GLP1 pharmaceutical composition

Abstract

Capsule compositions of GLP1RA, including but not limited to GLP1RA - Ca, are provided that provide reliable PK capabilities in a dosage form that is easy for patients to swallow, have minimal potential for drug-drug interactions, and have reduced or no food effect.SOLUTION: 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-pyrazolo [4, 3-c] pyridine-5-carbonyl] indol-1-yl] - 2-methylcyclopropyl] - 4H, 124, - oxadiazol-5-one or pharmaceutically acceptable salts thereof; 4H, and a pH adjusting agent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a GLP-1 receptor agonist, 3-[(1S,2S)-1-[5-[ (4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro b-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole] -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 The present invention relates to an oral capsule composition of GLP1RA, or a pharmaceutically acceptable salt thereof. The compositions disclosed herein are useful for the treatment of type 2 diabetes mellitus (T2D) and weight management. could be. [Background technology]

[0002] Diabetes mellitus is a condition characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. T2D is a chronic disease characterized by impaired insulin secretion and insulin resistance. The combined effects are associated with elevated blood glucose levels. T2D is associated with a decline in the health and quality of life of patients. It is an increasingly prevalent disease that often leads to Effective oral treatments for use in dietary and / or weight management are desirable.

[0003] GLP1RA, i.e., 3-[(1S,2S)-1-[5-[(4S)-2,2-di methyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl phenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-o xoimidazol-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. No. 0,858,356 generally describes oral compositions.

[0004] GLP1RA may be prepared as a pharmaceutically acceptable salt. is calcium hemihydrate, 3-[(1S,2S)-1-[5-[(4S)-2,2 -dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl 3-[3-(4-fluoro-1-methylindazol-5-yl)-2-methylphenyl]- -oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[ 4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropane propyl]-4H-1,2,4-oxadiazol-5-one Ca 0.5 hydrate (herein In the present case, it is referred to as "GLP1RA-Ca") and has the structure shown below.

[0005] [ka]

[0006] GLP1RA is a weak acid with poor permeability and solubility, with a pKa of 5.1. LP1RA and its pharmaceutically acceptable salts exhibit the following properties in the physiological pH range and in simulated physiological fluids: GLP1RAs have very low water solubility. GLP1RAs are known to have strongly pH-dependent solubility characteristics. This has been observed to affect variability in absorption and therefore pharmacokinetic performance and potential food effects. This can lead to issues such as drug-drug interactions. Minimal potential for drug interactions and reduced or no food effect, GL A capsule composition of GLP1RA, including but not limited to GLP1RA-Ca, is desired. GLP1RA Compositions for Enhancing the Solubility and Dissolution Rate of Active Substances in Capsule Dosage Forms It may be desirable to deliver an effective amount of active GLP1RA to a targeted portion of the gastrointestinal tract. Pharmaceutically elegant dosage forms that are small enough to be easily swallowed by patients are desirable. It's nice. Summary of the Invention

[0007] The compositions described herein provide desired properties. or a pharmaceutically acceptable salt thereof, is subjected to a spray-dried dispersion (SDD) of the compound, The use of additives in conjunction with the particular grains described contributes to desirable properties. The diameter and specific composition of the SDD provide the desired properties. The compositions provide desirable pharmacokinetic performance and deliver an effective amount of active GLP1RA to the gastrointestinal tract. In some embodiments, disclosed herein are methods for delivering to a target area, such as those for dietary and fluid restrictions. It is an elegant dosage form that is convenient for patients to take without any side effects.

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

[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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [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 some embodiments, the pH adjuster is calcium carbonate, magnesium carbonate, sodium bicarbonate, or the like. Sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and The composition is selected from the group consisting of 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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [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 calcium carbonate, anhydrous calcium carbonate, bicarbonate Sodium, anhydrous sodium bicarbonate, sodium carbonate, anhydrous sodium carbonate, magnesium hydroxide and anhydrous magnesium hydroxide. do.

[0012] In one embodiment, the pH adjuster is sodium bicarbonate. The stabilizer is sodium carbonate.

[0013] In some embodiments, the pH adjuster is anhydrous. Sodium carbonate. In one embodiment, the pH adjuster is anhydrous sodium carbonate.

[0014] In some embodiments, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethylamino] xan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl )-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimide 4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c] Pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4 H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; a pH adjuster, wherein the pH adjuster is anhydrous sodium bicarbonate. is.

