, and comprising.

[0081] One embodiment is a tablet composition, and the composition The SDD of about 30% by weight 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 Ca0.5 hydrate, the remainder of the SDD being composed of PVP-VA, and the SDD being about 9.8% by weight of the total tablet weight, the SDD, and Sodium carbonate as a pH adjuster, the pH adjuster being about 8% by weight of the total tablet weight, the pH adjuster, and Crospovidone as a superdisintegrant, the superdisintegrant being about 10% by weight of the total tablet weight, the superdisintegrant, and An MCC, which is a filler, and the filler is about 71.7% by weight of the total tablet weight, including the filler.

[0082] One embodiment is a tablet composition, and the composition is The SDD of about 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-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 Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is about 3.9% by weight of the total tablet weight, including the SDD and A pH adjuster which is sodium carbonate, and the pH adjuster is about 8% by weight of the total tablet weight, including the pH adjuster and A superdisintegrant which is crospovidone, and the superdisintegrant is about 10% by weight of the total tablet weight, including the superdisintegrant and An MCC, which is a filler, and the filler is about 77.6% by weight of the total tablet weight, including the filler.

[0083] One embodiment is a tablet composition, and the composition is The SDD of about 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-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 Ca0.5 hydrate, the remainder of the SDD is composed of PVP-VA, and the SDD is about 3.2% by weight of the total tablet weight, including the SDD and A pH adjuster which is sodium carbonate, and the pH adjuster is about 8% by weight of the total tablet weight, including the pH adjuster and A superdisintegrant that is crospovidone, wherein the superdisintegrant is about 10% by weight of the total tablet weight, and the superdisintegrant, A filler that is MCC, wherein the filler is about 78.3% by weight of the total tablet weight, and the filler.

[0084] One embodiment is a tablet composition, and the composition is The SDD of about 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-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 Ca0.5 hydrate, the balance of the SDD is composed of PVP-VA, and the SDD is about 2.7% by weight of the total tablet weight, the SDD, A pH adjuster that is sodium carbonate, wherein the pH adjuster is about 8% by weight of the total tablet weight, and the pH adjuster. A superdisintegrant that is crospovidone, wherein the superdisintegrant is about 10% by weight of the total tablet weight, and the superdisintegrant, A filler that is MCC, wherein the filler is about 78.8% by weight of the total tablet weight, and the filler.

[0085] One embodiment is a tablet composition, and the composition is The SDD of about 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-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 Ca0.5 hydrate, with the balance of the SDD being composed of PVP-VA, and the SDD being about 2.0% by weight of the total tablet weight, and the A pH adjuster which is sodium carbonate, and the pH adjuster is about 8% by weight of the total tablet weight, and the pH adjuster, and the A superdisintegrant which is crospovidone, and the superdisintegrant is about 10% by weight of the total tablet weight, and the superdisintegrant, and the A filler which is MCC, and the filler is about 79.5% by weight of the total tablet weight, and the filler, and it contains.

[0086] One embodiment is the above tablet composition, and the composition further contains a lubricant which is magnesium stearate, and the lubricant is about 0.5% by weight of the total tablet weight, and the lubricant.

[0087] One embodiment is the above composition, and the composition further contains an immediate release coating.

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

[0089] Pharmaceutical compositions using amorphous forms of active substances are prepared using spray-dried dispersions (SDDs) for developing dosage forms of poorly soluble drugs. However, this SDD approach is complicated by the presence of polymeric functional excipients that may be required to maintain the drug in an amorphous state. Compositions that provide acceptable pharmacokinetic performance and desirable meal effect characteristics can be particularly difficult for molecules with strongly pH-dependent solubility characteristics. GLP1RA and GLP1RA-Ca exhibit such pH-dependent solubility characteristics. Weak acids can pose challenges in ensuring the elution of the active substance in the desired portions of the gastrointestinal tract, particularly the stomach, where low pH can delay the elution of weakly acidic drugs. Certain excipients may become unstable when added to the tablet compositions described herein. In certain embodiments, the excipient is stable in a tablet composition containing a pH adjuster.

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

[0091] In certain embodiments, the GLP1RA or pharmaceutically acceptable salt composition comprises a pH adjuster that is sodium carbonate. In certain embodiments, the GLP1RA or pharmaceutically acceptable salt composition comprises a pH adjuster that is anhydrous sodium carbonate.

