GLP1 tablet composition

Abstract

Disclosed herein is a tablet composition comprising 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-oxoimidazol-1-yl]-4-methyl-6, 7-dihydro-4H-pyrazolo [4, 3-c] pyridin-5-carbonyl] indol-1-yl]-2-methylcyclopropyl]-4H-1, 2, 3-triazolo [4, 3-c] pyridin-5-yl] indol-1-yl]-2-methylcyclopropyl]-1, 2, 3-triazolo [4, 3-c] pyridin-5-yl]- The invention relates to 1, 2, 4-oxadiazole-5-one or a pharmaceutically acceptable salt thereof and a pH regulator. In one embodiment, a tablet composition comprises 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-oxoimidazol-1-yl]-4-methyl-6, 7-dihydro-4H-pyrazolo [4, 3-c] pyridine-5-carbonyl] indol-1-yl]-2-methylcyclopropyl]-4H-1, 2, 3-triazolo [4, 3-c] pyridin-5-yl] indol-1-yl]-2-methylcyclopropyl]-1, 2, 3-triazolo [4, 3-c] pyridin-5-yl] The present invention relates to a spray-dried dispersion (SDD) of 1, 2, 4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof, wherein the SDD further comprises a polymer to maintain an amorphous state.

Description

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

[0002] Diabetes is a chronic disorder characterized by hyperglycemia caused by defects in insulin secretion, insulin action, or both. In T2D, the combined effects of impaired insulin secretion and insulin resistance are associated with elevated blood glucose levels. T2D is an increasingly prevalent disease that often results in a decline in the patient's health and quality of life. Effective oral treatments are needed to manage T2D and / or for weight management.

[0003] 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 pharmaceutically acceptable salt thereof, is described and claimed in US Pat. US Pat. No. 10,858,356 generally describes an oral composition.

[0004] GLP1RA can be prepared as a pharmaceutically acceptable salt. One salt of GLP1RA is a hemi-calcium 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, 0.5Ca hydrate (referred to herein as "GLP1RA-Ca"), having the structure shown below.

[0005]

[0006] GLP1RA is a weak acid with poor permeability and poor solubility, with a pKa of 5.1. GLP1RA has very low water solubility within the physiological pH range and in simulated physiological fluids. It has been observed that GLP1RA and its pharmaceutically acceptable salts have a strongly pH-dependent solubility curve, which poses challenges such as absorption variability and thus variability in pharmacokinetic performance and potential food effects. It is expected that GLP1RA (including but not limited to GLP1RA-Ca) tablet compositions provide reliable PK performance in a patient-friendly dosage form with minimal drug-drug interaction potential and reduced food effect or no food effect. GLP1RA compositions that enhance the solubility and dissolution rate of the active substance in the tablet dosage form may be needed. A pharmaceutically sophisticated dosage form is needed to deliver an effective amount of active GLP1RA to a target portion of the gastrointestinal tract while being small enough to facilitate patient swallowing.

[0007] The compositions described herein provide desired properties. In one aspect, as described herein, a spray-dried dispersion (SDD) of a GLP1RA or a pharmaceutically acceptable salt thereof is used together with a pH adjuster to contribute to the desired properties. In one aspect, the specific particle size of the SDD and the specific composition as described provide the desired properties. In one aspect, the compositions disclosed herein provide ideal pharmacokinetic properties and deliver an effective amount of active GLP1RA to a target portion of the gastrointestinal tract. In one aspect, disclosed herein is a sophisticated dosage form that is convenient for patients to take without restrictions on food or water.

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

[0009] In one embodiment is a tablet composition comprising:

[0010] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and

[0011] pH adjuster.

[0012] In one embodiment, the tablet composition disclosed herein is an oral solid composition.

[0013] 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.

[0014] In one embodiment is a solid oral tablet composition comprising

[0015] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and

[0016] pH adjuster; wherein the pH adjuster is selected from the group consisting of calcium carbonate, anhydrous calcium carbonate, sodium bicarbonate, anhydrous sodium bicarbonate, sodium carbonate, anhydrous sodium carbonate, hydrated sodium carbonate, magnesium hydroxide and anhydrous magnesium hydroxide.

[0017] In one embodiment, the pH adjusting agent is sodium carbonate. In one embodiment, the pH adjusting agent is anhydrous. In one embodiment, the pH adjusting agent is anhydrous sodium carbonate.

[0018] In one embodiment, the pH adjusting agent is hydrated sodium carbonate.

[0019] In one embodiment, the pH adjusting agent is sodium bicarbonate. In one embodiment, the pH adjusting agent is anhydrous. In one embodiment, the pH adjusting agent is anhydrous sodium bicarbonate.

[0020] In one embodiment is a tablet composition comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and

[0021] pH adjuster; wherein the pH adjuster is anhydrous sodium carbonate.

[0022] In one embodiment is a tablet composition, wherein the composition comprises

[0023] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof;

[0024] pH adjusters; and

[0025] Super disintegrant.

[0026] In one embodiment, the super disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof. In one embodiment, the super disintegrant is selected from the group consisting of croscarmellose sodium and crospovidone.

[0027] In one embodiment is a tablet composition, wherein the composition comprises

[0028] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof;

[0029] pH adjusters; and

[0030] Lubricant.

[0031] In one embodiment, the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and mixtures thereof. In one embodiment, the lubricant comprises magnesium stearate. In one embodiment, the lubricant is magnesium stearate.

[0032] In one embodiment is a tablet composition, wherein the composition comprises

[0033] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof;

[0034] pH adjusters;

[0035] super disintegrants; and

[0036] Lubricant.

[0037] In one embodiment is a tablet composition, wherein the composition comprises

[0038] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof;

[0039] pH adjusters;

[0040] a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone; and

[0041] A lubricant which is magnesium stearate.

[0042] In one embodiment is a tablet composition, wherein the composition comprises

[0043] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof;

[0044] pH adjusters; and

[0045] Crospovidone.

[0046] In one embodiment, the tablet composition comprises an enteric coating.In one embodiment, the tablet composition comprises an immediate release coating.In one embodiment, the tablet composition comprises an immediate release coating and an enteric coating.

[0047] In one embodiment, a tablet composition comprises 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-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 hydrate; and a pH adjuster.

[0048] In one embodiment, the tablet composition comprises 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-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 in an amount of about 0.5 to about 75 mg per tablet composition.

[0049] In one embodiment, the tablet composition comprises 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-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 in an amount of about 0.5 to about 60 mg per tablet composition; or more specifically, about 0.5 to about 45 mg; or more specifically, about 0.5 to about 36 mg; or still more specifically, about 0.8 to about 36 mg.

[0050] In one embodiment, the tablet composition comprises 3-[(1S,2S)-1-[5- ... -[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-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 hydrate.

[0051] As described herein, the conversion factor of GLP1RA / GLP1RA-Ca (ie, the hemi-calcium salt hydrate of GLP1RA) is assumed to be approximately 0.91. As the skilled artisan will readily appreciate, the exact conversion ratio may vary slightly depending on the actual content of the hydrate.

[0052] In one embodiment is a tablet composition, wherein the composition comprises

[0053] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount of about 0.5 mg to about 75 mg (based on the free acid);

[0054] a pH adjuster in an amount of about 5 mg to about 15 mg selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate, magnesium hydroxide, and mixtures thereof;

[0055] a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of about 2 mg to about 25 mg; and

[0056] A lubricant in an amount of about 0.5 mg to about 5 mg selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and mixtures thereof.

[0057] In one embodiment is a tablet composition, wherein the composition comprises

[0058] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount of about 0.7 mg to about 60 mg (based on the free acid);

[0059] a pH adjuster in an amount of about 5 mg to about 15 mg selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate, magnesium hydroxide, and mixtures thereof;

[0060] a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of about 2 mg to about 25 mg; and

[0061] A lubricant in an amount of about 0.5 mg to about 5 mg, which is magnesium stearate.

