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 pharma- ceutically acceptable salt thereof. The compositions disclosed herein may be useful for the treatment of type 2 diabetes mellitus (T2D) and for 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 the health and quality of life of patients. Effective oral therapies 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 its pharma- ceutically acceptable salts, are described and claimed in U.S. Pat. No. 10,858,356, which generally describes oral compositions.

[0004] GLP1RA can be prepared as a pharma- ceutically 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 0.5 hydrate (herein "GLP1RA-Ca"), which has the structure shown below.

[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 physiological pH ranges and simulated physiological fluids. GLP1RA has been observed to have strong pH-dependent solubility properties, which contribute to challenges such as variability in absorption and therefore 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 may be desirable to enhance the solubility and dissolution rate of the active agent in a capsule dosage form. A pharmaceutically elegant dosage form for delivering an effective amount of active GLP1RA to a target 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 the desired properties. In some embodiments, the use of a spray-dried dispersion (SDD) of GLP1RA or a pharma- ceutically acceptable salt thereof with a pH adjuster as described herein contributes to the desired properties. In some embodiments, the particular particle size of the SDD and the particular composition described provide the desired properties. In some embodiments, the compositions disclosed herein provide desirable pharmacokinetic performance and deliver effective amounts of active GLP1RA to targeted portions of the gastrointestinal tract. In some 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 one embodiment, 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.

[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 one embodiment, 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 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 adjusting agent is anhydrous. In some embodiments, the pH adjusting agent is anhydrous sodium bicarbonate. In some embodiments, the pH adjusting agent 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt thereof; and a pH adjuster, the pH adjuster being 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 Ca 0.5 hydrate 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 0.5 hydrate 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 pharma- ceutically 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 pharma- ceutically acceptable salt thereof is prepared under the conditions described in Example 2 or Alternative Example 2.

[0024] In one embodiment, the present invention relates to a method for treating a subject with a 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 a 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 0.5 hydrate) is present in the compositions described herein as an SDD preparation.

[0025] In general, the SDD preparations disclosed herein comprise GLP1RA or a pharma- ceutically acceptable salt thereof, and a polymer for maintaining the amorphous state of GLP1RA or a pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt thereof and the 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 being PVP-VA, In one embodiment, the SDD preparation comprises about 30% by weight of GLP1RA or GLP1RA-Ca, with the remainder being 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 one embodiment, GLP1RA or a pharma- ceutically 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, hydroxypropyl methylcellulose, 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 one embodiment, GLP1RA or a pharma- ceutically 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, hydroxypropyl methylcellulose, 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 one embodiment, GLP1RA or a pharma- ceutically 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 one embodiment, GLP1RA or a pharma- ceutically acceptable salt thereof, in an amount of about 1 mg to about 45 mg; a pH adjuster, the pH adjuster being 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, hydroxypropyl methylcellulose, 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 pharma- ceutically acceptable salt thereof, is in the form of an SDD preparation.

[0036] In one embodiment, An SDD of about 20% by weight to about 40% by weight of GLP1RA, or a pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt thereof, with the remainder being composed of 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 one embodiment, A filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, 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 one embodiment, GLP1RA or a pharma- ceutically acceptable salt thereof, in an amount of about 0.7 mg to about 50 mg; a pH adjuster, the pH adjuster being 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, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0.1 mg to about 80 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.

[0041] In one embodiment, 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 certain embodiments of the above composition, the composition comprises: Optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, 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.

[0045] 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, or a pharma- ceutical acceptable salt thereof, in an amount of about 0.7 mg to about 50 mg based on the free acid, a pH adjuster, the pH adjuster being 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, hydroxypropyl methylcellulose, 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 certain 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 Ca 0.5 hydrate in an amount of about 0.7 mg to about 45 mg on a free acid basis, with the remainder of the SDD being composed of PVP-VA; a pH adjuster, the pH adjuster being 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, hydroxypropyl methylcellulose, 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 certain 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 Ca 0.5 hydrate, in an amount of about 1 mg to about 36 mg on a free acid basis, with the remainder of the SDD being composed of PVP-VA; a pH adjuster, the pH adjuster being 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, hydroxypropyl methylcellulose, 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 certain embodiments of the above composition, the SDD has an average particle size diameter of about 5 μm to about 113 μm.