[0092] Certain embodiments are compositions comprising a 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 a 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 a GLP1RA or a pharmaceutically acceptable salt thereof and a pH adjuster is uncoated.

[0095] In one embodiment, the tablet composition is prepared as an immediate release (IR) dosage form that releases the GLP1RA or a pharmaceutically acceptable salt thereof in the gastric compartment. An excess amount of the pH adjuster in the tablet may affect the absorption of a co-administered drug whose absorption is pH-sensitive. In one embodiment, the pH adjuster is in a sufficiently low amount such that it does not increase the pH of the entire stomach during dissolution but is sufficient to promote the dissolution of the GLP1RA or a pharmaceutically acceptable salt thereof. An immediate release dosage form with a sufficiently low amount of the pH adjuster may be desirable to minimize the potential for an increase in gastric pH and drug-drug interaction (DDI) with a co-administered drug.

[0096] In one embodiment, the tablet composition comprising a 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 that is primarily intended for aesthetic purposes and is 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, such as, but not limited to, Opadry® Clear (03K19229) (Colorcon Inc). As is common in moisture-sensitive SDD-based formulations, protection from moisture may be desired to ensure the functionality and appearance of the product over its shelf life. This protection can be achieved by packaging and by the use of coating materials to minimize the tablet's moisture absorption. One known immediate release coating having this functionality is Opadry® ambII (Colorcon).

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

[0099] In certain embodiments, a tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof and a pH adjuster is prepared as a delayed release (DR) dosage form further comprising an enteric coating. Compositions further comprising an enteric coating can be released in the intestine at a pH of 5.5 or greater. Release in the intestine may be desirable for the GLP1RA or a pharmaceutically acceptable salt thereof to limit the risks potentially associated with the presence of a pH regulator in the tablet. The DR composition can minimize the potential impact of diet and can have other favorable effects on the pharmacokinetic profile, such as, but not limited to, the regulation of total exposure and Cmax.

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

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

[0102] One embodiment is a tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof, a pH adjuster, and a superdisintegrant.

[0103] One embodiment is a tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof, a pH adjuster, a superdisintegrant, and a lubricant.

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

[0105] One embodiment is a tablet composition comprising a 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 "superdisintegrant" and "disintegrant" are interchangeable and mean excipients for facilitating the desired elution of GLPRA or a pharmaceutically acceptable salt thereof, including but not limited to croscarmellose sodium and crospovidone. The term "superdisintegrant" preferably refers to an excipient that promotes the elution of GLP1RA or a pharmaceutically acceptable salt thereof within 30 to about 60 minutes. In certain embodiments, the tablet composition comprises a GLP1RA or a pharmaceutically acceptable salt thereof, a pH adjuster, and a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

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

[0108] In certain embodiments, the desired tablet composition provides reliable PK performance in a dosage form that is easy for the patient to take. The dosage form of the tablet composition that is easy for the patient to take facilitates swallowing during daily administration, has minimal potential for drug-drug interactions (DDIs) with other co-administered drugs, minimizes the effect of food, avoids restrictions on administration time, and has minimal use restrictions such as avoiding restrictions on the amount of liquid used to assist swallowing, and desirably has an acceptable size.

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

[0110] Certain abbreviations are defined as follows: "cfm" refers to cubic feet per minute, "Cmax" refers to the maximum plasma concentration achieved by a drug in the test area after drug administration and before the second administration, "DDI" refers to drug-drug interaction, "DR" refers to delayed release, "EtOH" refers to ethanol or ethyl alcohol, "FaSSiF" refers to fasted-state simulated intestinal fluid, "FaSSGF" refers to fasted-state simulated gastric fluid, "FeSSIF" refers to fed-state simulated intestinal fluid, "hr" refers to hour, "hrs" refers to hours, "IR" refers to immediate release, "PK" refers to pharmacokinetics, "MeOH" refers to methanol or methyl alcohol, "rpm" refers to revolutions per minute, "PVP-VA" refers to polyvinylpyrrolidone / vinyl acetate copolymer, "SDD" refers to spray-dried dispersion, "SIF" refers to simulated 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] One skilled in the art can prepare a spray-dried dispersion (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-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, 0.5Ca using various apparatuses under various processing conditions to produce a substance with suitable quality and important characteristics.