[0062] In one embodiment is a tablet composition, wherein the composition comprises

[0063] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount of about 0.8 mg to about 45 mg (based on the free acid);

[0064] a pH adjuster in an amount of about 5 mg to about 15 mg selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate, magnesium hydroxide, and mixtures thereof;

[0065] a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of about 2 mg to about 17.5 mg; and

[0066] A lubricant in an amount of about 1 mg to about 2.5 mg which is magnesium stearate.

[0067] In one embodiment is a tablet composition, wherein the composition comprises

[0068] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount of about 1 to about 36 mg (based on the free acid);

[0069] a pH adjuster in an amount of about 5 mg to about 10 mg selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate and magnesium hydroxide and mixtures thereof;

[0070] a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of about 5 mg to about 20 mg; and

[0071] A lubricant in an amount of about 1 mg to about 2.5 mg which is magnesium stearate.

[0072] In one embodiment is a tablet composition, wherein the composition comprises

[0073] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount of about 1 mg to about 30 mg (based on the free acid);

[0074] a pH adjuster in an amount of about 6 mg to about 8 mg selected from the group consisting of anhydrous calcium carbonate, anhydrous sodium bicarbonate, anhydrous sodium carbonate, hydrated sodium carbonate, and anhydrous magnesium hydroxide;

[0075] a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of about 10 mg to about 18 mg; and

[0076] A lubricant in an amount of about 1.5 mg to about 2 mg, which is magnesium stearate.

[0077] In one embodiment is a tablet composition, wherein the composition comprises

[0078] 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 hydrate in an amount of about 0.8 mg to about 45 mg (based on the free acid);

[0079] a pH adjuster in an amount of about 8 mg, which is anhydrous sodium carbonate;

[0080] a superdisintegrant which is crospovidone in an amount of about 17.5 mg; and

[0081] A lubricant in an amount of about 2 mg, which is magnesium stearate.

[0082] In one embodiment is a tablet composition, wherein the composition comprises

[0083] 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 hydrate in an amount of about 1 mg to about 36 mg (based on the free acid);

[0084] a pH adjuster in an amount of about 8 mg, which is anhydrous sodium carbonate;

[0085] a superdisintegrant which is crospovidone in an amount of about 17.5 mg; and

[0086] A lubricant in an amount of about 2 mg, which is magnesium stearate.

[0087] In one embodiment is a tablet composition, wherein the composition comprises

[0088] 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 hydrate in an amount of about 45 mg to about 60 mg (based on the free acid);

[0089] a pH adjuster in an amount of about 8 mg, which is anhydrous sodium carbonate;

[0090] a superdisintegrant which is crospovidone in an amount of about 17.5 mg; and

[0091] A lubricant in an amount of about 2 mg, which is magnesium stearate.

[0092] In one embodiment, a GLP1RA or a pharmaceutically acceptable salt thereof is prepared as a spray dried dispersion (SDD) for use as an active drug in a tablet composition. In one embodiment, a SDD of a GLP1RA or a pharmaceutically acceptable salt thereof is prepared under conditions as described in Preparation 2 or Preparation 3 below.

[0093] In one embodiment, GLP1RA ("3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one") or GLP1RA-Ca (" 3-[(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 hydrate") is present in the compositions described herein as an SDD formulation.

[0094] In general, the SDD formulations disclosed herein comprise a GLP1RA or a pharmaceutically acceptable salt thereof, and a polymer as a balance component to maintain the amorphous state of the GLP1RA or a pharmaceutically acceptable salt thereof. In one embodiment, the polymer is selected from the group consisting of polyvinylpyrrolidone (also known as "povidone" or "PVP") and polyvinylpyrrolidone vinyl acetate (also known as "copovidone" or "PVP-VA"). In one embodiment, the polymer is PVP-VA. In one embodiment, the polymer is PVP.

[0095] In embodiments where the weight percentage of the GLP1RA or a pharmaceutically acceptable salt thereof in the SDD formulation is specified, the balance of the SDD is a polymer selected from PVP and PVP-VA, i.e., the total weight percentage of the GLP1RA or a pharmaceutically acceptable salt thereof and the polymer is 100 weight percent. In one embodiment, the polymer is PVP-VA. In one embodiment, the polymer is PVP.

[0096] In one embodiment, the SDD formulation comprises about 20 wt % to about 40 wt % of the GLP1RA or GLP1RA-Ca, with the balance consisting of PVP-VA. In one embodiment, the SDD formulation comprises about 30 wt % to about 35 wt % of the GLP1RA or GLP1RA-Ca, with the balance consisting of PVP-VA. In one embodiment, the SDD formulation comprises about 30 wt % of the GLP1RA or GLP1RA-Ca, with the balance consisting of PVP-VA. In one embodiment, the SDD formulation comprises about 30 wt % of the GLP1RA-Ca, with the balance consisting of PVP-VA.

[0097] 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.

[0098] In one embodiment is a tablet composition comprising:

[0099] SDD comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and

[0100] pH adjuster.

[0101] In one embodiment, the pH adjusting agent is selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and mixtures thereof. In one embodiment, the pH adjusting agent is sodium bicarbonate. In one embodiment, the pH adjusting agent is sodium carbonate. In one embodiment, the pH adjusting agent is anhydrous sodium carbonate.

[0102] In one embodiment is a tablet composition comprising:

[0103] about 20 wt % to about 40 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and

[0104] 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.

[0105] In one embodiment is a tablet composition comprising:

[0106] about 30% to about 35% by weight of SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and

[0107] A pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0108] In one embodiment is a tablet composition comprising:

[0109] about 30 wt % to about 35 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter; and

[0110] A pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0111] In one embodiment is a tablet composition comprising:

[0112] about 30 wt % to about 35 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance consisting of a polymer selected from the group consisting of PVP-VA and PVP; wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter; and

[0113] A pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0114] In one embodiment is a tablet composition comprising:

[0115] about 30 wt % to about 35 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate in an amount of about 0.5 mg to about 60 mg (based on the free acid); and the balance consisting of a polymer selected from PVP-VA and PVP; and

[0116] A pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0117] In one embodiment is a tablet composition comprising:

[0118] about 30 wt % to about 35 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate in an amount of about 0.8 mg to about 45 mg (based on the free acid); and the balance consisting of a polymer in the form of PVP-VA; and

[0119] A pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0120] In one embodiment is a tablet composition comprising:

[0121] about 30 wt % to about 35 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate in an amount of about 0.5 mg to about 60 mg (based on the free acid); and the balance consisting of a polymer in the form of PVP-VA; and

[0122] A pH adjuster in an amount of about 1 mg to about 100 mg selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0123] In one embodiment of the above tablet composition, the SDD has an average particle size of about 5 μm to about 113 μm in diameter; and

[0124] The pH adjuster was sodium carbonate.

[0125] In one embodiment of the above-mentioned tablet composition, the composition further comprises:

[0126] a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone; and

[0127] Lubricant.

[0128] In one embodiment of the above tablet composition, the super disintegrant is crospovidone in an amount of about 2 mg to about 250 mg; and

[0129] The lubricant is magnesium stearate in an amount of about 0.1 mg to about 10 mg.

[0130] In one embodiment, disclosed herein is a tablet composition selected from the group consisting of Composition 1 (Comp.1), Composition 2 (Comp.2), Composition 3 (Comp.3), Composition 4 (Comp.4), Composition 5 (Comp.5), Composition 6 (Comp.6), Composition 7 (Comp.7) and Composition 8 (Comp.8) as shown in the following table, wherein the amount of each component of a particular composition is shown as the target amount of the composition. In one embodiment, GLP1RA-Ca is used as an active ingredient, and the amount of each GLP1RA in the composition is based on the free acid.

