GLP1 pharmaceutical composition

Abstract

The present invention relates to an oral capsule 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, 5-a] pyrimidine-2-yl]-3-(4-fluoro-1-methylindazol-5-yl)-4-methyl-6, 7-dihydro-4H-pyrazolo [4, 5-a] pyrimidine-2-yl]-3-(4-fluoro-1-methylindazol-5-yl)-4, 4 '- The invention relates to a pharmaceutical composition, in particular to a pharmaceutical composition containing 4-(2, 3-c) pyridine-5-carbonyl] indole-1-yl]-2-methylcyclopropyl]-4H-1, 2, 4-oxadiazole-5-ketone or a pharmaceutically acceptable salt thereof. And a pH adjusting agent.

Description

[0001] The present invention relates to an oral capsule 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 and its pharmaceutically acceptable salts have very low water solubility within the physiological pH range and in simulated physiological fluids. It has been observed that GLP1RA has a strongly pH-dependent solubility curve, which poses challenges such as absorption variability and the resulting pharmacokinetic performance and potential food effects. It is expected that GLP1RA (including but not limited to GLP1RA-Ca) capsule 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 capsule dosage form may be required. 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 treatment for chronic weight management.

[0009] In one embodiment is a capsule 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 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.

[0013] In one embodiment is a capsule composition comprising

[0014] 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

[0015] 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, magnesium hydroxide and anhydrous magnesium hydroxide.

[0016] In one embodiment, the pH adjusting agent is sodium bicarbonate. In one embodiment, the pH adjusting agent is sodium carbonate.

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

[0018] In one embodiment is a capsule composition comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and

[0019] A pH adjuster, wherein the pH adjuster is anhydrous sodium bicarbonate.

[0020] In one embodiment is a composition, wherein the composition comprises

[0021] 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

[0022] pH adjuster, wherein the pH adjuster is selected from sodium bicarbonate, anhydrous sodium bicarbonate, hydrated sodium bicarbonate, sodium carbonate and anhydrous sodium carbonate.

[0023] In one embodiment is a composition, wherein the composition comprises

[0024] 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

[0025] A pH adjuster, wherein the pH adjuster is sodium bicarbonate.

[0026] In one embodiment is a composition, wherein the composition comprises

[0027] 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

[0028] A pH adjuster, wherein the pH adjuster is sodium bicarbonate.

[0029] In one embodiment is a composition, wherein the composition comprises

[0030] 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

[0031] A pH adjuster, wherein the pH adjuster is sodium carbonate.

[0032] In one embodiment, a capsule composition comprises 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one; and a pH adjuster.

[0033] In one embodiment is a capsule composition comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate in an amount of about 0.5 to about 46 mg per capsule composition.

[0034] In one embodiment is a composition comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate in an amount of about 46 mg per capsule composition.

[0035] In one embodiment is a method of preparing a capsule composition as disclosed herein comprising an amorphous dispersion process. In one embodiment is a method of preparing a capsule composition as claimed herein comprising a spray dried dispersion (SDD) process.

[0036] 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 capsule composition. In one embodiment, an SDD of a GLP1RA or a pharmaceutically acceptable salt thereof is prepared under the conditions described in Example 2 or Alternate Example 2.

[0037] 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 composition described herein as an SDD formulation.

[0038] In general, the SDD formulations disclosed herein comprise a GLP1RA or a pharmaceutically acceptable salt thereof, and a polymer 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.

[0039] 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. In one embodiment, a small or trace amount of one or more processing solvents may be present in the SDD formulation.

[0040] In one embodiment, the SDD formulation comprises about 20 wt% to about 40 wt% GLP1RA or GLP1RA-Ca, with the balance consisting of PVP-VA. In one embodiment, the SDD formulation comprises about 30 wt% GLP1RA or GLP1RA-Ca, with the balance consisting of PVP-VA.

[0041] 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.

[0042] In one embodiment, the SDD formulation comprises about 20 wt% to about 40 wt% GLP1RA-Ca, with the balance consisting of PVP-VA. In one embodiment, the SDD formulation comprises about 30 wt% GLP1RA or GLP1RA-Ca, with the balance consisting of PVP-VA.