[0112] In certain embodiments, the GLP1RA or GLP1RA-Ca in the SDD preparation is amorphous with a desired weight percentage of drug (30%) and PVP-VA (70%) as measured by XRPD, has a particle size that allows for isolation and forward processing, and contains process-related impurities and excessive residual solvents to an acceptable extent.

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

[0114] Capsules are prepared for the assays 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-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 Ca0.5 hydrate

[0116]

Chemical formula

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

[0118] The title compound has an alias. For example, it is also known as the hemicalcium salt hydrate of orfoglipron.

[0119] Another name for the title compound is 1,2,4-oxadiazol-5(2H)-one, 3-[(1S,2S)-1-[2-[[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2,3-dihydro-2-oxo-1H-imidazol-1-yl]-2,4,6,7-tetrahydro-4-methyl-5H-pyrazolo[4,3-c]pyridin-5-yl]carbonyl]-5-[(4S)-tetrahydro-2,2-dimethyl-2H-pyran-4-yl]-1H-indol-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-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 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-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 Ca0.5 SDD is prepared by dissolving 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-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 Ca0.5 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 dissolution of the solids, the solution is spray dried in a conventional spray dryer equipped with a pressure nozzle. The following parameters in Table 1 are used for the preparation of the dispersion using a laboratory scale spray dryer. Spray drying can be started when the spray dryer temperature exceeds 33 °C. The material is collected and dried under vacuum at 50 °C overnight to obtain the title compound (21.99 g, 7.0 g, potency 92%, recovery 80%), and it is observed by optical microscopy that the material is microscopically non-birefringent particles with a diameter of about 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-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 Ca0.5 hydrate Dissolve 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-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 Ca0.5 hydrate in MeOH-modified EtOH (5% v / v or w / w). A 20% w / w solid solution is prepared with a 30% w / w (on free acid basis) solid fraction consisting of the title compound and the remainder consisting of PVP-VA. This is interpreted as 6% of the title compound (on free acid basis), 14% PVP-VA, and 80% modified EtOH SDA-3A (all fractions as w / w). After spray drying, the solid formed consists of 30% w / w (on free acid basis) of the solid fraction consisting of the title compound and the remainder consisting of PVP-VA. The % 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 upon entry. The heated drying gas enters in co-current flow with the atomized liquid at the top of the spray drying chamber at a spray solution to drying gas ratio of approximately 0.044 kg / kg. The inlet temperature is adjusted to provide an outlet temperature of 35 - 45 °C. The solids formed in the spray dryer are recovered from the cyclone and the filter housing on the gas stream. The solvent is removed by passing the gas through a condenser maintained at -3 °C (down to a dew point of -3 °C). The gas is then heated back 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-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 Ca0.5 hydrate Capsule formulation First, capsules are prepared by adding sodium bicarbonate (600 mg) to size 0 hypromellose capsules, followed by the SDD of Preparation 3 (54 mg).

[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-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 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-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 Ca0.5 hydrate (13.3% w / w) and the excipients except magnesium stearate (described in Examples 1 to 7) 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 about 10 minutes. The mixture blend is passed through a sieve (600 μm) and mixed twice using a mixer at 32 rpm for about 10 minutes each time Mix. Add magnesium stearate and mix the mixture at 32 rpm for about 3 minutes. Compress the mixture blend on a single-station tablet press using a 14.10 × 7.75 mm elliptical tablet tool to produce tablets (400.0 mg) having a hardness of 30 kP

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

[0143] Immediate Release Coating of Examples 1 to 7 Immediate Release Tablets Coating The core tablet compositions prepared substantially as described by each of Examples 1 to 7 are film-coated to a target increase of 3% by weight of an immediate-release coating such as Opadry® Clear (03K19229) (Colorcon Inc) (tolerance range 2.5 to 3.5 percent). The tablets are coated using water as the base of the spray suspension with a conventional pan-coating apparatus and coating conditions recommended by the vendor. Compositions of Examples 1 to 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 substantially as described above with Opadry® Clear. The tablets coated with Opadry® Clear are further enteric-coated to a target increase of 6.75% by weight using Acryl-EZE® (93A18597) (Colorcon Inc) and PEG8000 as a plasticizer at 8% by weight relative to Acryl-EZE (tolerance range 6.25 to 7.25 percent). The tablets are coated using water as the base of the spray suspension with a conventional pan-coating apparatus and coating conditions recommended by the vendor.