[0131]

[0132]

[0133] As the skilled person in pharmaceutical preparation can realize, the amount of one or more ingredients of the composition can be changed within certain limits, while maintaining the desired properties of the composition. In addition, when changing the amount of one ingredient, the amount of one or more other ingredients can be adjusted accordingly within a certain range to keep the total weight of the composition constant and maintain the desired properties of the composition.

[0134] In one embodiment of a particular composition shown in the table above, the amount of each ingredient is within the range of the corresponding variable A shown in parentheses as the target amount while maintaining the desired properties of the corresponding composition.

[0135] In one embodiment of a particular composition shown in the table above, the amount of each ingredient is within the range of the corresponding variable B shown in parentheses as the target amount while maintaining the desired properties of the corresponding composition.

[0136] In one embodiment is a method of preparing a composition as claimed herein comprising a spray drying dispersion process.

[0137] In one embodiment is a tablet composition, wherein the composition comprises:

[0138] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount between about 0.5 mg and about 75 mg based on the free acid;

[0139] a pH adjuster in an amount of about 1 mg to about 150 mg selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate, magnesium hydroxide, and mixtures thereof;

[0140] a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of about 1 mg to about 250 mg; and

[0141] A lubricant in an amount of about 0.1 mg to about 10 mg, which is magnesium stearate.

[0142] In one embodiment is a tablet composition as claimed in claim 21, wherein the composition comprises:

[0143] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount between about 0.7 mg and about 60 mg based on the free acid;

[0144] a pH adjuster in an amount of about 2 mg to about 100 mg selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate, magnesium hydroxide, and mixtures thereof;

[0145] a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of about 2 mg to about 200 mg; and

[0146] A lubricant in an amount of about 0.1 mg to about 2.5 mg, which is magnesium stearate.

[0147] In one embodiment is a tablet composition, wherein the composition comprises:

[0148] SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and

[0149] pH adjuster.

[0150] In one embodiment is a tablet composition, wherein the composition comprises:

[0151] about 30 wt % to about 35 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount of about 0.5 mg to about 75 mg based on the free acid; and the balance of the SDD consists of PVP-VA; and

[0152] A pH adjuster in an amount between about 1 mg and about 150 mg selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0153] In one embodiment is a tablet composition, wherein the composition comprises:

[0154] 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-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 0.5Ca hydrate in an amount between about 0.7 mg and about 60 mg based on the free acid; and the balance of the SDD consists of PVP-VA; and

[0155] A pH adjuster in an amount between about 5 mg and about 100 mg selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0156] In one embodiment is a tablet composition, wherein the composition comprises:

[0157] about 30 wt% SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or its 0.5Ca hydrate; the amount of SDD is between about 1.7 mg and about 250 mg; and the balance of the SDD consists of PVP-VA; wherein the SDD is between about 2 wt% and about 25 wt% of the total tablet weight; and

[0158] A pH adjuster in an amount between about 6 mg and about 100 mg, which is sodium carbonate; wherein the pH adjuster is between about 5 wt % and about 15 wt % of the total tablet weight.

[0159] In one embodiment is a tablet composition, wherein the composition comprises:

[0160] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; an amount between about 1.7 mg and about 14.3 mg of SDD; and the balance of the SDD consists of PVP-VA; wherein the SDD is between about 2 wt % and about 16.9 wt % of the total tablet weight; and

[0161] A pH adjuster in an amount of about 6.8 mg, which is sodium carbonate; wherein the pH adjuster is about 8 weight % of the total tablet weight.

[0162] In one embodiment is a tablet composition, wherein the composition comprises:

[0163] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; an amount between about 16.7 mg and about 120 mg of SDD; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 19.5 wt % of the total tablet weight; and

[0164] A pH adjuster in an amount between about 6.8 mg and about 49.2 mg, which is sodium carbonate; wherein the pH adjuster is about 8 weight % of the total tablet weight.

[0165] In one embodiment is a tablet composition, wherein the composition comprises:

[0166] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; an amount between about 150 mg and about 250 mg of SDD; and the balance of the SDD consists of PVP-VA; wherein the SDD is between about 21 wt % and about 25 wt % of the total tablet weight; and

[0167] A pH adjuster in an amount between about 57.1 mg and about 80 mg, which is sodium carbonate; wherein the pH adjuster is about 8 weight % of the total tablet weight.

[0168] In one embodiment of the tablet composition as described above, the SDD has an average particle size of about 5 μm to about 113 μm in diameter.

[0169] In one embodiment is a tablet composition, wherein the composition further comprises: a super disintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

[0170] In one embodiment is a tablet composition wherein:

[0171] The super disintegrant is crospovidone in an amount between about 8.5 mg and about 170 mg; wherein the super disintegrant is between about 10 wt % and about 17 wt % of the total tablet weight.

[0172] In one embodiment is a tablet composition, wherein the composition further comprises:

[0173] A filler in an amount between about 67 mg and about 495 mg, which is MCC; wherein the filler is between about 49.5 wt % and about 79.5 wt % of the total tablet weight.

[0174] In one embodiment is a tablet composition, wherein the composition further comprises:

[0175] An amount of between about 0.4 mg and about 5 mg of a lubricant which is magnesium stearate; wherein the lubricant is between about 0.1 wt % and about 1 wt % of the total tablet weight.

[0176] In one embodiment is a tablet composition, wherein the composition comprises:

[0177] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 19.5 wt % of the total tablet weight;

[0178] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0179] A super disintegrant which is crospovidone; wherein the super disintegrant is about 17 weight % of the total tablet weight; and

[0180] A filler which is MCC; wherein the filler is approximately 55 weight % of the total tablet weight.

[0181] In one embodiment is a tablet composition, wherein the composition comprises:

[0182] about 30 wt % of an SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 25 wt % of the total tablet weight;

[0183] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0184] A super disintegrant which is crospovidone; wherein the super disintegrant is about 17 weight % of the total tablet weight; and

[0185] A filler which is MCC; wherein the filler is approximately 49.5 wt % of the total tablet weight.

[0186] In one embodiment is a tablet composition, wherein the composition comprises:

[0187] about 30 wt % of an SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 21 wt % of the total tablet weight;

[0188] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0189] A super disintegrant which is crospovidone; wherein the super disintegrant is about 17 weight % of the total tablet weight; and

[0190] A filler which is MCC; wherein the filler is approximately 53.5 wt % of the total tablet weight.

[0191] In one embodiment is a tablet composition, wherein the composition comprises:

[0192] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 16.9 wt % of the total tablet weight;

[0193] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0194] A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and

[0195] A filler which is MCC; wherein the filler is approximately 64.6 wt % of the total tablet weight.

[0196] In one embodiment is a tablet composition, wherein the composition comprises:

[0197] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 11.8 wt % of the total tablet weight;

[0198] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0199] A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and

[0200] A filler which is MCC; wherein the filler is approximately 69.7 wt % of the total tablet weight.

[0201] In one embodiment is a tablet composition, wherein the composition comprises:

[0202] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 9.8 wt % of the total tablet weight;

[0203] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0204] A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and

[0205] A filler which is MCC; wherein the filler is approximately 71.7 weight % of the total tablet weight.

[0206] In one embodiment is a tablet composition, wherein the composition comprises:

[0207] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 3.9 wt % of the total tablet weight;

[0208] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0209] A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and

[0210] A filler which is MCC; wherein the filler is approximately 77.6 wt % of the total tablet weight.

[0211] In one embodiment is a tablet composition, wherein the composition comprises:

[0212] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 3.2 wt % of the total tablet weight;

[0213] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0214] A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and

[0215] A filler which is MCC; wherein the filler is approximately 78.3 wt % of the total tablet weight.