[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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [Carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4- oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and a pH adjuster, which may be sodium bicarbonate, anhydrous sodium bicarbonate, or sodium bicarbonate. It is selected from sodium carbonate 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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [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-methylindazole-5-yl] [2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyridyl Lazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl cyclopropyl]-4H-1,2,4-oxadiazol-5-one, a pH adjuster, Includes:

[0020] In some embodiments, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethylamino] xan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl )-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimide 4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c] Pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4 H-1,2,4-oxadiazol-5-one Ca 0.5 hydrate per capsule composition It is a capsule composition containing about 0.5 to about 46 mg of the active ingredient.

[0021] In some embodiments, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethylamino] xan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl )-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimide 4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c] Pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4 H-1,2,4-oxadiazol-5-one Ca 0.5 hydrate per capsule composition The composition contains about 46 mg of the compound.

[0022] Some embodiments provide a capsule composition disclosed herein that includes an amorphous dispersion process. Some embodiments include a spray-drying dispersion (SDD) process. SUMMARY OF THE INVENTION A process for preparing the capsule compositions claimed herein is provided.

[0023] In one embodiment, the GLP1RA or a pharmaceutically acceptable salt thereof is present in a capsule composition. In one embodiment, the active agent is prepared into a spray-dried dispersion (SDD) for use as an active agent of In the above, the SDD of GLP1RA or a pharmaceutically acceptable salt thereof is It is prepared under the conditions described in 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-pyrazo [4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclohexyl [4H-1,2,4-oxadiazol-5-one] or GLP1RA-C a(3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxane-4-yl] yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3- (4-Fluoro-1-methylindazol-5-yl)-2-oxoimidazole-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) is included in the compositions described herein. It exists as an SDD preparation.

[0025] Generally, the SDD preparations disclosed herein contain GLP1RA or a pharmaceutically acceptable salt thereof. and a salt thereof for maintaining the amorphous state of GLP1RA or a pharmaceutically acceptable salt thereof. In some embodiments, the polymer is polyvinylpyrrolidone ("povidone"). or "PVP") and polyvinylpyrrolidone vinyl acetate ("Copovidone" " or "PVP-VA"). In some embodiments, the polymer is PVP-VA. In some embodiments, the polymer is PVP.

[0026] The weight percentage of GLP1RA or a pharmaceutically acceptable salt thereof in the SDD preparation is specified. In certain embodiments, the remaining components of the SDD are poly(vinyl ether) selected from PVP and PVP-VA. a polymer, i.e., a total of GLP1RA or a pharmaceutically acceptable salt thereof and a polymer Weight percentages are 100% by weight. In one embodiment, the polymer is PVP-VA. In some embodiments, the polymer is PVP. A physical solvent may be present in the SDD preparation.

[0027] In one embodiment, the SDD preparation comprises about 20% to about 40% by weight of a GLP1RA or In one embodiment, the S The DD preparation contains approximately 30% by weight of GLP1RA or GLP1RA-Ca, with the remainder being PV. It is composed of P-VA.

[0028] In one embodiment, the mean particle size of a GLP1RA or GLP1RA-Ca SDD is 0.01 mm in diameter. In one embodiment, the average particle size of the SDD is about 5 μm in diameter to about 150 μm. In one embodiment, the average particle size of the SDD is about 40 μm to about 6 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-C a, with the remainder consisting of PVP-VA. In one embodiment, the SDD preparation comprises about Contains 30% by weight of GLP1RA or GLP1RA-Ca, with the remainder consisting of PVP-VA will be done.

[0030] In one embodiment, the average particle size of the GLP1RA-Ca SDD is about 5 μm to about 15 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 some embodiments, the average particle size of the SDD is about 40 μm to about 50 μm in diameter. In this 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; Calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, hydroxide a pH adjuster selected from the group consisting of magnesium, and mixtures thereof; Optionally, sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and mixtures thereof; and Optionally, colloidal silicon dioxide, talc, magnesium carbonate, and mixtures thereof. and a glidant selected from the group consisting of

[0032] In some embodiments, GLP1RA or a pharmaceutically acceptable salt thereof in an amount of about 0.7 mg to about 80 mg and a GLP1RA or a pharmaceutically acceptable salt thereof. Calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, hydroxide a pH adjusting agent selected from the group consisting of magnesium, and mixtures thereof, having a pH of about a pH adjuster in an amount of 20 mg to about 800 mg; Sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose , hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a filler selected from the group consisting of a mixture of , a filler; Optionally, silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof. a glidant selected from the group consisting of: and a motility enhancer.