[0145] Example 9 Enteric-coated tablet composition - An enteric-coated tablet is prepared using a tablet composition substantially as described in Examples 1 to 6, except that the weight percentage of sodium carbonate is adjusted and the microcrystalline cellulose content is adjusted. The tablets are coated in a spray suspension with 8% solids by weight to a target weight gain of 3% with Opadry® 03K19229 (Colorcon Inc.). A bench-top pan coater is used to coat the tablets with a spray nozzle spray gun with a 0.8 mm orifice equipped with an AntiBearding Cap, an inlet air flow 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 enteric-coated to a target weight percentage increase of approximately 6.5% with Acryl-EZE 93A18597 (Colorcon Inc.) using the same apparatus. An aqueous suspension is prepared with 20% Acryl-EZE powder having 8% by weight of PEG-8000 as a plasticizer for Acryl-EZE. The coating conditions are as follows. A spray nozzle spray gun with a 0.8 mm orifice equipped with an AntiBearding Cap, an inlet air flow 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 Alternative tablet composition containing croscarmellose sodium superdisintegrant

[0149] [Table 13]

[0150] Example 12 Alternative tablet composition superdisintegrant containing crospovidone

[0151]

Table 14

[0152] The tablet composition is prepared using these superdisintegrants according to the formulations as shown in Tables 11 and 12. Add all materials except magnesium stearate to a brown glass bottle and mix at 22 rpm for 10 minutes using a rotary diffusion mixer. Pass the blend through a #35 mesh screen and then mix for an additional 10 minutes. Pass magnesium stearate through a #35 mesh, add it to the bottle, and mix for 5 minutes. Compress the blend using a single-station tablet press with a compression force of 6 kN and a modified elliptical tool. Core tablets are coated to a target weight gain of 3% with Opadry® 03K19229 (Colorcon Inc.) using 8% solids in a spray suspension. Coat the tablets using a bench-top pan coater with a spray nozzle spray gun with an 0.8 mm orifice with AntiBearding Cap, an inlet air flow 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. Then, coat the tablets to a target weight % gain of 6.5% with Acryl-Eze 93A18597 (Colorcon Inc.) using the same apparatus. Prepare an aqueous suspension with 20% Acryl-EZE powder having 8% by weight of PEG-8000 as a plasticizer relative to Acryl-EZE. The coating conditions are as follows. Spray nozzle spray gun with an 0.8 mm orifice with AntiBearding Cap, an inlet air flow 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.

[0153] Example 13 Tablets with a total weight of 400 mg of the tablet composition Prepare the total weight tablets (400 mg) using the ratios in Table 14. Prepare the tablets and coat them with an immediate release coating and then an enteric coating substantially as described in Example 9.

[0154] [Table 15]

[0155] Example 14 Tablet compositions 9 - 30 Prepare the core tablet compositions 9 - 30 (Comp. 9 - Comp. 30) using the ratios in the following table and the method described above. The core tablets can be prepared and coated with an immediate release coating and 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 SDD 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. The volume - based distribution was measured and the (D10, D50, D90) quantiles were reported.

[0159] The SDD of Preparations 2 and 3 has an average particle size with a diameter measured by the above method of about 40 - about 65 μm, or more specifically about 40 - about 50 μm.

[0160] Solubility test Water solubility of crystalline GLP1RA-Ca at 25°C for 24 hours

[0161]

Table 17

[0162] An embodiment of the present invention is an oral tablet formulation containing an amorphous SDD of GLP1RA-Ca. The crystalline form of GLP1RA-Ca has low water solubility as shown in Table 15. The 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 can be seen in Tables 16 and 17, Preparation 3 has pH-dependent solubility. When the pKa is 5.1, the solubility of the drug begins to increase 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 the SDD and a sufficient amount of sodium bicarbonate to raise the pH of the acidic dissolution medium to near the pKa were evaluated in a dissolution experiment compared to tablets containing much less pH adjuster. The quantitative formulations are shown in Table 11 for tablets and Table 3 for capsules.

[0166] Formulation dissolution test The formulation is evaluated in a two-stage dissolution test consisting of a 1-hour acid stage (500 mL of 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 fasting state intestinal fluid. For the preparation of each 1 L of concentrated FaSSiF, sodium phosphate dibasic anhydrous (5.714 g), sodium phosphate monobasic anhydrous (2.906 g), and NaCl (12.354 g) are added with water to make 1 L and mixed well. The pH should be approximately 7.0. Add SIF powder (5.6 g) (FaSSIF / FeSSIF / FaSSGF powder (Biorelevant)).

