GLP1 pharmaceutical composition

Abstract

The present invention relates to an oral capsule 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharma- ceutically acceptable salt thereof, and a pH adjuster.

Description

[Technical Field]

[0001] The present invention relates to an oral capsule composition of the 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-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 (herein GLP1RA), 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 technology]

[0002] Diabetes mellitus is a chronic disease characterized by hyperglycemia due to 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 results in a decline in patients' health and quality of life. Effective oral treatments for managing T2D and / or for use in weight management are desirable.

[0003] GLP1RA, i.e., 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, is described and claimed in U.S. Patent No. 10,858,356, which 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-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 Ca sesquihydrate (herein "GLP1RA-Ca"), which has the following structure:

[0005] [ka]

[0006] GLP1RA is a weak acid with low permeability and low solubility, with a pKa of 5.1. GLP1RA and its pharmaceutically acceptable salts have very low water solubility in the physiological pH range and in simulated physiological fluids. GLP1RA has been observed to have a strongly pH-dependent solubility profile, which contributes to challenges such as variability in absorption, pharmacokinetic performance, and potential food effects. A capsule composition of GLP1RA, including but not limited to GLP1RA-Ca, is desired that provides reliable PK performance in a dosage form that is easy for patients to swallow, with minimal potential for drug-drug interactions, and reduced or no food effects. GLP1RA compositions that enhance the solubility and dissolution rate of the active substance in a capsule dosage form may be desirable. A pharmaceutically elegant dosage form for delivering an effective amount of active GLP1RA to a targeted portion of the gastrointestinal tract, small enough to be easily swallowed by patients, is desirable. Summary of the Invention

[0007] The compositions described herein provide desired properties. In certain embodiments, the use of a spray-dried dispersion (SDD) of GLP1RA or a pharmaceutically acceptable salt thereof together with a pH adjuster described herein contributes to the desired properties. In certain embodiments, the particular particle size of the SDD and the particular composition described provide the desired properties. In certain embodiments, the compositions disclosed herein provide desirable pharmacokinetic performance and deliver effective amounts of active GLP1RA to targeted portions of the gastrointestinal tract. In certain embodiments, disclosed herein are elegant dosage forms that are convenient for patients to take without dietary or fluid restrictions.

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

[0009] In some embodiments, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and a pH adjuster.

[0010] In one embodiment is a composition 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.

[0011] In some embodiments, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and a pH adjuster 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.

[0012] In some embodiments, the pH adjuster is sodium bicarbonate. In some embodiments, the pH adjuster is sodium carbonate.

[0013] In some embodiments, the pH adjuster is anhydrous. In some embodiments, the pH adjuster is anhydrous sodium bicarbonate. In some embodiments, the pH adjuster is anhydrous sodium carbonate.

[0014] One embodiment is a combination 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, or a pharmaceutically acceptable salt thereof; and a pH adjusting agent, wherein the pH adjusting agent is anhydrous sodium bicarbonate.

[0015] In one embodiment is a 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and a pH adjuster selected from sodium bicarbonate, anhydrous sodium bicarbonate, sodium bicarbonate hydrate, sodium carbonate, and anhydrous sodium carbonate.

[0016] In one embodiment is a 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and a pH adjuster, wherein the pH adjuster is sodium bicarbonate.

[0017] In one embodiment is a 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-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 Ca 0.5 hydrate, and a pH adjuster, wherein the pH adjuster is sodium bicarbonate.

[0018] In one embodiment is a 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and a pH adjuster, wherein the pH adjuster is sodium carbonate.

[0019] In one embodiment, the capsule composition comprises 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one and a pH adjuster.

[0020] One embodiment is a capsule 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-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 calcium sesquihydrate in an amount of about 0.5 to about 46 mg per capsule composition.

[0021] In one embodiment is a 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-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 Ca sesquihydrate in an amount of about 46 mg per capsule composition.

[0022] In one embodiment is a process for preparing the capsule compositions disclosed herein that includes an amorphous dispersion process. In one embodiment is a process for preparing the capsule compositions claimed herein that includes a spray-dried dispersion (SDD) process.

[0023] In one embodiment, GLP1RA or a pharmaceutically acceptable salt thereof is prepared into a spray-dried dispersion (SDD) for use as the active drug in a capsule composition. In one embodiment, an SDD of GLP1RA or a pharmaceutically acceptable salt thereof is prepared under the conditions described in Example 2 or Alternative Example 2.