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

[0044] In one embodiment is a capsule composition comprising:

[0045] GLP1RA or a pharmaceutically acceptable salt thereof;

[0046] A pH adjuster selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate, magnesium hydroxide, and mixtures thereof;

[0047] Optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, calcium hydrogen phosphate, and mixtures thereof; and

[0048] Optionally, a glidant selected from the group consisting of colloidal silicon dioxide, talc, magnesium carbonate and mixtures thereof.

[0049] In one embodiment is a composition comprising:

[0050] An amount of about 0.7 mg to about 80 mg of a GLP1RA or a pharmaceutically acceptable salt thereof;

[0051] a pH adjuster selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, hydrated sodium carbonate, magnesium hydroxide, and mixtures thereof in an amount of about 20 mg to about 800 mg;

[0052] A filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dibasic calcium phosphate, and mixtures thereof in an amount of about 0.1 mg to about 400 mg; and

[0053] Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate and mixtures thereof in an amount of about 0 mg to about 20 mg.

[0054] In one embodiment is a composition comprising:

[0055] An amount of about 0.7 mg to about 50 mg of a GLP1RA or a pharmaceutically acceptable salt thereof;

[0056] a pH adjuster selected from the group consisting of sodium bicarbonate and sodium carbonate in an amount of about 150 mg to about 700 mg; and

[0057] A glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate and mixtures thereof in an amount of about 0.1 mg to about 10 mg.

[0058] In one embodiment is a composition comprising:

[0059] An amount of about 1 mg to about 45 mg of a GLP1RA or a pharmaceutically acceptable salt thereof;

[0060] a pH adjuster, sodium bicarbonate, in an amount from about 150 mg to about 650 mg;

[0061] a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dibasic calcium phosphate, and mixtures thereof in an amount of about 1 mg to about 150 mg; and

[0062] A glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate and mixtures thereof in an amount of about 0.1 mg to about 5 mg.

[0063] In one embodiment is a composition as described above, wherein 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one ("GLP1RA") or a pharmaceutically acceptable salt thereof is in the form of an SDD formulation.

[0064] In one embodiment is a capsule composition comprising:

[0065] about 20 wt % to about 40 wt % SDD of a GLP1RA or a pharmaceutically acceptable salt thereof; and the balance of said SDD consists of a polymer selected from the group consisting of PVP-VA and PVP; and

[0066] pH adjuster; wherein the pH adjuster is selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide and anhydrous magnesium hydroxide.

[0067] In one embodiment is a composition as described above, wherein the SDD comprises about 30 wt % to about 35 wt % of a GLP1RA or a pharmaceutically acceptable salt thereof; and the balance of the SDD consists of PVP-VA; and

[0068] pH adjuster; wherein the pH adjuster is selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0069] In one embodiment is a composition as described above, wherein the SDD comprises about 30% by weight of a GLP1RA or a pharmaceutically acceptable salt thereof; and the balance consists of PVP-VA; wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter; and

[0070] A pH adjuster, which is sodium bicarbonate.

[0071] In one embodiment is a composition as described above, further comprising:

[0072] a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, calcium hydrogen phosphate, and mixtures thereof; and

[0073] Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate and mixtures thereof.

[0074] In one embodiment is a capsule composition comprising:

[0075] An amount of about 0.7 mg to about 50 mg of a GLP1RA or a pharmaceutically acceptable salt thereof;

[0076] a pH adjuster, sodium bicarbonate, in an amount from about 150 mg to about 650 mg;

[0077] A filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dibasic calcium phosphate, and mixtures thereof in an amount of about 0.1 mg to about 80 mg; and

[0078] Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof in an amount of about 0 mg to about 5 mg.

[0079] In one embodiment is a composition comprising:

[0080] 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 the balance of the SDD consists of a polymer selected from the group consisting of PVP-VA and PVP; and

[0081] pH adjuster; wherein the pH adjuster is selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, anhydrous magnesium hydroxide and mixtures thereof.