[0167] The test is conducted at 100 rpm using a USP II dissolution apparatus. A portion is removed, filtered through a 0.22 micrometer filter, diluted 1:1 with MeOH to prevent precipitation of the drug, and analyzed by HPLC.

[0168] Surprisingly, although the capsule formulation increased the pH in the medium above 5 by a large amount of sodium bicarbonate and the tablet did not affect the pH of the medium and remained at pH 2, the IR tablets were found to function better at the gastric stage than the capsule formulation.

[0169]

Table 20

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

[0171] Surprisingly, despite the presence of a significant amount of sodium bicarbonate that should promote elution from the SDD capsules, the IR tablets again released faster than the capsules here, achieving 100% release within 30 minutes, while the capsules achieved only 35% release in 30 minutes and did not achieve more than 90% release until about 75 minutes.

[0172]

Table 21

[0173]

Table 22

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

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

[0176]

Table 23

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

[0178] Surprisingly, croscarmellose sodium used in Example 11 was unable to provide the desired release characteristics, while crospovidone used in Example 12 was found to provide the desired release characteristics.

[0179]

Table 24

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

[0181] Controlled release from tablets is often achieved using rate-controlling polymers such as hypromellose, such as in hydrophilic sustained-release matrix tablets. The problem 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 is released gradually over a long time without maximizing the drug concentration in the intestinal lumen, the flux through the intestinal epithelium can decrease and subsequent absorption can be reduced.

[0182] Surprisingly, it has been found that by controlling the amount of superdisintegrant in the enteric-coated dosage form, a significant degree of control over the release rate can be achieved over a desired complete release time within 30 minutes.

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

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

[0185] [Table 25]

[0186] Another means of regulating drug release from enteric-coated tablets is to vary the amount of sodium carbonate. The tablets are subjected to dissolution in a pH 6.8 phosphate buffer containing 2% sodium lauryl sulfate as described herein. The results of this study demonstrate that there is a synergistic effect between the level of disintegrant and the amount of pH adjuster that can be used to control drug release from the tablets. Further, the release is controlled within a desired range of from within 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 A repeated ascending dose study was conducted to characterize and compare the pharmacokinetics (PK) of prototype formulations of Preparation 4 (capsules), Example 1 (DR tablet composition T1 with an enteric coating prepared as in Example 9, hereinafter referred to as T1 DR tablets), and Example 7 (IR tablet composition E with an immediate release coating, hereinafter referred to as E IR tablets). The study was conducted in two parts, A and B.

[0189] Part A evaluated the safety, tolerability, and PK of repeated oral administrations of GLP1RA formulation prototypes T1 and E in healthy participants, compared to the reference capsule preparation 4. The dose escalation period was from day 1 to day 18, and participants were administered increasing amounts of GLP1RA in the capsules for dose escalation. The within-treatment 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 the reference capsule preparation 4 (16 mg QD), and then entered the test phase from days 25 to 36. During test period 1, participants were randomized to receive the GLP1RA prototype tablet (16 mg QD) formulation. The participants were then crossovered on day 31 of period 2 and received the second prototype tablet (16 mg QD) until day 36.

[0190]

Table 27

[0191] The results of Part A showed that the mean peak and total exposure levels (measured by Cmax and AUC(0-24)) of the 16 mg DR tablet T1 were approximately 67% and 50% higher, respectively, than those of the 16 mg reference preparation 4 capsules. 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 tablet, the mean peak and total exposure levels (measured by Cmax and AUC(0-24)) were approximately 47% and 41% higher, respectively, 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 tablet E IR tablets with respect to the effects of food and the DDI effect with co - administered proton pump inhibitors (PPIs). Similar to Part A, the escalating treatment was performed every 6 days during the escalation period and reached a maximum dose of 16 mg QD on day 19. Then, treatment was advanced in the fasting or fed state using GLP1RA and in the fasting state with co - administered PPI. Each option started with a 6 - day reference period (16 mg QD) using tablet E IR tablets as a reference, followed by two 6 - day test periods (16 mg QD).

[0194]

Table 28

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

[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 of the embodiments and further embodiments thereof, in addition to those shown and described herein, will be apparent to those skilled in the art from the entire contents of this specification.

Claims

1. A tablet composition 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-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, the tablet composition.