[0024] 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one) or GLP1RA-Ca (3-[(1 S,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 Ca hemihydrate) is present in the compositions described herein as an SDD preparation.

[0025] In general, the SDD preparations disclosed herein comprise GLP1RA or a pharmaceutically acceptable salt thereof and a polymer for maintaining the amorphous state of GLP1RA or a pharmaceutically acceptable salt thereof. In some embodiments, the polymer is selected from the group consisting of polyvinylpyrrolidone (also known as "povidone" or "PVP") and polyvinylpyrrolidone vinyl acetate (also known as "copovidone" or "PVP-VA"). In some embodiments, the polymer is PVP-VA. In some embodiments, the polymer is PVP.

[0026] In embodiments where the weight percentage of GLP1RA or a pharmaceutically acceptable salt thereof in the SDD preparation is specified, the remaining component of the SDD is a polymer selected from PVP and PVP-VA, i.e., the total weight percentage of GLP1RA or a pharmaceutically acceptable salt thereof and polymer is 100% by weight. In some embodiments, the polymer is PVP-VA. In some embodiments, the polymer is PVP. In some embodiments, small or trace amounts of processing solvent may be present in the SDD preparation.

[0027] In one embodiment, the SDD preparation comprises about 20% to about 40% by weight of GLP1RA or GLP1RA-Ca, with the remainder consisting of PVP-VA, hi one embodiment, the SDD preparation comprises about 30% by weight of GLP1RA or GLP1RA-Ca, with the remainder consisting of PVP-VA.

[0028] In one embodiment, the average particle size of the GLP1RA or GLP1RA-Ca SDD is about 5 μm to about 150 μm in diameter. In one embodiment, the average particle size of the SDD is about 5 μm to about 113 μm in diameter. In one embodiment, the average particle size of the SDD is about 40 μm to about 65 μm in diameter. In one embodiment, the average particle size of the SDD is about 40 μm to about 50 μm in diameter. In one embodiment, the average particle size of the SDD is about 5 μm to about 25 μm in diameter.

[0029] In one embodiment, the SDD preparation comprises about 20% to about 40% by weight of GLP1RA-Ca, with the remainder consisting of PVP-VA, hi one embodiment, the SDD preparation comprises about 30% by weight of GLP1RA or GLP1RA-Ca, with the remainder consisting of PVP-VA.

[0030] In one embodiment, the average particle size of the GLP1RA-Ca SDD is about 5 μm to about 150 μm in diameter. In one embodiment, the average particle size of the SDD is about 5 μm to about 113 μm in diameter. In one embodiment, the average particle size of the SDD is about 40 μm to about 65 μm in diameter. In one embodiment, the average particle size of the SDD is about 40 μm to about 50 μm in diameter. In one embodiment, the average particle size of the SDD is about 5 μm to about 25 μm in diameter.

[0031] In some embodiments, GLP1RA or a pharmaceutically acceptable salt thereof; a pH adjuster selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and mixtures thereof; optionally a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof; and optionally a glidant selected from the group consisting of colloidal silicon dioxide, talc, magnesium carbonate, and mixtures thereof.

[0032] In some embodiments, GLP1RA or a pharmaceutically acceptable salt thereof in an amount of about 0.7 mg to about 80 mg; 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 20 mg to about 800 mg; a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0.1 mg to about 400 mg; and optionally a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0 mg to about 20 mg.

[0033] In some embodiments, GLP1RA or a pharmaceutically acceptable salt thereof in an amount of about 0.7 mg to about 50 mg; a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate, in an amount of about 150 mg to about 700 mg; and a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0.1 mg to about 10 mg.

[0034] In some embodiments, GLP1RA or a pharmaceutically acceptable salt thereof in an amount of about 1 mg to about 45 mg; a pH adjuster that is sodium bicarbonate in an amount of about 150 mg to about 650 mg; a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 1 mg to about 150 mg; and a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0.1 mg to about 5 mg.

[0035] In one embodiment is the above composition, wherein 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 ("GLP1RA"), or a pharmaceutically acceptable salt thereof, is in the form of an SDD preparation.