[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; The glidant, if present, is silicone oil or silicon dioxide in an amount from about 0.1 mg to about 5 mg.

[0050] In one embodiment, 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 5-hydrate in an amount of about 1 mg on a free acid basis; a pH adjuster, said pH adjuster being sodium bicarbonate in an amount of about 200 mg; a filler, the filler being 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 one embodiment, 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 5-hydrate in an amount of about 1 mg (free acid basis); a pH adjuster, said pH adjuster being sodium bicarbonate in an amount of about 200 mg; a filler, the filler being MCC PH-102, in an amount of about 44 mg; a glidant which is silicon oil or silicon dioxide in an amount of about 2.5 mg; The total weight of the composition is about 250 mg.

[0052] In one embodiment, 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 5-hydrate in an amount of about 16 mg on a free acid basis; a pH adjuster, said pH adjuster being sodium bicarbonate in an amount of about 200 mg; a filler, the filler being 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; The total weight of the composition is about 260 mg.

[0053] In one embodiment, 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 5-hydrate in an amount of about 16 mg (free acid basis); a pH adjuster, said pH adjuster being sodium bicarbonate in an amount of about 200 mg; a filler, the filler being MCC PH-102, in an amount of about 7 mg; a glidant which is silicon oil or silicon dioxide in an amount of about 2.6 mg; The total weight of the composition is about 260 mg.

[0054] In one embodiment, 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 5-hydrate in an amount of about 6 mg on a free acid basis and about 70% by weight of PVP-VA in an amount of about 14 mg; a pH adjuster, said pH adjuster being sodium bicarbonate in an amount of about 600 mg; and a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg.

[0055] In one embodiment, 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 sesquihydrate in an amount of about 6 mg (free acid basis) and about 70% by weight of PVP-VA in an amount of about 14 mg; a pH adjuster, said pH adjuster being sodium bicarbonate in an amount of about 600 mg; and a glidant which is silicon oil or silicon dioxide in an amount of about 6 mg.

[0056] In one embodiment, 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 5-hydrate in an amount of about 12 mg on a free acid basis and about 70% by weight of PVP-VA in an amount of about 28 mg; a pH adjuster, said pH adjuster being sodium bicarbonate in an amount of about 600 mg; and a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg.

[0057] In one embodiment, 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 12 mg (free acid basis) and about 70% by weight PVP-VA in an amount of about 28 mg; a pH adjuster, said pH adjuster being sodium bicarbonate in an amount of about 600 mg; and a glidant which is silicon oil or silicon dioxide in an amount of about 6 mg.

[0058] In one embodiment, 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 5-hydrate 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, said pH adjuster being sodium bicarbonate in an amount of about 600 mg; and a glidant that is a silicone oil in an amount of about 1 mg to about 10 mg.

[0059] In one embodiment, 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 5-hydrate 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, said pH adjuster being sodium bicarbonate in an amount of about 600 mg; and 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, hi some embodiments, the capsule shell is an HPMC capsule shell. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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 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 hours, "hrs" refers to hours, "IR" refers to immediate release, "PK" refers to pharmacokinetics, "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 process 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 of drug (30%) and PVP-VA (70%) as measured by XRPD, of a particle size that allows for 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 a composition for use in preparing a composition.