[0216] In one embodiment is a tablet composition, wherein the composition comprises:

[0217] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 2.7 wt % of the total tablet weight;

[0218] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0219] A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and

[0220] A filler which is MCC; wherein the filler is approximately 78.8 weight % of the total tablet weight.

[0221] In one embodiment is a tablet composition, wherein the composition comprises:

[0222] about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 2.0 wt % of the total tablet weight;

[0223] a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight;

[0224] A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and

[0225] A filler which is MCC; wherein the filler is approximately 79.5 weight % of the total tablet weight.

[0226] In one embodiment is a tablet composition as described above, wherein said composition further comprises a lubricant which is magnesium stearate; wherein said lubricant is about 0.5 weight % of the total tablet weight.

[0227] In one embodiment is a composition as described above, wherein the composition further comprises an immediate release coating.

[0228] In one embodiment is a tablet composition as described above, wherein the composition further comprises an enteric coating on the immediate release coating.

[0229] Spray dried dispersions (SDD) have been used to prepare pharmaceutical compositions using actives in amorphous form to develop dosage forms for poorly soluble drugs. However, the presence of polymer functional excipients that may be required to maintain the drug in an amorphous state complicates this SDD approach. Compositions that provide acceptable pharmacokinetic performance and a desired food effect profile are particularly challenging for molecules with a strong pH dependent solubility profile. GLP1RA and GLP1RA-Ca exhibit such a pH dependent solubility profile. Weak acids may pose challenges in ensuring that dissolution of the active substance is achieved in the desired portion of the gastrointestinal tract, particularly the stomach, where low pH may delay dissolution of weakly acidic drugs. Certain excipients may become unstable when added to the tablet compositions described herein. In one embodiment, the excipient is stable in a tablet composition with a pH adjuster.

[0230] As used herein, pH adjusters refer to inorganic alkaline salts that can slightly increase pH during tablet disintegration and dissolution, including but not limited to calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, including anhydrous and hydrated forms of the respective salts.

[0231] In one embodiment, a GLP1RA or pharmaceutically acceptable salt composition comprises a pH adjuster that is sodium carbonate. In one embodiment, a GLP1RA or pharmaceutically acceptable salt composition comprises a pH adjuster that is sodium carbonate in anhydrous form.

[0232] In one embodiment is a composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof, and a pH adjuster selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, and mixtures thereof.

[0233] In one embodiment is a composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof, and a pH adjuster selected from the group consisting of calcium carbonate, anhydrous calcium carbonate, sodium bicarbonate, anhydrous sodium bicarbonate, sodium carbonate, anhydrous sodium carbonate, magnesium hydroxide, and anhydrous magnesium hydroxide.

[0234] In one embodiment, the tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof and a pH adjuster is uncoated.

[0235] In one embodiment, the tablet composition is prepared as an immediate release (IR) dosage form, which releases the GLP1RA or a pharmaceutically acceptable salt thereof in the gastric compartment. Excessive pH adjusting agents in the tablet may affect the absorption of co-administered drugs whose absorption is pH sensitive. In one embodiment, the amount of pH adjusting agent is low enough so that it does not increase the overall gastric pH during dissolution, but is sufficient to promote the dissolution of the GLP1RA or a pharmaceutically acceptable salt thereof. An immediate release dosage form with a sufficiently low amount of pH adjusting agent may be required to minimize the possibility of increased gastric pH and drug-drug interactions (DDIs) with co-administered drugs.

[0236] In one embodiment, the tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof and a pH adjuster is coated with an immediate release coating.

[0237] As used herein, the term "immediate release coating" refers to a coating that is primarily intended for aesthetics and is not intended to alter the disintegration and / or dissolution of the tablet. As used herein, suitable immediate release coatings may be selected from known coatings, such as, but not limited to, Clear (03K19229) (Colorcon Inc). Common to moisture-sensitive SDD-based formulations, moisture protection may be required to ensure product functionality and elegance throughout the shelf life. This protection can be achieved through packaging and by using coating materials to minimize moisture absorption by the tablet. One known immediate release coating that performs this function is ambII (Colorcon).

[0238] In one embodiment is a composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof; a pH adjuster; and an immediate release coating.

[0239] In one embodiment, a tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof and a pH adjuster is prepared as a delayed release (DR) dosage form further comprising an enteric coating. The composition further comprising an enteric coating can be released in the intestine at a pH of 5.5 or higher. The GLP1RA or a pharmaceutically acceptable salt thereof may need to be released in the intestine to limit the risks that may be associated with the presence of a pH adjuster in the tablet. The DR composition can minimize potential food effects and can have other favorable effects on pharmacokinetic characteristics, such as, but not limited to, regulation of overall exposure and Cmax.

[0240] As used herein, "enteric coating" refers to a functional coating intended to prevent tablet disintegration and / or dissolution in the gastric environment and instead dissolve in the intestinal environment.

[0241] In one embodiment is a composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof; a pH adjuster; and an enteric coating.

[0242] In one embodiment is a tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof; a pH adjuster; and a superdisintegrant.

[0243] In one embodiment is a tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof; a pH adjuster; a superdisintegrant; and a lubricant.

[0244] In one embodiment is a tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof; a pH adjuster; a superdisintegrant; and an enteric coating on the tablet.

[0245] In one embodiment is a tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof; a pH adjuster; a superdisintegrant; and an immediate release coating on the tablet.

[0246] As used herein, the terms "superdisintegrant" and "disintegrant" are interchangeable and refer to excipients that promote the desired dissolution of a GLPRA or a pharmaceutically acceptable salt thereof, including but not limited to croscarmellose sodium and crospovidone. The term "superdisintegrant" refers to an excipient that preferably promotes the dissolution of a GLP1RA or a pharmaceutically acceptable salt thereof within 30 to about 60 minutes. In one embodiment, a tablet composition comprises a GLP1RA or a pharmaceutically acceptable salt thereof; a pH adjuster; and a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

[0247] In one embodiment is a tablet composition comprising a GLP1RA or a pharmaceutically acceptable salt thereof; a pH adjuster and crospovidone.

[0248] In one embodiment, the desired tablet composition provides reliable PK performance in a patient-friendly dosage form. A patient-friendly tablet composition dosage form with an acceptable size is desired to facilitate swallowing during daily administration, has minimal potential for drug-drug interactions (DDI) with other concomitant medications, and has minimal restrictions on use, including minimizing food effects, avoiding restrictions on dosing time, and avoiding restrictions on the volume of liquid used to aid swallowing.

[0249] Tablet compositions can be released in the gastric compartment or in the intestine (enteric) by an erosion mechanism. The dosage forms of the present invention offer the potential for improved absorption / PK performance. The dosage forms provided herein can reduce unwanted drug-drug interactions.

[0250] Certain abbreviations are defined as follows: “cfm” means cubic feet per minute; “Cmax” means the maximum plasma concentration of the drug achieved in the test area after administration of the drug and before administration of the second dose; “DDI” means drug-drug interaction; “DR” means delayed release; “EtOH” means ethanol or ethyl alcohol; “FaSSiF” means fasted state simulated intestinal fluid; “FaSSGF” means fasted state simulated gastric fluid; “FeSSIF” means fed state simulated intestinal fluid; “hr” means hour; “hrs” means hours; “IR” means immediate release; “PK” means pharmacokinetics;

[0251] "MeOH" refers to methanol or methyl alcohol; "rpm" refers to revolutions per minute; "PVP-VA" refers to polyvinyl pyrrolidone / vinyl acetate copolymer; "SDD" refers to spray dried dispersion;

[0252] "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 the mass of material required / total mass; XRPD refers to X-ray powder diffraction. As used herein, "prep" refers to a preparation.