[0036] In some embodiments, An SDD comprising about 20% to about 40% by weight of GLP1RA, or a pharmaceutically acceptable salt thereof, the remainder of the SDD being composed of a polymer selected from PVP-VA and PVP; and a pH adjusting agent, wherein the pH adjusting agent is selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, and anhydrous magnesium hydroxide.

[0037] In one embodiment, the SDD comprises about 30% to about 35% by weight of GLP1RA or a pharmaceutically acceptable salt thereof, and the remainder of the SDD is composed of PVP-VA; and The pH adjuster is a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0038] In one embodiment, the SDD comprises about 30% by weight of GLP1RA or a pharmaceutically acceptable salt thereof, the remainder being PVP-VA, and the SDD has an average particle size of about 5 μm to about 113 μm in diameter; and Sodium bicarbonate is a pH adjuster.

[0039] In some embodiments, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof; Optionally, the composition further comprises a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof.

[0040] In some embodiments, GLP1RA or a pharmaceutically acceptable salt thereof in an amount of about 0.7 mg to about 50 mg; a pH adjuster that is sodium bicarbonate in an amount of about 150 mg to about 650 mg; a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0.1 mg to about 80 mg; and optionally a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0 mg to about 5 mg.

[0041] In some embodiments, an SDD of 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, wherein the remainder of the SDD is composed of a polymer selected from PVP-VA and PVP; and a pH adjuster selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, anhydrous magnesium hydroxide, and mixtures thereof.

[0042] In some embodiments of the above composition, the SDD comprises 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, and the remainder of the SDD is composed of a polymer that is PVP-VA; The pH adjuster is selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0043] In some embodiments of the above composition, the SDD comprises 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, and the remainder of the SDD is composed of PVP-VA; and the SDD has an average particle size of about 5 μm to about 113 μm in diameter; A pH adjuster that is sodium bicarbonate.

[0044] In some embodiments of the above composition, the composition comprises: optionally a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof; Optionally, further comprising a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof.

[0045] In some embodiments, the capsule composition comprises: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.7 mg to about 50 mg based on the free acid; a pH adjuster that is sodium bicarbonate in an amount of about 150 mg to about 650 mg; optionally a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0 mg to about 200 mg; Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0 mg to about 5 mg.

[0046] In some embodiments of the above composition, the composition comprises: an 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-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 calcium pentose hydrate in an amount of about 0.7 mg to about 45 mg on a free acid basis, with the remainder of the SDD consisting of PVP-VA; a pH adjuster that is sodium bicarbonate in an amount of about 200 mg to about 650 mg; optionally a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0 mg to about 60 mg; Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0 mg to about 5 mg.

[0047] In some embodiments of the above composition, the composition comprises: 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-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 calcium pentose hydrate, in an amount of about 1 mg to about 36 mg on a free acid basis, with the remainder of the SDD consisting of PVP-VA; a pH adjuster that is sodium bicarbonate in an amount of about 200 mg to about 600 mg; optionally a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0 mg to about 60 mg; Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0 mg to about 5 mg.

[0048] In some embodiments of the above composition, the SDD has an average particle size of about 5 μm to about 113 μm in diameter.

[0049] In some embodiments of the above composition, the filler, if present, is MCC PH-102 in an amount of about 2 mg to about 25 mg; The glidant, if present, is silicone oil or silicon dioxide in an amount of from about 0.1 mg to about 5 mg.

[0050] In some embodiments, the composition comprises: 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-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 Ca hemihydrate, in an amount of about 1 mg on a free acid basis; a pH adjuster in an amount of about 200 mg, wherein the pH adjuster is sodium bicarbonate; a filler, wherein the filler is MCC PH-102, in an amount of about 40 mg to about 50 mg; a glidant that is silicone oil or silicon dioxide in an amount of about 1 mg to about 5 mg; The total weight of the composition is about 250 mg.

[0051] In some embodiments, the composition comprises: 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-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 calcium hemihydrate, in an amount of about 1 mg (free acid basis); a pH adjuster in an amount of about 200 mg, wherein the pH adjuster is sodium bicarbonate; a filler, wherein the filler is MCC PH-102, in an amount of about 44 mg; a glidant which is silicone oil or silicon dioxide in an amount of about 2.5 mg; The total weight of the composition is about 250 mg.