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

[0034] In some embodiments, GLP1RA or a pharmaceutically acceptable salt thereof in an amount of about 1 mg to about 45 mg, GLP1RA or a pharmaceutically acceptable salt thereof; A pH adjuster that is sodium bicarbonate in an amount of about 150 mg to about 650 mg, H regulators, Sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose , hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a filler selected from the group consisting of a mixture of Filler and Consists of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof a glidant selected from the group consisting of: A composition comprising:

[0035] In some embodiments, 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethylamino] xan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl )-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimide 4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c] Pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4 H-1,2,4-oxadiazol-5-one ("GLP1RA"), or its pharmaceutically acceptable salts The acceptable salt is the above composition in the form of an SDD preparation.

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

[0037] In one embodiment, the SDD comprises about 30% to about 35% by weight of a GLP1RA or pharmaceutical composition thereof. The above composition, wherein the remainder of the SDD is PVP-VA, and the remainder of the SDD is PVP-VA. and The pH adjuster is selected from the group consisting of sodium bicarbonate and sodium carbonate. It is an adjuster.

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

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

[0040] In some embodiments, GLP1RA or a pharmaceutically acceptable salt thereof in an amount of about 0.7 mg to about 50 mg and a GLP1RA or a pharmaceutically acceptable salt thereof. A pH adjuster that is sodium bicarbonate in an amount of about 150 mg to about 650 mg, H regulators, Sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose , hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a filler selected from the group consisting of a mixture of A filler; Optionally, silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof. a glidant selected from the group consisting of: and a facilitator.

[0041] In some embodiments, About 20% by weight to about 40% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2 -dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl 3-[3-(4-fluoro-1-methylindazol-5-yl)-2-methylphenyl]- -oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[ 4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropane propyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof The remainder of the SDD is a polymer selected from PVP-VA and PVP. SDD, which consists of and a pH adjuster, wherein the pH adjuster is calcium carbonate, sodium bicarbonate, sodium carbonate, The group consisting of sodium, magnesium hydroxide, anhydrous magnesium hydroxide, and mixtures thereof The composition is selected from:

[0042] In some embodiments of the above composition, SDD is about 30% by weight 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-methylindazole-5- yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H- Pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methyl cyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutical the remainder of the SDD is composed of a polymer which is PVP-VA; The pH adjuster is selected from the group consisting of sodium bicarbonate and sodium carbonate. Adjuster.

[0043] In some embodiments of the above composition, SDD is about 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-di methyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl phenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-o xoimidazol-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 remainder of the SDD is composed of PVP-VA, and the SDD has a diameter of about 5 μm to about 11 μm. having an average particle size of 3 μm, A pH adjuster that is sodium bicarbonate.

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

[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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [Carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4- Oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, having a molecular weight of about 1,000,000, based on the free acid. an amount of 0.7 mg to about 50 mg of the compound or a pharmaceutically acceptable salt thereof; A pH adjuster that is sodium bicarbonate in an amount of about 150 mg to about 650 mg, H regulators, Optionally, sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and mixtures thereof, and g of filler; Optionally, silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof. a glidant selected from the group consisting of: and a promoter.

[0046] In some embodiments of the above composition, the composition comprises: About 30% by weight to about 35% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2 -dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl 3-[3-(4-fluoro-1-methylindazol-5-yl)-2-methylphenyl]- -oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[ 4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropane propyl]-4H-1,2,4-oxadiazol-5-one Ca 0.5 hydrate SDD The amount is about 0.7 mg to about 45 mg on a free acid basis, and the remainder of the SDD is PVP-V A consists of SDD and A pH adjuster that is sodium bicarbonate in an amount of about 200 mg to about 650 mg, H regulators, Optionally, sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and mixtures thereof, and a filler in an amount of Optionally, silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof. a glidant selected from the group consisting of: and a promoter.

[0047] In some embodiments of the above composition, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, The amount is about 1 mg to about 36 mg on a standard basis, and the remainder of the SDD is PVP-VA. SDD and A pH adjuster that is sodium bicarbonate in an amount of about 200 mg to about 600 mg, H regulators, Optionally, sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and mixtures thereof, and a filler in an amount of Optionally, silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof. a glidant selected from the group consisting of: and a promoter.