2. The composition according to claim 1, wherein 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.

3. The composition according to claim 2, 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, magnesium hydroxide, and anhydrous magnesium hydroxide.

4. The composition according to claim 3, wherein the pH adjuster is anhydrous.

5. The composition according to claim 3, wherein the pH adjuster is sodium carbonate.

6. The composition according to claim 5, wherein the pH adjuster is anhydrous sodium carbonate.

7. The composition further 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-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; a pH adjuster; and a superdisintegrant, the composition according to any one of claims 1 to 6.

8. The composition according to claim 7, wherein the superdisintegrant is selected from the group consisting of croscarmellose sodium and crospovidone.

9. The composition according to claim 8, wherein the superdisintegrant is crospovidone.

10. The composition further comprises: 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, a pH adjuster, a superdisintegrant, and a lubricant, the composition according to any one of claims 1 to 9.

11. The composition according to claim 10, wherein the lubricant is magnesium stearate.

12. The composition according to any one of claims 1 to 11, further comprising an immediate release coating.

13. The composition according to any one of claims 1 to 12, further comprising an enteric coating.

14. The 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 salt is 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 Ca0.5 hydrate, the composition according to any one of claims 1 to 13.

15. The compound 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, The composition according to any one of claims 1 to 14, which is 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 Ca0.5 hydrate and is said compound in an amount of about 0.7 to about 50 mg on a free acid basis per tablet composition.

16. The composition according to claim 15, wherein the 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 Ca0.5 hydrate is in an amount of about 48 mg per tablet.

17. The composition according to any one of claims 1 to 16 for use in the treatment of type 2 diabetes.

18. The composition according to any one of claims 1 to 16 for use in weight management.

19. A process for preparing the tablet composition according to any one of claims 1 to 16, comprising a 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-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.

20. The process according to claim 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-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, further comprises a PVP-VA polymer.

21. A tablet composition, wherein the composition comprises an amount of from about 0.5 mg to about 75 mg, on a free acid basis, 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-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 selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof, in an amount of from about 1 mg to about 150 mg, and a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of from about 1 mg to about 250 mg A lubricant which is magnesium stearate in an amount of about 0.1 mg to about 10 mg, and A tablet composition comprising the same.

22. 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-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, in an amount of about 0.7 mg to about 60 mg based on the free acid, A pH adjuster 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 2 mg to about 100 mg, A superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone, in an amount of about 2 mg to about 200 mg, A lubricant which is magnesium stearate in an amount of about 0.1 mg to about 2.5 mg, and The tablet composition according to claim 21, comprising the same.

23. A tablet composition, wherein the composition 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-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, A pH adjuster, and a tablet composition comprising the same.

24. The composition is An SDD of about 30% to about 35% by weight 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, in an amount of about 0.5 mg to about 75 mg on a free acid basis, the balance of said SDD being composed of PVP-VA, an SDD, and a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate in an amount of about 1 mg to about 150 mg, and The tablet composition according to claim 23, comprising.

25. The composition is An SDD of about 30% to about 35% by weight 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 the Ca0.5 hydrate thereof, in an amount of about 0.7 mg to about 60 mg on a free acid basis, the balance of said SDD being composed of PVP-VA, an SDD, and a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate in an amount of about 5 mg to about 100 mg, and The tablet composition according to any one of claims 23 to 24, comprising.

26. The composition is About 30% by weight 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 its Ca0.5 hydrate SDD, in an amount of about 1.7 mg to about 250 mg, the remainder of the SDD being composed of PVP-VA, the SDD being about 2% to about 25% by weight of the total tablet weight, the SDD, Sodium carbonate as the pH adjuster, in an amount of about 6 mg to about 100 mg, the pH adjuster being about 5% to about 15% by weight of the total tablet weight, the pH adjuster, comprising the tablet composition according to claim 24.

27. The composition is About 30% by weight 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 Ca0.5 hydrate SDD, in an amount of about 1.7 mg to about 14.3 mg of the SDD, the remainder of the SDD being composed of PVP-VA, the SDD being about 2% to about 16.9% by weight of the total tablet weight, the SDD, A pH adjuster which is sodium carbonate in an amount of about 6.8 mg, the pH adjuster being about 8% by weight of the total tablet weight, the pH adjuster, Comprising the tablet composition according to claim 26.