[0052] In some embodiments, the composition comprises: 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-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 calcium hemihydrate, in an amount of about 16 mg on a free acid basis; a pH adjuster in an amount of about 200 mg, wherein the pH adjuster is sodium bicarbonate; a filler, wherein the filler is MCC PH-102, in an amount of about 5 mg to about 10 mg; a glidant that is silicone oil or silicon dioxide in an amount of about 1 mg to about 5 mg; The total weight of the composition is about 260 mg.

[0053] In some embodiments, the composition comprises: 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-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 calcium hemihydrate, in an amount of about 16 mg (free acid basis); a pH adjuster in an amount of about 200 mg, wherein the pH adjuster is sodium bicarbonate; a filler, wherein the filler is MCC PH-102, in an amount of about 7 mg; a glidant which is silicone oil or silicon dioxide, in an amount of about 2.6 mg; The total weight of the composition is about 260 mg.

[0054] In some embodiments, the composition comprises: an SDD of about 30% by weight 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 Ca sesquihydrate in an amount of about 6 mg on a free acid basis and about 70% by weight PVP-VA in an amount of about 14 mg; a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant that is silicone oil in an amount of about 1 mg to about 10 mg.

[0055] In some embodiments, the composition comprises: an SDD of about 30 wt% 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 Ca hemihydrate in an amount of about 6 mg (free acid basis) and about 70 wt% PVP-VA in an amount of about 14 mg; a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant which is silicon oil or silicon dioxide, in an amount of about 6 mg.

[0056] In some embodiments, the composition comprises: an SDD of about 30 wt% 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 Ca hemihydrate in an amount of about 12 mg on a free acid basis and about 70 wt% PVP-VA in an amount of about 28 mg; a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant that is silicone oil in an amount of about 1 mg to about 10 mg.

[0057] In some embodiments, the composition comprises: an SDD of about 30 wt% 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 Ca hemihydrate in an amount of about 12 mg (free acid basis) and about 70 wt% PVP-VA in an amount of about 28 mg; a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant which is silicon oil or silicon dioxide, in an amount of about 6 mg.

[0058] In some embodiments, the composition comprises: an SDD of about 30 wt% 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 Ca hemihydrate in an amount of about 36 mg on a free acid basis and about 70 wt% PVP-VA in an amount of about 83 mg; a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant that is silicone oil in an amount of about 1 mg to about 10 mg.

[0059] In some embodiments, the composition comprises: an SDD of about 30 wt% 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 Ca hemihydrate in an amount of about 36 mg on a free acid basis and about 70 wt% PVP-VA in an amount of about 83 mg; a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant which is silicon oil or silicon dioxide, in an amount of about 6 mg.

[0060] In some embodiments, the composition is encapsulated in a capsule shell, which in some embodiments is an HPMC capsule shell. DETAILED DESCRIPTION OF THE INVENTION

[0061] Certain abbreviations are defined as follows: "cfm" refers to cubic feet per minute, "Cmax" refers to the maximum plasma concentration that a drug achieves in the test area after drug administration and before a second dose, "DDI" refers to a 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 time, "hrs" refers to time, "IR" refers to immediate release, "PK" refers to pharmacokinetics, and "MeOH" refers to methanol or methyl alcohol. alcohol), "rpm" refers to revolutions per minute, "PVP-VA" refers to polyvinylpyrrolide / 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 Pharmacopoeia, "wt %" refers to mass of desired material / total mass, and XRPD refers to X-ray powder diffraction. As used herein, "prep" means a preparation.

[0062] One skilled in the art can prepare spray-dried dispersion (SDD) preparations of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-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, 0.5Ca under a variety of processing conditions and using a variety of equipment to produce materials of suitable quality and key characteristics. In some embodiments, the product is amorphous with the desired weight percent drug (30%) and PVP-VA (70%) as measured by XRPD, of a particle size that allows isolation and forward processing, and is acceptably free of process-related impurities and excess residual solvent. In some embodiments, the amorphous solid dispersion can be used in the preparation process. In some embodiments, the particle size is about 5 to about 113 μm for use in preparing compositions for use in preparing compositions.

[0063] Example 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-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 calcium hemihydrate

[0064] [ka]

[0065] Example 1 can be prepared as described in WO 18 / 056453.

[0066] The title compound has other names, such as the hemicalcium salt hydrate of orforglipron.

[0067] 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.