[0253] A skilled person can prepare 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, spray dried dispersion (SDD) formulation under various processing conditions and using various equipment to produce materials with suitable quality and key properties.

[0254] In one embodiment, the GLP1RA or GLP1RA-Ca in the SDD formulation is amorphous, has the desired weight % of drug (30%) and PVP-VA (70%), has a particle size that can be isolated and further processed, and is acceptably free of process-related impurities and excess residual solvents as measured by XRPD.

[0255] In one embodiment, an amorphous solid dispersion may be used in the preparation method. In one embodiment, the particle size is about 5 to about 113 μm for preparing the tablet composition.

[0256] Capsules used in the assays herein were prepared using conventional encapsulation methods.

[0257] Preparation 1

[0258] 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 hydrate

[0259]

[0260] Example 1 can be prepared as described in WO 18 / 056453.

[0261] The title compound has aliases. For example, it is also known as the hemi-calcium salt hydrate of orforglipron.

[0262] 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.

[0263] Preparation 2

[0264] 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 hydrate, SDD preparation

[0265] The 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate (8.7 g, 92% potency) and PVP-VA (also known as copolyvidone, CA) were prepared by mixing at room temperature 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 hydrate (8.7 g, 92% potency) and PVP-VA (also known as copolyvidone, CA S#25086-89-9) (18.7 g) was dissolved in EtOH (200 mL) to prepare 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, 0.5 Ca SDD. After the solids were dissolved, the solution was spray dried on a conventional spray dryer with a pressure nozzle. The following parameters in Table 1 were used to make the dispersion using a laboratory scale spray dryer. Spray drying can be started when the spray dryer temperature is above 33° C. The material is collected and dried under vacuum at 50° C. overnight to give the title compound (21.99 g, 7.0 g, 92% potency, 80% recovery), which is observed by microscopy as non-birefringent particles with a diameter of approximately 5-25 μm under a microscope.

[0266] SDD parameters

[0267] Table 1

[0268] Process parameters value Suction device 100％ Atomization flow 37mm(~400L / hr) Solution flow 40%(12.5mL / min) Cooler temperature -20℃ Drying gas inlet temperature 120℃ Spray dryer outlet temperature (℃) 75℃

[0269] Preparation 3

[0270] 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 hydrate, SDD preparation

[0271] 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 hydrate was dissolved in EtOH and denatured with MeOH (5% v / v or w / w). A solution with 20% w / w solids content (based on free acid) was prepared with 30% w / w of the solid fraction consisting of the title compound, the balance consisting of PVP-VA. This translates to 6% of the title compound (based on free acid), 14% PVP-VA and 80% of denatured EtOH SDA-3A - all fractions are w / w. After spray drying, the solid formed consisted of 30% w / w of a solid fraction consisting of the title compound (based on free acid) and the remainder consisted of PVP-VA. The % values ​​are shown in Table 2 below.

[0272] Formulation of Preparation 3SDD

[0273] Table 2

[0274] Solution (mass fraction) Amorphous SDD (mass fraction) Title compound 6％ 30.0％ PVP-VA 14％ 70.0％ EtOH SDA-3A 80％ EtOH 76％ MeOH 4％

[0275] Once the solution is prepared, it is pumped into a spray dryer where it is atomized upon entry. The heated drying gas enters the top of the spray drying chamber co-currently with the atomized liquid, with a ratio of spray solution to drying gas of approximately 0.044 kg / kg. The inlet temperature is adjusted to provide an outlet temperature of 35 to 45°C. The solids formed in the spray dryer are collected from the cyclone separator and the filter housing on the gas stream. The gas passes through a condenser maintained at -3°C to remove (to a dew point of -3°C) the solvent. The gas is then heated to the inlet temperature and sent back to the spray dryer.

[0276] Preparation 4

[0277] 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 hydrate

[0278] Capsule preparation

[0279] Capsules were prepared by first adding sodium bicarbonate (600 mg) to a size 0 hypromellose capsule and then adding Formulation 3 SDD (54 mg).

[0280] Quantitative capsule composition, preparation 4

[0281] Table 3

[0282] capsule weight% mg / tablet Preparation 3SDD 8.26 54 Sodium bicarbonate (anhydrous) 91.74 600 total 100 654

[0283] Preparation 5

[0284] 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 hydrate, tablet formulation

[0285] Tablet composition preparation

[0286] To prepare the tablet core, 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 hydrate (13.3% w / w) SDD and excipients except magnesium stearate (as shown in Examples 1 to 7) were sieved through a 600 μm sieve before use. The materials were added to a container (1000 mL) and mixed with a mixer at 32 rpm for approximately 10 minutes. The mixture blend was passed through a screen (600 μm) and mixed twice with a mixer at 32 rpm for about 10 minutes. Magnesium stearate was added and the mixture was mixed at 32 rpm for about 3 minutes. The mixture blend was compressed on a single station tablet press using 14.10×7.75 mm oval tablet tools to produce tablets (400.0 mg) with a hardness of 30 kP.

[0287] Tablet compositions were prepared substantially as described above using the parameters of Tables 4 to 10 below to prepare corresponding Examples 1 to 7 (compositions T1, T2, A, B, C, D and E). Each of Examples 1 to 7 includes an IR coating substantially as described herein, and the tablets in Examples 1-6 may additionally include an enteric coating. The tablet of Example 7 includes only an IR coating.

[0288] Example 1 Tablet composition T1

[0289] Table 4

[0290]

[0291]

[0292] Example 2 Tablet composition T2 Table 5

[0293]

[0294] Example 3 Tablet Composition A Table 6

[0295]

[0296]

[0297] Example 4 Tablet Composition B Table 7

[0298]

[0299] Example 5 Tablet Composition C Table 8

[0300]

[0301]

[0302] Example 6 Tablet Composition D

[0303] Table 9

[0304]

[0305] Example 7 Tablet Composition E

[0306] Table 10

[0307]

[0308] *The numbers in () represent the theoretical target of GLP1RA. The immediate-release coated immediate-release tablets used in Examples 1 to 7

[0309] Coating

[0310] A core composition prepared substantially as described in each of Examples 1 to 7 is film coated with an immediate release coating, such as Clear (03K19229) (Colorcon Inc) with a target 3 wt% weight gain (acceptable range is 2.5 to 3.5%). Tablets were coated using water as the base of the spray suspension using conventional pan coating equipment and the coating conditions recommended by the supplier. Composition Examples 1 to 7 were coated using this immediate release coating.

[0311] Example 8

[0312] Delayed release tablet composition coating (enteric coating)

[0313] The tablet compositions of Examples 1-6 are prepared substantially as described above. Clear coating. Clear coated tablets (93Al 8597) (Colorcon Inc) and 8 wt% PEG 8000 as plasticizer relative to Acryl-EZE were further enteric coated to a target 6.75 wt% weight gain (acceptable range 6.25 to 7.25%). Tablets were coated using conventional pan coating equipment under the coating conditions recommended by the supplier using water as the base for the spray suspension.

[0314] Example 9

[0315] Enteric Coated Tablet Compositions - Enteric coated tablets were prepared using tablet compositions substantially as described in Examples 1 to 6 except that the weight % of sodium carbonate was adjusted and compensated by adjusting the microcrystalline cellulose content. 03K19229 (Colorcon Inc.) using 8 wt% solids in the spray suspension to a target weight gain of 3%. The tablets were coated using a benchtop coating pan with a 0.8 mm orifice spray nozzle spray gun with an AntiBearding Cap, an inlet air flow of 30 cfm, an inlet air temperature of 70°C, a spray suspension rate of 2.3 g / min, an atomization pressure of 1.5 bar, a pattern air pressure of 0.25 bar, and a pan speed of 32 rpm. The tablets were then enteric coated with Acryl-EZE 93A18597 (Colorcon Inc.) using the same equipment to a target weight gain of approximately 6.5%. An aqueous suspension was prepared at 20 wt% Acryl-EZE powder, and 8 wt% PEG-8000 was added as a plasticizer relative to Acryl-EZE. The coating conditions were as follows: 0.8 mm orifice spray nozzle spray gun with AntiBearding Cap, 25 cfm inlet air flow, 60°C inlet air temperature, 4.1 g / min spray suspension rate, 1.5 bar atomization pressure, 0.25 bar pattern air pressure, and 35 rpm pan speed.