[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. It has.

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

[0050] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, SDD, which is about 1 mg in standard, a pH adjuster in an amount of about 200 mg, wherein the pH adjuster is sodium bicarbonate; a filler that is MCC PH-102 in an amount of about 40 mg to about 50 mg; and, a glidant which is silicone oil or silicon dioxide in an amount of about 1 mg to about 5 mg; a glidant, The total weight of the composition is about 250 mg.

[0051] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, about 1 m g (free acid basis) of SDD; 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; an accelerator; The total weight of the composition is about 250 mg.

[0052] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, SDD, which is about 16 mg based on the standard, a pH adjuster in an amount of about 200 mg, wherein the pH adjuster is sodium bicarbonate; 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 in an amount of about 1 mg to about 5 mg; a glidant, The total weight of the composition is about 260 mg.

[0053] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, mg (free acid basis) of SDD, and 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; an accelerator; The total weight of the composition is about 260 mg.

[0054] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, The SD is about 6 mg of PVP-VA by weight, and about 70% by weight of PVP-VA is about 14 mg. D and a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg; Includes:

[0055] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, about 6 m g (free acid basis), and about 70 wt% PVP-VA in an amount of about 14 mg. DD and a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant which is silicone oil or silicon dioxide in an amount of about 6 mg; and,

[0056] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, % PVP-VA in an amount of about 28 mg. DD and a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg; Includes:

[0057] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, mg (free acid basis), and about 70 wt% PVP-VA in an amount of about 28 mg. SDD and a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant which is silicone oil or silicon dioxide in an amount of about 6 mg; and,

[0058] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, % PVP-VA in an amount of about 83 mg. DD and a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg; Includes:

[0059] In some embodiments, the composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, % PVP-VA in an amount of about 83 mg. DD and a pH adjuster in an amount of about 600 mg, wherein the pH adjuster is sodium bicarbonate; a glidant which is silicone oil or silicon dioxide in an amount of about 6 mg; and,

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

[0061] Certain abbreviations are defined as follows: "cfm" stands for cubic feet per minute; "Cmax" is the maximum dose achieved by a drug in the test area after administration and before the second administration. "DDI" refers to drug-drug interactions, and "DR" refers to delayed release. "EtOH" stands for ethanol or ethyl alcohol. "FaSSiF" refers to simulated fasting intestinal fluid, and "FaSSGF" refers to simulated fasting intestinal fluid. "FeSSIF" refers to simulated gastric fluid, "FeSSIF" refers to fed-state simulated intestinal fluid, and "hr" refers to time. "hrs" refers to time, "IR" refers to immediate release, and "PK" refers to pharmacokinetics. "MeOH" stands for methanol or methyl alcohol "rpm" refers to revolutions per minute, and "PVP-VA" refers to polyvinylpyrrolidone. "SDD" refers to spray-dried dispersion, and "SIF" refers to suspected dispersion. "T2D" refers to type 2 diabetes mellitus, and "THF" refers to tetrahydrofuran ( tetrahydrofuran), "USP" refers to the United States Pharmacopoeia, and "wt%" refers to the amount of the desired material. As used herein, "mass of material" refers to mass of material / total mass, and "XRPD" refers to X-ray powder diffraction. "prep" means a preparation.

[0062] Those skilled in the art will recognize that 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxane -4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3 -[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazole [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinyl-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinyl Indol-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1 Spray-dried dispersion (SDD) preparation of 2,4-oxadiazol-5-one, 0.5Ca are prepared under various processing conditions and with various equipment to produce materials of suitable quality and important characteristics. In some embodiments, the product can have the desired The amorphous mixture of drug (30%) and PVP-VA (70%) by weight was isolated and processed further. The particle size is such that it can be processed with acceptable levels of process-related impurities and excess residual solvent. In some embodiments, an amorphous solid dispersion may be used in the preparation process. In some embodiments, the particle size is determined based on the amount of the active ingredient in the composition for use in preparing the composition. For this purpose, the particle diameter is about 5 to about 113 μm.

[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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [Carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4- Oxadiazol-5-one Ca 0.5 hydrate

[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. Also known as

[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-dimethyl phenyl)-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]carbohydrate 5-[(4S)-tetrahydro-2,2-dimethyl-2H-pyran-4-yl]- ]-1H-indol-1-yl]-2-methylcyclopropyl]-calcium salt (2: 1) It is a hydrate.