[0068] Example 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 Ca 0.5 hydrate 30% 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 Ca 0.5 hydrate SDD is a compound containing 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4 S)-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 Ca sesquihydrate (8.7 g, titer 92%) and polyvinylpyrrolide / vinyl acetate copolymer (PVP-VA, Kollidon® VA64) (18.7 g) were dissolved in EtOH (200 mL) at room temperature. After dissolution of the solids, the solution was spray-dried using a conventional spray dryer equipped with a pressure nozzle. A dispersion with Buchi B290 / B295 was prepared using the following parameters in Table 1: Spray drying can begin when the spray dryer temperature exceeds 33° C. The material is collected and dried overnight under vacuum at 50° C. to give the title compound (21.99 g, 7.0 g, 92% titer, 80% recovery), which is observed by light microscopy to be microscopically non-birefringent particles approximately 5-25 μm in diameter.

[0069] SDD parameters

[0070] [Table 1]

[0071] Alternative Example 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 Ca 0.5 hydrate 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-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 Ca 0.5 hydrate was dissolved in methanol-denatured ethanol (5% v / v or w / w). A 20% w / w solid solution was prepared with a 30% w / w (based on the free acid) solid fraction consisting of the title compound, the remainder consisting of PVP-VA. This translates to 6% of the title compound (free acid basis), 14% PVP-VA, and 80% denatured ethanol SDA-3A (all fractions as w / w). After spray drying, the solid that forms consists of 30% w / w (free acid basis) of the solid fraction consisting of the title compound, with the remainder consisting of PVP-VA. The % values ​​are shown in Table 2 below.

[0072] Alternative Example 2 SDD Formulation

[0073] [Table 2]

[0074] A solution is prepared and pumped into a spray dryer, where it is atomized as it enters. Heated drying gas enters cocurrently 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. Solids formed in the spray dryer are collected from a cyclone as well as a filter housing above the gas stream. The gas is passed through a condenser maintained at -3°C to remove the solvent (to a dew point of -3°C). The gas is then heated to the inlet temperature and returned to the spray dryer.

[0075] Example 3 Capsule formulation 1 mg and 15 mg capsule formulations 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 calcium sesquihydrate Dispense SDD, NaHCO3, microcrystalline cellulose (MCC PH-102), and SiO2 into separate low-density polyethylene (LDPE) bags. Pass NaHCO3 and MCC PH-102 sequentially through a screen (30 mesh) into separate LDPE bags. Add ~25% of the sieved NaHCO3 to a 10 L mixing vessel. Add sieved MCC to the bag containing SDD and mix by hand for at least 2 minutes. Then add SiO2 to the MCC and SDD blend and mix by hand for at least another 2 minutes. Sift the blend through a 30 mesh screen into a vessel. Rinse the LDPE bag of blend with the remaining NaHCO3 and sieve it into a vessel through a 30 mesh screen. Blend at 20 RPM for 15 minutes. Sift the blend through a 30 mesh screen and blend again at 20 RPM for 15 minutes. The blend is filled into empty No. 0 capsule shells to the target fill weight using a semi-automatic filling machine (eg, Dott-Bonapace).

[0076] [Table 3] * As described herein, the conversion factor for GLP1RA / GLP1RA-Ca (i.e., the hemicalcium salt hydrate of GLP1RA) is assumed to be approximately 0.91. As one skilled in the art will readily appreciate, the exact conversion factor may vary slightly depending on the actual content of the hydrate.

[0077] Example 4 Capsule formulation 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3hou5-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 calcium hemihydrate (13.3% w / w) Capsule formulation First, sodium bicarbonate (600 mg) is added to a size 0 hypromellose (short for hydroxypropyl methylcellulose (HPMC)) capsule, followed by 10 mg of SDD in the capsule to prepare the capsules, resulting in capsules with an active ingredient strength of 3 mg.

[0078] In vitro dissolution test of capsules In vitro dissolution of the capsules is performed using USP Apparatus II under the following conditions: paddle speed 50 rpm for up to 60 minutes, 250 rpm from 60 to 90 minutes, 900 mL of 0.01 N hydrochloric acid held at 37°C, and the use of a basket sinker to reduce capsule buoyancy. Six replicates are tested, and samples are removed from the dissolution vessel at 10, 15, 20, 30, 45, 60, and 90 minutes, and the amount of drug dissolved relative to the label claim is determined using conventional HPLC with UV detection. The results can be found in the table below.