[0316] Example 10

[0317] Quantitative IR tablet composition

[0318] Table 11

[0319] IR Tablets weight% mg / tablet Preparation 3SDD 13.3 53.3 Microcrystalline cellulose 102 64.2 256.7 Sodium carbonate (anhydrous) 15 60 Crospovidone 5 20 Magnesium Stearate 0.5 2 Silicon dioxide 2 8 total 100 400

[0320] Embodiment 11

[0321] Alternative tablet compositions with super disintegrant croscarmellose sodium

[0322] Table 12

[0323] weight% mg / tablet Preparation 3SDD 13.9 55.8 Microcrystalline cellulose 102 58 232 Sodium carbonate (anhydrous) 20 80 Croscarmellose Sodium 5 20 Magnesium Stearate 1 4 Silicon dioxide 2 8 total 100 400

[0324] Example 12

[0325] Alternative tablet compositions with superdisintegrant crospovidone

[0326] Table 13

[0327]

[0328]

[0329] Tablet compositions were prepared with these superdisintegrants in the formulations shown in Tables 11 and 12. All materials except magnesium stearate were added to an amber glass jar and mixed using a rotary diffusion mixer at 22 rpm for 10 minutes. The blend was passed through a #35 mesh screen and then mixed for an additional 10 minutes. Magnesium stearate was passed through a #35 mesh screen and added to the jar and blended for 5 minutes. The blend was compressed using a single station tablet press using a modified oval tool at a compression force of 6 kN. The core tablets were 03K19229 (Colorcon Inc.) using 8 wt% solids in the spray suspension to a 3% weight gain target. The tablets were coated using a benchtop coating pan with a 0.8 mm orifice spray nozzle spray gun with an AntiBearding Cap, an inlet air flow of 30 cfm, an inlet air temperature of 70°C, a spray suspension rate of 2.3 g / min, an atomization pressure of 1.5 bar, a pattern air pressure of 0.25 bar, and a pan speed of 32 rpm. The tablets were then enteric coated with Acryl-EZE 93A18597 (Colorcon Inc.) using the same equipment to a 6.5% weight % weight gain target. An aqueous suspension was prepared at 20 wt% Acryl-EZE powder, and 8 wt% PEG-8000 was added as a plasticizer relative to Acryl-EZE. The coating conditions were as follows: 0.8 mm orifice spray nozzle spray gun with AntiBearding Cap, 25 cfm inlet air flow, 60°C inlet air temperature, 4.1 g / min spray suspension rate, 1.5 bar atomization pressure, 0.25 bar pattern air pressure, and 35 rpm pan speed.

[0330] Embodiment 13

[0331] Tablet composition 400 mg total weight tablet

[0332] Total weight tablets (400 mg) were prepared using the percentages in Table 14. Tablets were prepared essentially as described in Example 9, coated with an immediate release coating and then with an enteric coating.

[0333] Table 14

[0334]

[0335]

[0336] Embodiment 14

[0337] Tablet composition 9-30

[0338] Tablet core compositions 9-30 (Comp. 9 - Comp. 30) were prepared using the percentages in the table below and as described above. Tablet cores were prepared essentially as described in Example 9, coated with an immediate release coating, and optionally, further coated with an enteric coating.

[0339]

[0340]

[0341]

[0342]

[0343] Particle size measurement

[0344] The 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%, universal model. Volume-based distribution was measured and (D10, D50, D90) quantiles were reported.

[0345] The average particle size of the SDD of Formulations 2 and 3, as measured by the method described above, was about 40 to about 65 μm in diameter, or more specifically, about 40 to about 50 μm in diameter.

[0346] Solubility studies

[0347] 24-hour water solubility of crystalline GLP1RA-Ca at 25°C

[0348] Table 15

[0349] Solvents Medium pH Solubility at 25℃(mg / mL) water NM* 0.028 0.1N HCl 1.01 <0.001 0.01N HCl 1.98 <0.001 pH 4.5 Acetate Buffer (USP) 4.5 <0.001 pH 6.0 Phosphate Buffer (USP) 5.99 <0.001 pH 7.5 Phosphate Buffer (USP) 7.44 0.003 Simulated gastric fluid 1.97 0.003 Fasting state simulated intestinal fluid 6.49 0.002 Simulated intestinal fluid in the fed state 4.93 0.013

[0350] *Not measured

[0351] One embodiment of the present invention is an oral tablet formulation comprising an amorphous SDD of GLP1RA-Ca. The crystalline form of GLP1RA-Ca has poor water solubility as shown in Table 15. Amorphous SDD of GLP1RA-Ca using PVP-VA as a carrier polymer has been shown to provide improved hydrophilicity and solubility compared to crystalline GLP1RA-Ca (Table 16).

[0352] 24-hour water solubility of formulation 3SDD at 25°C

[0353] Table 16

[0354]

[0355]

[0356] 24-hour water solubility of formulation 3SDD at 37°C

[0357] Table 17

[0358]

[0359] As seen in Tables 16 and 17, Formulation 3 has pH-dependent solubility. At a pKa of 5.1, it is expected that the solubility of the drug begins to increase at pH values ​​close to the pKa, and the dissolution performance improves at pH values ​​equal to or above the pKa. To test this, capsules containing SDD and sodium bicarbonate in an amount sufficient to raise the pH of the acidic dissolution medium to near the pKa were evaluated in dissolution experiments compared to tablets containing much less pH adjusters. The quantitative formulations of the tablets are shown in Table 11 and the quantitative formulations of the capsules are shown in Table 3.

[0360] Dose dissolution studies

[0361] The dosage form was evaluated in a 2-stage dissolution test consisting of an acid stage (500 mL 0.0133N HCl / 8.12 mM NaCl) for 1 hour followed by the addition of concentrated FaSSIF (400 mL) to convert the medium to the same pH and composition as normal fasting state intestinal fluid. To prepare each 1 L of concentrated FaSSiF, sodium phosphate dibasic anhydrous (5.714 g), sodium phosphate monobasic anhydrous (2.906 g) and NaCl (12.354 g) were added to 1 L along with water and mixed thoroughly. The pH should be approximately 7.0. SIF powder (5.6 g) (FaSSIF / FeSSIF / FaSSGF powder (Biorelevant)) was added.

[0362] The assay was performed using a USPII dissolution apparatus at 100 rpm. Aliquots were removed, filtered through a 0.22 micron filter, diluted 1 :1 with MeOH to prevent drug precipitation and analyzed by HPLC.

[0363] It was surprisingly found that the IR tablets performed better than the capsule formulation in the gastric phase, although the capsule formulation raised the pH in the medium to above 5 due to the large amount of sodium bicarbonate and the tablets had no effect on the medium pH, which remained at pH 2.

[0364] Comparison of dissolution between Example 10 tablets and Formulation 4 capsules

[0365] Table 18

[0366]

[0367] StDev refers to standard deviation.

[0368] Alternative dissolution conditions were also used to compare Capsule Formulation 4 and IR Tablet Composition Example 7. The conditions used were USPII paddle at 100 rpm with 50 mM pH 6.8 phosphate buffer containing 2% sodium dodecyl sulfate as the dissolution medium. The samples were analyzed by HPLC.