[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 Ca0.5 hydrate

[0064] [ka]

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

[0066] The title compound has other names, for example, it is also known 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 Ca0.5 hydrate SDD is a 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 0.5 hydrate (8.7 g, titer 92%) and polyvinylpyrrolide / vinyl acetate copolymer (PVP-VA, Kollidon® VA64) (18.7 g) were prepared by dissolving in EtOH (200 mL) at room temperature. After dissolution of the solids, the solution is spray-dried in a conventional spray dryer equipped with a pressure nozzle. The following parameters from Table 1 are used to make a dispersion with Buchi B290 / B295. 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 optical 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 Ca0.5 hydrate is dissolved in methanol-denatured ethanol (5% v / v or w / w). A 20% w / w solid solution is prepared with a solid fraction of 30% w / w (based on free acid) consisting of the title compound, the remainder consisting of PVP-VA. This translates to 6% title compound (free acid basis), 14% PVP-VA and 80% denatured ethanol SDA-3A (all fractions as w / w). After spray drying, the solid formed is composed of 30% w / w (free acid basis) of the solid fraction consisting of the title compound, 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 the solution is pumped into the spray dryer where it becomes atomized as it enters. Heated drying gas enters co-currently with the atomized liquid at the top of the spray drying chamber at a ratio of approximately 0.044 kg / kg of spray solution to drying gas. The inlet temperature is adjusted to provide an outlet temperature of 35-45°C. 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 Ca 0.5 hydrate SDD, NaHCO 3 , microcrystalline cellulose (MCC PH-102), and SiO 2 Dispense NaHCO into separate low density polyethylene (LDPE) bags. 3 and MCC PH-102 are successively passed through a screen (30 mesh) into separate LDPE bags. 3 Add ~25% of the SiO2 to a 10 L mixing vessel. Add the sieved MCC to the bag containing the SDD and mix by hand for at least 2 minutes. 2 Add to the MCC and SDD blend and hand mix for at least an additional 2 minutes. Sift the blend through a 30 mesh screen into a container. Sift the LDPE bag of blend into the remaining NaHCO 3Rinse with 100% water and sift through a 30 mesh screen into a container. Blend for 15 minutes at 20 RPM. Sift the blend through a 30 mesh screen and blend again for 15 minutes at 20 RPM. Fill the blend into empty No. 0 capsule shells to target fill weight using a semi-automatic filling machine (e.g., Dott-Bonapace).

[0076] [Table 3] * As described herein, the conversion factor for GLP1RA / GLP1RA-Ca (i.e., hemicalcium salt hydrate of GLP1RA) is assumed to be about 0.91. As one skilled in the art will readily appreciate, the exact conversion factor may vary slightly depending on the actual content of 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 Ca 0.5 hydrate (13.3% w / w) Capsule formulation Capsules are prepared by first adding sodium bicarbonate (600 mg) to a size 0 hypromellose (short for hydroxypropyl methylcellulose (HPMC)) capsule, followed by 10 mg of SDD into the capsule to obtain a capsule with an active moiety strength of 3 mg.

[0078] In vitro dissolution test of capsules In vitro dissolution of the capsules is performed using USP Apparatus II with the following conditions: paddle speed 50 rpm until 60 minutes, 250 rpm from 60 to 90 minutes, 900 mL of 0.01 N hydrochloric acid held at 37°C, and 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 label claim is detected 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 Ca0.5 hydrate

[0083] [Table 6] The amount of A GLP1RA-0.5Ca hydrate may be adjusted based on release potency 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. C If necessary, the amount of SDD may be adjusted to account for the assay. Total capsule fill weight is adjusted accordingly.

[0084] [Table 7] The amount of A GLP1RA-0.5Ca hydrate may be adjusted based on release potency 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. C If necessary, the amount of SDD may be adjusted to account for the assay. Total capsule fill weight is adjusted accordingly.

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

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

[0089] As an alternative encapsulation process, the 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 some detail with reference to certain 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.

Claims

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

2. The composition according to 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 according to claim 1, wherein the pH adjuster is anhydrous.

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

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

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

7. 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-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, the composition according to 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-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one is the Ca0.5 hydrate.

8. 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, is the composition according to claim 7, which is 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one Ca0.5 hydrate in an amount of about 1.2 to about 46 mg on a free acid basis per capsule composition.