[0079] [Table 4]

[0080] Clinical trial results Surprisingly, despite relatively poor dissolution in 0.01 N HCl, capsules prepared with SDD and sodium bicarbonate showed an increase in both Cmax and AUC compared to capsules with SDD alone when tested in clinical trial GZGA.

[0081] [Table 5]

[0082] Example 4 Capsule formulation 3-[(1S,2S)-1-[5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3hou5-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 calcium hemihydrate

[0083] [Table 6] The amount of A GLP1RA-0.5Ca hydrate can be adjusted based on release efficacy to maintain the target concentration in the SDD. The conversion factor for GLP1RA / GLP1RA hemicalcium is approximately 0.98. B Ethanol and methanol are removed to residual levels during drying. If necessary, the amount of SDD may be adjusted to account for the assay. The total capsule fill weight is adjusted accordingly.

[0084] [Table 7] The amount of A GLP1RA-0.5Ca hydrate can be adjusted based on release efficacy to maintain the target concentration in the SDD. The conversion factor for GLP1RA / GLP1RA hemicalcium is approximately 0.98. B Ethanol and methanol are removed to residual levels during drying. If necessary, the amount of SDD may be adjusted to account for the assay. The total capsule fill weight is adjusted accordingly.

[0085] Example 5 Particle size measurement The particle size of SDD was determined by laser diffraction using wet dispersion in a Malvern Mastersizer 3000 (Malvern Instruments Ltd., UK) equipped with a Hydro MV (medium volume) liquid disperser. Optical model: Mie model, obscuration limit: 5–30%, general-purpose model. Volume-based distributions were measured, and the (D10, D50, D90) quantiles were reported.

[0086] The SDD of Example 2 and Alternative Example 2 have an average particle size of about 40 to about 65 μm, or more specifically about 40 to about 50 μm in diameter as measured by the method described above.

[0087] Manufacturing Process An amorphous solid dispersion consisting of 30% by weight of GLP1RA free acid is separately prepared using a spray-drying process. GLP1RA-Ca and PVP / VA are dissolved in a solvent mixture containing ethanol and methanol. The mixture is spray-dried at elevated temperature with a nitrogen stream to remove the solvent. This process results in the drug substance being an amorphous solid dispersion of GLP1RA-Ca in a PVP / VA matrix. The GLP1RA-Ca SDD may be dried to further reduce residual solvent levels.

[0088] For the encapsulation process, the GLP1RA-Ca SDD is filled into capsules using automated equipment as the first fill in a two-stage process. The sodium bicarbonate containing 1% silicone is filled into capsules using automated equipment as the second fill. The sodium bicarbonate containing 1% silicone is separately produced using a liquid additive blending process, such as a high-shear ring-bed mixer, a liquid-capable tumbling vessel equipped with an I-bar, continuous twin-screw wet granulation, or ribbon blending. The double powder filling method addresses powder segregation that can occur due to very low drug loadings and differences in particle size and density between the GLP1RA-Ca SDD and the sodium bicarbonate. This encapsulation process allows for batches as small as 12 capsules, while accommodating substantially larger batch sizes, including, but not limited to, more than 100,000 capsules per batch.

[0089] As an alternative encapsulation process, GLP1RA-Ca SDD may first be blended with a mixture of sodium bicarbonate and 1% silicone and then filled into capsules using automated equipment.

[0090] Although the present invention has been described in considerable detail with reference to specific aspects 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 become apparent to those skilled in the art from the full contents of this specification. The inventions described in the original claims of this application are set forth below. [1] An oral capsule 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and a pH adjuster. [2] The composition according to [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 [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 described in [2], wherein the pH adjuster is anhydrous. [5] The composition described in [2], wherein the pH adjuster is sodium bicarbonate. [6] The composition described in [5], wherein the pH adjuster is anhydrous sodium bicarbonate. [7] 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-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; The composition according to any one of [1] to [6], further comprising anhydrous sodium bicarbonate. [8] The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, The composition according to any one of [1] to [6], 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-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 Ca 0.5 hydrate. [9] The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, [8] The composition according to [8], 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-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 Ca 0.5 hydrate in an amount of about 1.2 to about 46 mg based on the free acid per capsule composition.

[10] The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, The composition of [9] 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-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 Ca 0.5 hydrate in an amount of approximately 46 mg based on the free acid per capsule.