28. The composition is About 30% by weight 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 Ca0.5 hydrate SDD, in an amount of about 16.7 mg to about 120 mg of the SDD, the balance of the SDD being composed of PVP-VA, the SDD being about 19.5% by weight of the total tablet weight, the SDD, A pH adjuster which is sodium carbonate in an amount of about 6.8 mg to about 49.2 mg, the pH adjuster being about 8% by weight of the total tablet weight, the pH adjuster, The tablet composition according to claim 26, comprising.

29. The composition being, About 30% by weight 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 Ca0.5 hydrate SDD, in an amount of about 150 mg to about 250 mg of the SDD, the balance of the SDD being composed of PVP-VA, the SDD being about 21% to about 25% by weight of the total tablet weight, the SDD, A pH adjuster which is sodium carbonate in an amount of about 57.1 mg to about 80 mg, the pH adjuster being about 8% by weight of the total tablet weight, the pH adjuster, The tablet composition according to claim 26, comprising.

30. The SDD having an average particle size of about 5 μm to about 113 μm, The tablet composition according to any one of claims 21 to 29, wherein the pH adjuster is sodium carbonate.

31. The composition being, The tablet composition according to claim 30, further comprising a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

32. The tablet composition according to claim 31, wherein the superdisintegrant is crospovidone in an amount of about 8.5 mg to about 170 mg, and the superdisintegrant is about 10% to about 17% by weight of the total tablet weight.

33. The composition further comprises a filler which is MCC, in an amount of about 67 mg to about 495 mg, and the filler is about 49.5% to about 79.5% by weight of the total tablet weight. The tablet composition according to claim 32.

34. The composition further comprises a lubricant which is magnesium stearate, in an amount of about 0.4 mg to about 5 mg, and the lubricant is about 0.1% to about 1% by weight of the total tablet weight. The tablet composition according to claim 33.

35. The composition further comprises a SDD of about 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-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 Ca0.5 hydrate, the balance of the SDD being composed of PVP-VA, and the SDD is about 19.5% by weight of the total tablet weight, an a pH adjuster which is sodium carbonate, and the pH adjuster is about 8% by weight of the total tablet weight, a pH adjuster, a superdisintegrant which is crospovidone, and the superdisintegrant is about 17% by weight of the total tablet weight, a superdisintegrant, a filler which is MCC, and the filler is about 55% by weight of the total tablet weight, a filler, comprising the tablet composition according to claim 26.

36. The composition further comprises a About 30% by weight 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 Ca0.5 hydrate SDD, wherein the balance of the SDD is composed of PVP-VA and the SDD is about 25% by weight of the total tablet weight, an SDD, and A pH adjuster which is sodium carbonate, wherein the pH adjuster is about 8% by weight of the total tablet weight, a pH adjuster, and A superdisintegrant which is crospovidone, wherein the superdisintegrant is about 17% by weight of the total tablet weight, a superdisintegrant, and A filler which is MCC, wherein the filler is about 49.5% by weight of the total tablet weight, a filler, and The tablet composition according to claim 26, comprising.

37. The composition is About 30% by weight 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 Ca0.5 hydrate SDD, wherein the balance of the SDD is composed of PVP-VA and the SDD is about 21% by weight of the total tablet weight, an SDD, and A pH adjuster which is sodium carbonate, wherein the pH adjuster is about 8% by weight of the total tablet weight, a pH adjuster, and A superdisintegrant which is crospovidone, wherein the superdisintegrant is about 17% by weight of the total tablet weight, a superdisintegrant, and A filler which is MCC, wherein the filler is about 53.5% by weight of the total tablet weight, a filler, and The tablet composition according to claim 26, comprising.

38. The composition is An SDD of about 30% by weight 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 Ca0.5 hydrate, wherein the balance of the SDD is composed of PVP-VA and the SDD is about 16.9% by weight of the total tablet weight, the SDD, and A pH adjuster which is sodium carbonate, wherein the pH adjuster is about 8% by weight of the total tablet weight, the pH adjuster, and A superdisintegrant which is crospovidone, wherein the superdisintegrant is about 10% by weight of the total tablet weight, the superdisintegrant, and A filler which is MCC, wherein the filler is about 64.6% by weight of the total tablet weight, the filler, and The tablet composition according to claim 26, comprising.