9. 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, is The composition according to claim 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-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one Ca 0.5 hydrate in an amount of about 46 mg per capsule on a free acid basis.

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

11. A composition comprising: A spray-dried dispersion (SDD) of about 30 wt% to about 35 wt% of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.7 mg to about 50 mg on a free acid basis, the balance of the SDD being composed of PVP-VA, and A composition comprising a pH adjuster selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and mixtures thereof. **Claim 12** wherein the composition is the SDD of about 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, in an amount of about 0.7 mg to about 45 mg on a free acid basis, the SDD, a pH adjuster which is sodium bicarbonate, in an amount of about 150 mg to about 650 mg, the pH adjuster, optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0 mg to about 200 mg, the filler, 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 glidant, and comprising the composition according to claim 11. **Claim 13** wherein the composition SDD of about 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one Ca0.5 hydrate, in an amount of about 1 mg to about 36 mg on a free acid basis, the remainder of said SDD being composed of PVP-VA, and a pH adjuster which is sodium bicarbonate, in an amount of about 200 mg to about 600 mg of the pH adjuster, and optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, dicalcium phosphate, and mixtures thereof, in an amount of about 0 mg to about 60 mg of the filler, and optionally, a flow promoter 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 of the flow promoter, and The composition according to claim 12, comprising.

14. The filler is MCC PH-102 in an amount of about 2 mg to about 25 mg, The flow promoter is silicone oil or silicon dioxide in an amount of about 0.1 mg to about 5 mg, The composition according to claim 13.

15. No filler is present, The flow promoter is silicone oil in an amount of about 0.1 mg to about 5 mg, The composition according to claim 13.

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

17. The composition is SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one Ca0.5 hydrate in an amount of about 1 mg on a free acid basis, the SDD, and A pH adjuster which is sodium bicarbonate, the pH adjuster in an amount of about 200 mg, and An excipient which is MCC PH-102, the excipient in an amount of about 40 mg to about 50 mg, and A glidant which is silicone oil or silicon dioxide, the glidant in an amount of about 1 mg to about 5 mg, comprising The composition according to claim 13, wherein the total weight of the composition is about 250 mg.

18. The composition, wherein SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one Ca0.5 hydrate in an amount of about 16 mg on a free acid basis, the SDD, and A pH adjuster which is sodium bicarbonate, the pH adjuster in an amount of about 200 mg, and An excipient which is MCC PH-102, the excipient in an amount of about 5 mg to about 10 mg, and A glidant which is silicone oil or silicon dioxide, the glidant in an amount of about 1 mg to about 5 mg, comprising The composition according to claim 13, wherein the total weight of the composition is about 260 mg.

19. The composition is SDD of about 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one Ca0.5 hydrate, in an amount of about 6 mg on a free acid basis, and about 70% by weight of PVP-VA in an amount of about 14 mg, A pH adjuster which is sodium bicarbonate, in an amount of about 600 mg of the pH adjuster, A flow promoter which is silicone oil, in an amount of about 1 mg to about 10 mg of the flow promoter, The composition according to claim 13, comprising

20. The composition is SDD of about 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one Ca0.5 hydrate, in an amount of about 12 mg on a free acid basis, and about 70% by weight of PVP-VA in an amount of about 28 mg, A pH adjuster which is sodium bicarbonate, in an amount of about 600 mg of the pH adjuster, A flow promoter which is silicone oil, in an amount of about 1 mg to about 10 mg of the flow promoter, The composition according to claim 13, comprising

21. The composition is An SDD of about 30% by weight of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxolan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one Ca0.5 hydrate, which is in an amount of about 36 mg on a free acid basis, and about 70% by weight of PVP-VA is in an amount of about 83 mg, and A pH adjuster which is sodium bicarbonate, and a pH adjuster in an amount of about 600 mg, and A flow promoter which is silicone oil, and a flow promoter in an amount of about 1 mg to about 10 mg, and The composition according to claim 13, comprising.

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

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

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

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

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

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