[11] The composition according to any one of [1] to [6], wherein the amount of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof is about 1 mg to about 45 mg of the free acid per capsule.

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

[11] and

[15] to

[29] for use in treating type 2 diabetes.

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

[11] and

[15] to

[29] for use in weight management.

[14] A process for preparing the composition according to any one of [1] to

[11] , which comprises an amorphous dispersion.

[15] A composition comprising: an 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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.7 mg to about 50 mg on a free acid basis, with the remainder of the SDD consisting of PVP-VA; 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.

[16] The composition, an SDD of about 30% by weight 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.7 mg to about 45 mg on a free acid basis; a pH adjuster that is sodium bicarbonate in an amount of about 150 mg to about 650 mg; optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0 mg to about 200 mg; optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0 mg to about 5 mg;

[15] The composition according to claim 15,

[17] The composition, 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-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 calcium pentose hydrate, in an amount of about 1 mg to about 36 mg on a free acid basis, with the remainder of the SDD consisting of PVP-VA; a pH adjuster that is sodium bicarbonate in an amount of about 200 mg to about 600 mg; optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0 mg to about 60 mg; optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0 mg to about 5 mg;

[16] The composition according to

[16] .

[18] The filler is MCC PH-102 in an amount of about 2 mg to about 25 mg. the glidant is silicone oil or silicon dioxide in an amount of about 0.1 mg to about 5 mg;

[17] The composition described in

[17] .

[19] No filler is present; the glidant is silicone oil in an amount of about 0.1 mg to about 5 mg;

[17] The composition described in

[17] .

[20] The composition according to any one of

[15] to

[19] , wherein the SDD has an average particle diameter of about 5 μm to about 113 μm.

[21] The composition, 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-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 Ca hemihydrate, in an amount of about 1 mg on a free acid basis; a pH adjuster that is sodium bicarbonate in an amount of about 200 mg; a filler that is MCC PH-102 in an amount of about 40 mg to about 50 mg; a glidant that is silicone oil or silicon dioxide in an amount of about 1 mg to about 5 mg;

[17] The composition according to

[17] , wherein the total weight of the composition is about 250 mg.

[22] The composition, 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-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 calcium hemihydrate, in an amount of about 16 mg on a free acid basis; a pH adjuster that is sodium bicarbonate in an amount of about 200 mg; a filler that is MCC PH-102 in an amount of about 5 mg to about 10 mg; a glidant that is silicone oil or silicon dioxide in an amount of about 1 mg to about 5 mg;

[17] The composition according to

[17] , wherein the total weight of the composition is about 260 mg.

[23] The composition, an SDD of about 30% by weight 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 Ca sesquihydrate in an amount of about 6 mg on a free acid basis and about 70% by weight PVP-VA in an amount of about 14 mg; a pH adjuster that is sodium bicarbonate in an amount of about 600 mg; a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg;

[17] The composition according to claim 17,

[24] The composition, an SDD of about 30 wt% 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 Ca hemihydrate in an amount of about 12 mg on a free acid basis and about 70 wt% PVP-VA in an amount of about 28 mg; a pH adjuster that is sodium bicarbonate in an amount of about 600 mg; a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg;

[17] The composition according to claim 17,

[25] The composition, an SDD of about 30 wt% 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 Ca hemihydrate in an amount of about 36 mg on a free acid basis and about 70 wt% PVP-VA in an amount of about 83 mg; a pH adjuster that is sodium bicarbonate in an amount of about 600 mg; a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg;

[17] The composition according to claim 17,

[26] The composition according to any one of

[21] to

[25] , wherein the SDD has an average particle diameter of about 5 μm to about 113 μm.

[27] The composition according to

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

[28] The composition according to

[27] , wherein the composition is within a capsule shell.

[29] The composition described in

[28] , wherein the capsule shell is an HPMC capsule shell.

Claims

1. 1. A solid oral capsule composition comprising: a spray-dried dispersion (SDD) of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; 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; 1. A solid oral capsule composition comprising:

2. 10. The composition of claim 1, 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.

3. The composition described in claim 1, wherein the pH adjuster is anhydrous.

4. The composition of claim 1 , wherein the pH adjuster is sodium bicarbonate.

5. 5. The composition of claim 4, wherein the pH adjuster is anhydrous sodium bicarbonate.