39. The composition is An SDD of about 30% by weight 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 Ca0.5 hydrate, wherein the balance of the SDD is composed of PVP-VA and the SDD is about 11.8% by weight of the total tablet weight, the SDD, and A pH adjuster which is sodium carbonate, wherein the pH adjuster is about 8% by weight of the total tablet weight, the pH adjuster, and A superdisintegrant which is crospovidone, wherein the superdisintegrant is about 10% by weight of the total tablet weight, the superdisintegrant, and A filler which is MCC, wherein the filler is about 69.7% by weight of the total tablet weight, the filler, and The tablet composition according to claim 26, comprising.

40. The composition is An SDD of about 30% by weight 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 Ca0.5 hydrate, wherein the balance of the SDD is composed of PVP-VA and the SDD is about 9.8% by weight of the total tablet weight, the SDD, and A pH adjuster which is sodium carbonate, wherein the pH adjuster is about 8% by weight of the total tablet weight, the pH adjuster, and A superdisintegrant which is crospovidone, wherein the superdisintegrant is about 10% by weight of the total tablet weight, the superdisintegrant, and A filler which is MCC, wherein the filler is about 71.7% by weight of the total tablet weight, the filler, and The tablet composition according to claim 26, comprising.

41. The composition being An SDD of about 30% by weight 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 Ca0.5 hydrate, wherein the balance of the SDD is composed of PVP-VA and the SDD is about 3.9% by weight of the total tablet weight, the SDD, and A pH adjuster which is sodium carbonate, wherein the pH adjuster is about 8% by weight of the total tablet weight, the pH adjuster, and A superdisintegrant which is crospovidone, wherein the superdisintegrant is about 10% by weight of the total tablet weight, the superdisintegrant, and A filler which is MCC, wherein the filler is about 77.6% by weight of the total tablet weight, the filler, and The tablet composition according to claim 26, comprising.

42. The composition being About 30% by weight 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 Ca0.5 hydrate SDD, wherein the balance of the SDD is composed of PVP-VA, and the SDD is about 3.2% by weight of the total tablet weight, SDD, and A pH adjuster which is sodium carbonate, wherein the pH adjuster is about 8% by weight of the total tablet weight, pH adjuster, and A superdisintegrant which is crospovidone, wherein the superdisintegrant is about 10% by weight of the total tablet weight, superdisintegrant, and A filler which is MCC, wherein the filler is about 78.3% by weight of the total tablet weight, filler, and The tablet composition according to claim 26, comprising.

43. The composition is About 2.7% by weight 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 Ca0.5 hydrate SDD, wherein the balance of the SDD is composed of PVP-VA, and the SDD is about 2.7% by weight of the total tablet weight, SDD, and A pH adjuster which is sodium carbonate, wherein the pH adjuster is about 8% by weight of the total tablet weight, pH adjuster, and A superdisintegrant which is crospovidone, wherein the superdisintegrant is about 10% by weight of the total tablet weight, superdisintegrant, and A filler which is MCC, wherein the filler is about 78.8% by weight of the total tablet weight, filler, and The tablet composition according to claim 26, comprising.

44. The composition is The SDD of about 30% by weight 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 Ca0.5 hydrate, wherein the balance of the SDD is composed of PVP-VA, and the SDD is about 2.0% by weight of the total tablet weight, and the SDD, A pH adjuster which is sodium carbonate, and the pH adjuster is about 8% by weight of the total tablet weight, and the pH adjuster, A superdisintegrant which is crospovidone, and the superdisintegrant is about 10% by weight of the total tablet weight, and the superdisintegrant, A filler which is MCC, and the filler is about 79.5% by weight of the total tablet weight, and the filler, The tablet composition according to claim 26, comprising

45. The tablet composition according to any one of claims 35 to 44, wherein the SDD has an average particle size of about 5 μm to about 113 μm.

46. The tablet composition according to any one of claims 44, wherein the SDD has an average particle size of about 40 μm to about 65 μm.

47. The tablet composition according to any one of claims 21 to 46, wherein the composition further comprises a lubricant which is magnesium stearate, and the lubricant is about 0.5% by weight of the total tablet weight.

48. The tablet composition according to claim 47, wherein the composition further comprises an immediate release coating.

49. The tablet composition according to claim 48, wherein the composition further comprises an enteric coating on the immediate release coating.

50. The composition according to any one of claims 21 to 49, for use in the treatment of type 2 diabetes.

51. The composition according to any one of claims 21 to 49, for use in weight management.

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