[0068] Example 2 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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [Carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4- SDD preparation of oxadiazol-5-one Ca 0.5 hydrate 30% 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxane- 4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3- [3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazole -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 SDD is a 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 Ruindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6, 7-Dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole- 1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5- Calcium carbonate 0.5 hydrate (8.7 g, potency 92%) and polyvinylpyrrolide / vinyl acetate copolymer Polymer (PVP-VA, Kollidon® VA64) (18.7 g) The solid was dissolved in EtOH (200 mL) at room temperature. The mixture is spray dried in a conventional spray dryer equipped with a pressure nozzle using the following parameters in Table 1: The dispersion with Buchi B290 / B295 is prepared by spray drying. The dryer can be started when the temperature exceeds 33°C. Collect the material and dry it overnight under vacuum at 50°C. The title compound (21.99 g, 7.0 g, titer 92%, recovery rate 80%) was obtained. are microscopically non-birefringent particles with diameters of approximately 5-25 μm, as determined by optical microscopy. Observe.

[0069] SDD parameters

[0070] [Table 1]

[0071] Alternative Example 2 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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [Carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4- SDD preparation of 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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [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 / A 20% w / w solid solution was prepared by dissolving the title compound in a 30% w / w The solid fraction was prepared with 6% (based on free acid), and the remainder consisted of PVP-VA. of the title compound (based on the free acid), 14% PVP-VA and 80% denatured ethanol SDA -3A (all fractions w / w). After spray drying, the solid formed is The solid fraction consisted of 30% w / w (free acid basis) of the compound, the remainder being PVP-V A. The % values ​​are shown in Table 2 below.

[0072] Alternative Example 2 SDD Formulation

[0073] [Table 2]

[0074] A solution is prepared and the solution is pumped into a spray dryer, where it becomes atomized. The heated drying gas was used to spray dry the solution at a ratio of about 0.044 kg / kg of spray solution to drying gas. The atomized liquid enters the drying chamber at the top in a co-current manner. The inlet temperature is 35-45°C. The solids formed in the spray dryer are passed through a cyclone and a gas The gas is collected from the filter housing above the stream. The gas is passed through a condenser maintained at -3°C and dissolved. The solvent was removed (to a dew point of -3°C). The gas was then heated to the inlet temperature and returned to the spray dryer. vinegar.

[0075] Example 3 Capsule formulation 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 [4,3-c]pyridine-5-carboxylate]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [Carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4- Oxadiazol-5-one calcium pentose hydrate 1 mg and 15 mg capsule formulations SDD, NaHCO3, microcrystalline cellulose (MCC PH-102), and SiO2 Dispense into separate low-density polyethylene (LDPE) bags. H-102 was passed through a screen (30 mesh) and placed in separate LDPE bags. Add ~25% of the sieved NaHCO3 to a 10 L mixing vessel. Add the sieved MCC to the bag and mix by hand for at least 2 minutes. Then, add the SiO2. Add to the MCC and SDD blend and mix by hand for at least an additional 2 minutes. Sift through a 30 mesh screen into a container. NaHCO3 and sieve through a 30 mesh screen into a container. Blend for 15 minutes at 250°C. Sift the blend through a 30 mesh screen and Blend again at 0 RPM for 15 minutes. ce) to fill the blend into empty No. 0 capsule shells to the target fill weight.

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

[0077] Example 4 Capsule formulation 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-oxoimidazole-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 (13.3% w / w) Capsule formulation First, add sodium bicarbonate (600 mg) to No. 0 hypromellose (hydroxypropyl HPMC (Hydromethylcellulose) capsules, followed by 10 mg of SDD. The capsules are prepared by placing the tablets in a container to obtain capsules with an active ingredient strength of 3 mg.

[0078] In vitro dissolution test of capsules In vitro dissolution of the capsules was performed under the following conditions: paddle speed 50 rpm for 60 min; m, 250 rpm for 60 to 90 minutes, 900 mL of 0.01 N hydrochloric acid maintained at 37 °C, and USP Apparatus II, with the use of a basket sinker to reduce capsule buoyancy Six replicates were tested and the samples were divided into 10, 15, 20, 30, 45, 60 The dissolution vessel was removed at 10 and 90 minutes, and the amount of drug dissolved relative to the label claim was measured using UV The results are found in the table below.