6. The composition comprises: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, and anhydrous sodium bicarbonate.

7. 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, The composition of claim 1, 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-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 Ca 0.5 hydrate.

8. 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, 8. The composition of claim 7, wherein the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-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 Ca hemihydrate in an amount of about 1.2 to about 46 mg on a free acid basis per capsule composition.

9. The compound according to claim 1, wherein the 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, 10. The composition of claim 8, wherein the composition is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-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 Ca hemihydrate in an amount of about 46 mg on a free acid basis per capsule composition.

10. 2. The composition of claim 1, wherein the 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, is in an amount of about 1 mg to about 45 mg on a free acid basis per capsule.

11. 1. A composition comprising: a spray-dried dispersion (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-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.7 mg to about 50 mg on a free acid basis, with the remainder of the SDD consisting of PVP-VA; 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.

12. The composition comprises: an SDD of about 30% by weight 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.7 mg to about 45 mg on a free acid basis; a pH adjuster that is sodium bicarbonate in an amount of about 150 mg to about 650 mg; optionally a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0 mg to about 200 mg; optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0 mg to about 5 mg; The composition of claim 11 comprising:

13. The composition comprises: 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-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 Ca hemihydrate in an amount of about 1 mg to about 36 mg on a free acid basis, with the remainder of the SDD consisting of PVP-VA; a pH adjuster that is sodium bicarbonate in an amount of about 200 mg to about 600 mg; optionally a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0 mg to about 60 mg; optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof, in an amount of about 0 mg to about 5 mg; The composition of claim 12 comprising:

14. The filler of claim 13, wherein the filler is MCC PH-102 in an amount of about 2 mg to about 25 mg; the glidant is silicon oil or silicon dioxide in an amount of about 0.1 mg to about 5 mg; The composition of claim 13.

15. There is no filler present, the glidant is silicone oil in an amount of about 0.1 mg to about 5 mg; The composition of claim 13.

16. 12. The composition of claim 11, wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter.

17. The composition comprises: 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-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 Ca hemihydrate, in an amount of about 1 mg on a free acid basis; a pH adjuster that is sodium bicarbonate in an amount of about 200 mg; a filler that is MCC PH-102 in an amount of about 40 mg to about 50 mg; a glidant which is silicone oil or silicon dioxide, the glidant in an amount of about 1 mg to about 5 mg; 14. The composition of claim 13, wherein the total weight of the composition is about 250 mg.

18. The composition comprising: 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-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 Ca hemihydrate, in an amount of about 16 mg on a free acid basis; a pH adjuster that is sodium bicarbonate in an amount of about 200 mg; a filler that is MCC PH-102 in an amount of about 5 mg to about 10 mg; a glidant which is silicone oil or silicon dioxide, the glidant in an amount of about 1 mg to about 5 mg; 14. The composition of claim 13, wherein the total weight of the composition is about 260 mg.

19. The composition comprises: an SDD of about 30% by weight 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 Ca hemihydrate in an amount of about 6 mg on a free acid basis and about 70% by weight PVP-VA in an amount of about 14 mg; a pH adjuster that is sodium bicarbonate in an amount of about 600 mg; a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg; The composition of claim 13 comprising:

20. The composition comprises: an SDD of about 30% by weight 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 Ca hemihydrate in an amount of about 12 mg on a free acid basis and about 70% by weight PVP-VA in an amount of about 28 mg; a pH adjuster that is sodium bicarbonate in an amount of about 600 mg; a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg; The composition of claim 13 comprising:

21. The composition comprises: an SDD of about 30% by weight 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 Ca hemihydrate in an amount of about 36 mg on a free acid basis and about 70% by weight PVP-VA in an amount of about 83 mg; a pH adjuster that is sodium bicarbonate in an amount of about 600 mg; a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg; The composition of claim 13 comprising:

22. 18. The composition of claim 17, wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter.

23. 23. The composition of claim 22, wherein the SDD has an average particle size of about 40 μm to about 65 μm in diameter.

24. 24. The composition of claim 23, wherein the composition is within a capsule shell.

25. 25. The composition of claim 24, wherein the capsule shell is an HPMC capsule shell.

26. 26. Use of a composition according to any one of claims 1 to 25 in the manufacture of a medicament for the treatment of type 2 diabetes.

27. 22. Use of a composition according to any one of claims 1 to 21 in the manufacture of a medicament for use in weight management.

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