[0369] Surprisingly, despite the significant amount of sodium bicarbonate to promote dissolution of SDD from the capsules, the IR tablets still released faster than the capsules, achieving 100% release within 30 minutes, while the capsules only achieved 35% release at 30 minutes and did not achieve >90% release until approximately 75 minutes.

[0370] Alternative dissolution conditions for Formulation 4 capsules

[0371] Table 19

[0372] Time (minutes) %release 10 0.40 20 14.20 30 35.20 45 71.80 60 87.00 75 94.80 90 96.20 120 96.60

[0373] Composition Example 7 Alternative Dissolution Conditions

[0374] Table 20

[0375] Time (minutes) %release 15 90.90 30 100.50 45 100.70 60 100.70 90 100.80 120 100.80 150 100.80

[0376] The pH regulator in IR and DR tablets promotes the dissolution of weakly acidic drugs by increasing the local or micro pH of the tablets when the tablets disintegrate. Enteric tablets are used to find the content of pH regulators required for enteric tablet compositions. The enteric coated tablets of Example 9 were tested in a 2-stage dissolution test using a USPII device with a paddle speed of 100 rpm. First, an acid challenge stage was performed for 2 hours in pH 4.5 sodium acetate buffer (500 mL), after which the tablets were taken out and placed in FaSSiF (Biorelevant) (500 mL). An aliquot was taken out, filtered through a 0.22 micron filter, diluted with MeOH 1: 1 to prevent drug precipitation and analyzed by HPLC.

[0377] Surprisingly, very high levels of pH adjuster (20 wt% in tablet) resulted in poorer dissolution behavior for DR tablets compared to lower levels. In addition, optimal peak levels and more sustained dissolution were achieved at approximately 10 wt% sodium carbonate.

[0378] For dissolution studies of delayed-release tablets

[0379] Table 21

[0380]

[0381]

[0382] nm = not measured

[0383] Tablets of Example 11 and Example 12 were tested in a 2-stage dissolution test using a USPII apparatus with a paddle speed of 100 rpm. The acid challenge stage was 2 hours in pH 4.5 sodium acetate buffer (500 mL), after which the tablets were removed and placed in FaSSiF (Biorelevant) (500 mL). An aliquot was removed, filtered through a 0.22 micron filter, diluted 1:1 with MeOH to prevent drug precipitation and analyzed by HPLC.

[0384] Surprisingly it was found that croscarmellose sodium as used in Example 11 did not provide the desired release profile, whereas crospovidone as used in Example 12 did.

[0385] Two-stage dissolution testing of tablets

[0386] Table 22

[0387]

[0388]

[0389] In further embodiments, the rate of release from an enteric coated tablet may be controlled to affect specific aspects of the PK profile, such as Cmax or peak / trough plasma concentrations, as these may be beneficial to the patient to aid tolerability and / or efficacy.

[0390] As in hydrophilic sustained-release matrix tablets, controlled release of tablets is often achieved using rate-controlling polymers such as hypromellose. The challenge with hypromellose or similar polymers is that they tend to act over hours via diffusion and / or erosion mechanisms. This time span may be too long for low-permeability molecules, where if the drug is gradually released over many hours, the drug concentration in the intestinal lumen cannot be maximized, which may lead to reduced flux across the intestinal epithelium and subsequent lower absorption.

[0391] Surprisingly, it was found that controlling the amount of superdisintegrant in an enteric coated dosage form enables a significant degree of control over the release rate within the desired complete release time of less than 30 minutes.

[0392] Tablets T1 and T2 were evaluated in a 2-stage dissolution test essentially similar to that already described, except that the pH 4.5 sodium acetate stage was set for 1 hour and the tablets were then transferred to FaSSiF (Biorelevant). The results are shown in Table 23.

[0393] Surprisingly, simply adjusting the disintegrant content can achieve controlled release levels in FaSSiF.

[0394] Two-stage dissolution study of tablets T1 and T2 at pH 4.5

[0395] Table 23

[0396]

[0397] Another lever to adjust the release of drug from enteric coated tablets is to vary the amount of sodium carbonate. The tablets were dissolved in pH 6.8 phosphate buffer containing 2% sodium lauryl sulfate as described herein. The results of this study demonstrated that there is a synergistic effect between the amount of disintegrant content and the amount of pH adjuster that can be used to control the release of drug from the tablet. In addition, the release was controlled within a desired range of 30 minutes to no more than 3 hours to simulate the approximate in vivo transit time through the small intestine, where most drug absorption is expected to occur. The results are shown in Table 24.

[0398] Study on dissolution time of composite tablets T1, T2, A, B, C, D at pH 6.8

[0399] Table 24

[0400]

[0401] Clinical trials

[0402] A multiple dose escalation study was conducted to characterize and compare the pharmacokinetics (PK) of the prototype formulations of Formulation 4 (capsules), Example 1 (DR tablet composition T1 with enteric coating as prepared in Example 9, hereinafter referred to as T1DR tablets), and Example 7 (IR tablet composition E with immediate release coating, hereinafter referred to as E IR tablets). The study was conducted in two parts: A and B.

[0403] Part A evaluates the safety, tolerability and PK of multiple oral doses of GLP1RA preparation prototypes T1 and E relative to reference capsule preparation 4 in healthy participants. The dose titration period is from the 1st day to the 18th day, in which participants receive increasing doses of GLP1RA in capsules for dose titration. The intra-treatment dose escalation is once every 6 days, and the maximum dose of 16mgGLP1RA is reached on the 19th day, once a day (QD). From the 19th day to the 24th day, participants receive reference capsule preparation 4 (16mgQD) and then enter the trial period from the 25th day to the 36th day. During the trial period-1, according to their randomization, GLP1RA prototype tablets (16mg QD) preparations are administered to participants. Then participants cross into Phase 2 on Day 31 and receive the second prototype tablet (16mg QD) until Day 36.

[0404] Table 25. Geometric mean (geometric CV%) plasma pharmacokinetic parameters of GLP1RAs following single and multiple oral doses of GLP1RAs in healthy male and female participants

[0405]

[0406] Abbreviations: AUC(0-24) = area under the curve from 0 to 24 hours after dosing; Cmax = maximum observed concentration; Frel AUC(0-24) = relative bioavailability based on AUC(0-24); Frel Cmax = relative bioavailability based on Cmax; h = hours; N / A = not applicable

[0407] The results of Part A showed that the mean peak and total exposure levels (as measured by Cmax and AUC(0-24)) of the 16 mg DR tablets at T1 were approximately 67% and 50% higher than those of the 16 mg reference formulation 4 capsules, respectively. These increases were statistically significant at the 10% significance level (p<.001 for Cmax and AUC(0-24)).

[0408] Similarly, for the 16 mg Tablet E IR tablets, the mean peak and total exposure levels (as measured by Cmax and AUC(0-24)) were approximately 47% and 41% higher than the 16 mg reference capsules, respectively. These increases were statistically significant at the 10% significance level (p = .007 and p < .001 for Cmax and AUC(0-24), respectively).

[0409] Part B further evaluated Tablet E IR tablets in terms of food effect and DDI effect with co-administered proton pump inhibitors (PPIs). As in Part A, treatment escalation was performed every 6 days during the titration period, and the maximum dose of 16 mg QD was reached on Day 19. Treatment was then continued with GLP1RA in the fasting or fed state, and with co-administered PPIs in the fasting state. Each option started with a 6-day reference period (16 mg QD) using Tablet E IR tablets as a reference, followed by two 6-day test periods (16 mg QD).