[0079] [Table 4]

[0080] Clinical trial results Surprisingly, despite its relatively poor solubility in 0.01N HCl, clinical trials When tested in the GZGA, capsules prepared with SDD and sodium bicarbonate The cells showed an increase in both Cmax and AUC compared to capsules using only SDD. did.

[0081] [Table 5]

[0082] Example 4 Capsule formulation 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-oxoimidazole-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

[0083] [Table 6] Amount of GLP1RA-0.5Ca hydrate released to maintain target concentration during SDD Conversion factor for GLP1RA / GLP1RA hemi-calcium may be adjusted based on the efficacy of the drug. is approximately 0.98. B Ethanol and methanol are removed to residual levels during drying. C If necessary, the amount of SDD may be adjusted to account for the assay. The total capsule fill weight will be adjusted accordingly.

[0084] [Table 7] Amount of GLP1RA-0.5Ca hydrate released to maintain target concentration during SDD Conversion factor for GLP1RA / GLP1RA hemi-calcium may be adjusted based on the efficacy of the drug. is approximately 0.98. B Ethanol and methanol are removed to residual levels during drying. C If necessary, the amount of SDD may be adjusted to account for the assay. The total capsule fill weight will be adjusted accordingly.

[0085] Example 5 Particle size measurement SDD particle size was determined using a Malvern M equipped with a Hydro MV (medium volume) liquid disperser. astersizer 3000(Malvern Instruments Ltd. The optical model was determined by laser diffraction using a wet dispersion (UK). Obscuration limit: 5-30%, general-purpose model. Measures volume-based distribution, (D10, D50, D90) quantiles were reported.

[0086] The SDDs of Example 2 and Alternative Example 2 have diameters of about 40 to 100 mm as measured by the above method. It has an average particle size of about 65 μm, or more specifically, about 40 to about 50 μm.

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

[0088] For the encapsulation process, the GLP1RA-Ca SDD was subjected to a two-step filling process. The capsules are filled using automated equipment as the first fill in the The second fill, sodium bicarbonate, is filled into the capsules using automated equipment. A continuous twin-screw wet granulator, a liquid-tumble vessel equipped with an I-bar, or Use a liquid additive blending process such as ribbon blending to blend silicone 1 % sodium bicarbonate is separately prepared. The double powder filling method allows for very low drug loading, This may be due to differences in particle size and density between GLP1RA-Ca SDD and sodium bicarbonate This encapsulation process allows for batches as small as 12 capsules. while allowing for substantially larger batch sizes, for example, but not limited to, 1 batch Suitable for sizes exceeding 100,000 capsules per unit.

[0089] As an alternative encapsulation process, the GLP1RA-Ca SDD is first encapsulated in sodium bicarbonate. Blend with a mixture of 1% ethanol and silicone, then fill into capsules using automated equipment. You may do so.

[0090] Although the present invention has been described in considerable detail with reference to specific embodiments thereof, other variations are possible. The embodiments disclosed herein are for illustrative purposes only and are not intended to be limiting unless otherwise specified. Various modifications of the embodiments and further embodiments thereof in addition to those described and illustrated are contemplated herein. It will be clear to those skilled in the art from the entire contents of the document.

Claims

1. 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 [4,3-c]pyridine-5-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-yl 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 pH adjuster may be calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, Sodium, magnesium hydroxide, calcium hydroxide, magnesium oxide, and mixtures thereof 10. The composition of claim 1, wherein the composition is selected from the group consisting of:

3. The pH adjuster may be calcium carbonate, anhydrous calcium carbonate, sodium bicarbonate, anhydrous bicarbonate, Sodium carbonate, sodium carbonate, anhydrous sodium carbonate, magnesium hydroxide, and anhydrous 3. The composition of claim 2, selected from the group consisting of magnesium hydroxide.

4. The composition of claim 2 , wherein the pH adjuster is anhydrous.

5. The composition of claim 2 , wherein the pH adjuster is sodium bicarbonate.

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

7. 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 [4,3-c]pyridine-5-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-yl carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4- oxadiazol-5-one, and anhydrous sodium bicarbonate.

8. The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxane-4- yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3 -(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazole-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, 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 [4,3-c]pyridine-5-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-yl carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4- The compound according to any one of claims 1 to 6, which is oxadiazol-5-one Ca 0.5 hydrate. The composition described above.

9. The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxane-4- yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3 -(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazole-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, 3-[(1S,2S )-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylphenyl) [0043] [chilindazol-5-yl]-2-oxoimidazol-1-yl]-4-methyl-6 ,7-Dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indole -1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazole-5 The composition according to claim 8, wherein the compound is hydroxybenzoate Ca 0.5 hydrate.