[0410] Table 26: Geometric mean (geometric CV%) plasma pharmacokinetic parameters of GLP1RAs following single and multiple oral doses of GLP1RAs in healthy male and female participants

[0411]

[0412] Abbreviations: AUC(0-24) = area under the curve from 0 to 24 hours after dosing; Cmax = maximum observed concentration; Frel AUC(0-24) = relative bioavailability based on AUC(0-24); Frel Cmax = relative bioavailability based on Cmax; h = hours; N / A = not applicable

[0413] The results of Part B demonstrated that the mean peak and total exposure levels (as measured by Cmax and AUC(0-24)) of 16 mg Tablet E IR tablets in the fed state were comparable to those of 16 mg Tablet E IR tablets in the fasted state (i.e., fed exposures were within 11% and 4% of fasting exposures for Cmax and AUC(0-24), respectively) (p = .39 and p = .66 for Cmax and AUC(0-24), respectively).

[0414] For the 16 mg Tablet E IR tablets with PPI, mean peak and total exposure levels (as measured by Cmax and AUC(0-24)) were also comparable to the 16 mg IR tablet Composition E (i.e., 6% lower and 6% higher for Cmax and AUC(0-24), respectively) (p=.65 and p=.57 for Cmax and AUC(0-24), respectively).

[0415] Although the present invention has been described in considerable detail with reference to certain aspects of the invention, other versions are possible. The embodiments disclosed herein are for illustrative purposes only, and various modifications to the embodiments and further embodiments thereof, in addition to those shown and described herein, will be apparent to those skilled in the art from the full content of this specification.

Claims

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

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

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

4. The composition of claim 3, wherein the pH adjusting agent is anhydrous.

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

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

7. The composition according to any one of claims 1 to 6, wherein the composition comprises: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; pH adjusters; and Super disintegrant.

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

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

10. The composition according to any one of claims 1 to 9, wherein the composition comprises: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; pH adjusters; super disintegrants; and Lubricant.

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

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

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

14. The composition according to any one of claims 1 to 13, wherein the 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one salt is: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate.

15. The composition according to any one of claims 1 to 14, wherein the 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof is 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 hydrate; the amount is between about 0.7 and about 50 mg per tablet composition based on the free acid.

16. The composition of claim 15, wherein the 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate is in an amount of about 48 mg per tablet.

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

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

19. A method for preparing a composition according to any one of claims 1 to 16, comprising a spray-dried dispersion of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof.

20. The composition of claim 19, wherein the spray-dried dispersion of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof further comprises a PVP-VA polymer.

21. A tablet composition, wherein the composition comprises: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount between about 0.5 mg and about 75 mg based on the free acid; a pH adjuster in an amount of about 1 mg to about 150 mg selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate, magnesium hydroxide, and mixtures thereof; a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of about 1 mg to about 250 mg; and A lubricant in an amount of about 0.1 mg to about 10 mg, which is magnesium stearate.

22. The tablet composition according to claim 21, wherein the composition comprises: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount between about 0.7 mg and about 60 mg based on the free acid; a pH adjuster in an amount of about 2 mg to about 100 mg selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate, magnesium hydroxide, and mixtures thereof; a superdisintegrant selected from the group consisting of croscarmellose sodium and crospovidone in an amount of about 2 mg to about 200 mg; and A lubricant in an amount of about 0.1 mg to about 2.5 mg, which is magnesium stearate.

23. A tablet composition, wherein the composition comprises: SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and pH adjuster.

24. The tablet composition according to claim 23, wherein the composition comprises: about 30 wt % to about 35 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount of about 0.5 mg to about 75 mg based on the free acid; and the balance of the SDD consists of PVP-VA; and A pH adjuster in an amount between about 1 mg and about 150 mg selected from the group consisting of sodium bicarbonate and sodium carbonate.

25. A tablet composition according to any one of claims 23 to 24, wherein the composition comprises: 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-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 0.5Ca hydrate in an amount between about 0.7 mg and about 60 mg based on the free acid; and the balance of the SDD consists of PVP-VA; and A pH adjuster in an amount between about 5 mg and about 100 mg selected from the group consisting of sodium bicarbonate and sodium carbonate.

26. The tablet composition of claim 24, wherein the composition comprises: about 30 wt% SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or its 0.5Ca hydrate; the amount of SDD is between about 1.7 mg and about 250 mg; and the balance of the SDD consists of PVP-VA; wherein the SDD is between about 2 wt% and about 25 wt% of the total tablet weight; and A pH adjuster in an amount between about 6 mg and about 100 mg, which is sodium carbonate; wherein the pH adjuster is between about 5 wt % and about 15 wt % of the total tablet weight.

27. The tablet composition according to claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; an amount between about 1.7 mg and about 14.3 mg of SDD; and the balance of the SDD consists of PVP-VA; wherein the SDD is between about 2 wt % and about 16.9 wt % of the total tablet weight; and A pH adjuster in an amount of about 6.8 mg, which is sodium carbonate; wherein the pH adjuster is about 8 weight % of the total tablet weight.

28. The tablet composition according to claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; an amount between about 16.7 mg and about 120 mg of SDD; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 19.5 wt % of the total tablet weight; and A pH adjuster in an amount between about 6.8 mg and about 49.2 mg, which is sodium carbonate; wherein the pH adjuster is about 8 weight % of the total tablet weight.

29. The tablet composition according to claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; an amount between about 150 mg and about 250 mg of SDD; and the balance of the SDD consists of PVP-VA; wherein the SDD is between about 21 wt % and about 25 wt % of the total tablet weight; and A pH adjuster in an amount between about 57.1 mg and about 80 mg, which is sodium carbonate; wherein the pH adjuster is about 8 weight % of the total tablet weight.

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

31. The tablet composition of claim 30, wherein the composition further comprises: A super disintegrant selected from the group consisting of croscarmellose sodium and crospovidone.

32. The tablet composition according to claim 31, wherein: The super disintegrant is crospovidone in an amount between about 8.5 mg and about 170 mg; wherein the super disintegrant is between about 10 wt % and about 17 wt % of the total tablet weight.

33. The tablet composition of claim 32, wherein the composition further comprises: A filler in an amount between about 67 mg and about 495 mg, which is MCC; wherein the filler is between about 49.5 wt % and about 79.5 wt % of the total tablet weight.

34. The tablet composition of claim 33, wherein the composition further comprises: A lubricant in an amount between about 0.4 mg and about 5 mg, which is magnesium stearate; wherein the lubricant is between about 0.1 wt % and about 1 wt % of the total tablet weight.

35. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 19.5 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 17 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 55 weight % of the total tablet weight.

36. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % of an SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 25 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 17 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 49.5 wt % of the total tablet weight.

37. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % of an SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 21 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 17 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 53.5 wt % of the total tablet weight.

38. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 16.9 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 64.6 wt % of the total tablet weight.

39. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 11.8 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 69.7 wt % of the total tablet weight.

40. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 9.8 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 71.7 weight % of the total tablet weight.

41. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 3.9 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 77.6 wt % of the total tablet weight.

42. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 3.2 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 78.3 wt % of the total tablet weight.

43. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 2.7 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 78.8 weight % of the total tablet weight.

44. The tablet composition of claim 26, wherein the composition comprises: about 30 wt % SDD of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate; and the balance of the SDD consists of PVP-VA; wherein the SDD is about 2.0 wt % of the total tablet weight; a pH adjuster which is sodium carbonate; wherein the pH adjuster is approximately 8 weight % of the total tablet weight; A super disintegrant which is crospovidone; wherein the super disintegrant is about 10 weight % of the total tablet weight; and A filler which is MCC; wherein the filler is approximately 79.5 weight % of the total tablet weight.

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

46. ​​The tablet composition of claim 44, wherein the SDD has an average particle size of about 40 μm to about 65 μm in diameter.

47. A tablet composition according to any one of claims 21 to 46, wherein the composition further comprises a lubricant which is magnesium stearate; wherein the lubricant is approximately 0.5 wt% of the total tablet weight.

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

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

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

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

Images