10. The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxane-4- yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3 -(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazole-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, Each capsule contains approximately 46 mg of 3-[(1S,2S)-1-[5-[ (4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro b-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole -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 The composition of claim 9 which is a hydrate.

11. The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxane-4- yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3 -(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazole-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 administered free per capsule. The composition of any one of claims 1 to 6, in an amount of from about 1 mg to about 45 mg on a free acid basis. thing.

12. A compound according to any one of claims 1 to 11 and 15 to 29 for use in the treatment of type 2 diabetes. The composition described.

13. A composition according to any one of claims 1 to 11 and 15 to 29 for use in weight management. Finished product.

14. A process for preparing a composition according to any one of claims 1 to 11, comprising an amorphous dispersion. vinegar.

15. 1. A composition 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- ... 3-(4-fluoro-1-methylindazol-5-yl)-2-methylphenyl -oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[ 4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropane propyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof an amount of about 0.7 mg to about 50 mg of a salt of the SDD, based on the free acid; the remainder being composed of PVP-VA; and Calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide selected from the group consisting of cadmium, calcium hydroxide, magnesium oxide, and mixtures thereof and a pH adjuster selected from the group consisting of:

16. The composition comprises: Approximately 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxazolidinyl] 4-fluoro-3,5-dimethylphenyl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)- 3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazo [4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyrazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyrazole Indol-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H- SDD of 1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof. SDD in an amount of about 0.7 mg to about 45 mg on a free acid basis; a pH adjuster which is sodium bicarbonate in an amount of about 150 mg to about 650 mg; H regulator; Optionally, sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose cellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and A filler selected from the group consisting of mixtures thereof, from about 0 mg to about 200 mg an amount of filler; Optionally, silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof. a glidant selected from the group consisting of: 、 16. The composition of claim 15, comprising:

17. The composition comprises: About 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4,3-c]pyrazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, The remainder of the SDD is composed of PVP-VA. , SSD and A pH adjuster that is sodium bicarbonate in an amount of about 200 mg to about 600 mg. A regulator; Optionally, sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose cellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and A filler selected from the group consisting of mixtures thereof, in an amount of about 0 mg to about 60 mg A filler; Optionally, silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof. a glidant selected from the group consisting of: 、 17. The composition of claim 16, comprising:

18. 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. 、 18. The composition of claim 17.

19. There is no filler present, the glidant is silicone oil in an amount of about 0.1 mg to about 5 mg; 18. The composition of claim 17.

20. 20. The method of claim 15, wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter. The composition described in any one of claims 1 to 4.

21. The composition comprises: About 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4,3-c]pyrazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, SDD in an amount of about 1 mg on a 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 in an amount of about 1 mg to about 5 mg. and a promoter, 18. The composition of claim 17, wherein the total weight of the composition is about 250 mg.

22. The composition comprises: About 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4,3-c]pyrazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, SDD in an amount of about 16 mg on a 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 in an amount of about 1 mg to about 5 mg. and a promoter, 18. The composition of claim 17, wherein the total weight of the composition is about 260 mg.

23. The composition comprises: About 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4,3-c]pyrazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, SD is about 6 mg of PVP-VA by weight, and about 70% by weight of PVP-VA is about 14 mg. D and 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; 18. The composition of claim 17, comprising:

24. The composition comprises: About 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4,3-c]pyrazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, % PVP-VA in an amount of about 28 mg, and about 70% by weight PVP-VA in an amount of about 12 mg. D.D. and 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; 18. The composition of claim 17, comprising:

25. The composition comprises: About 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxy] San-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl) -3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazoline [4,3-c]pyrazole-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin Lysine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H SDD of 1,2,4-oxadiazol-5-one Ca 0.5 hydrate, % PVP-VA in an amount of about 83 mg. D.D. and 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; 18. The composition of claim 17, comprising:

26. 26. The method of claim 21, wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter. The composition described in any one of claims 1 to 4.

27. 27. The SDD of claim 26, wherein the SDD has an average particle size of about 40 μm to about 65 μm in diameter. composition.

28. 28. The composition of claim 27, wherein the composition is within a capsule shell.

29. 29. The composition of claim 28, wherein the capsule shell is an HPMC capsule shell.

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