[0082] In one embodiment of the above composition:

[0083] The SDD comprises 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 a pharmaceutically acceptable salt thereof; and the balance of the SDD consists of the polymer PVP-VA; and

[0084] pH adjuster; wherein the pH adjuster is selected from the group consisting of sodium bicarbonate and sodium carbonate.

[0085] In one embodiment of the above composition:

[0086] The SDD comprises about 30 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 a pharmaceutically acceptable salt thereof; and the balance of the SDD consists of PVP-VA; wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter; and

[0087] A pH adjuster, which is sodium bicarbonate.

[0088] In one embodiment of the above composition, the composition further comprises:

[0089] Optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, calcium hydrogen phosphate, and mixtures thereof; and

[0090] Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate and mixtures thereof.

[0091] In one embodiment, a capsule composition comprises:

[0092] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount of about 0.7 mg to about 50 mg based on the free acid;

[0093] a pH adjuster, sodium bicarbonate, in an amount from about 150 mg to about 650 mg;

[0094] Optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, calcium hydrogen phosphate, and mixtures thereof in an amount of about 0 mg to about 200 mg; and

[0095] Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof in an amount of about 0 mg to about 5 mg.

[0096] In one embodiment of the above composition, the composition comprises:

[0097] 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 0.7 mg to about 45 mg based on the free acid; and the balance of the SDD consists of PVP-VA;

[0098] a pH adjuster, sodium bicarbonate, in an amount of about 200 mg to about 650 mg;

[0099] Optionally, a filler in an amount of about 0 mg to about 60 mg selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dibasic calcium phosphate, and mixtures thereof; and

[0100] Optionally, a glidant in an amount of about 0 mg to about 5 mg selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate and mixtures thereof.

[0101] In one embodiment of the above composition, the composition comprises:

[0102] SDD of about 30 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, 0.5Ca hydrate in an amount between about 1 mg and about 36 mg based on the free acid; and the balance of the SDD consisting of PVP-VA;

[0103] a pH adjuster, sodium bicarbonate, in an amount from about 200 mg to about 600 mg;

[0104] Optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dibasic calcium phosphate, and mixtures thereof in an amount of about 0 mg to about 60 mg; and

[0105] Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof in an amount of about 0 mg to about 5 mg.

[0106] In one embodiment of the above composition, the SDD has an average particle size of about 5 μm to about 113 μm in diameter.

[0107] In one embodiment of the above composition:

[0108] When present, the filler is MCC PH-102; in an amount of about 2 mg to about 25 mg; and

[0109] When present, the glidant is silicone oil or silicon dioxide; the amount is from about 0.1 mg to about 5 mg.

[0110] In one embodiment, a composition comprises:

[0111] SDD of about 30 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, 0.5Ca hydrate in an amount of about 1 mg based on the free acid;

[0112] a pH adjuster, sodium bicarbonate, in an amount of about 200 mg;

[0113] filler MCC PH-102 in an amount of about 40 mg to about 50 mg; and

[0114] a glidant silicone oil or silicon dioxide in an amount of about 1 mg to about 5 mg;

[0115] The total weight of the composition is about 250 mg.

[0116] In one embodiment, a composition comprises:

[0117] SDD of about 30 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, 0.5Ca hydrate in an amount of about 1 mg (based on the free acid);

[0118] a pH adjuster, sodium bicarbonate, in an amount of about 200 mg;

[0119] A filler, MCC PH-102, in an amount of about 44 mg; and

[0120] About 2.5 mg of a glidant, silicone oil or silicon dioxide;

[0121] The total weight of the composition is about 250 mg.

[0122] In one embodiment, a composition comprises:

[0123] SDD of about 30 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, 0.5Ca hydrate in an amount of about 16 mg based on the free acid;

[0124] a pH adjuster, sodium bicarbonate, in an amount of about 200 mg;

[0125] filler MCC PH-102 in an amount of about 5 mg to about 10 mg; and

[0126] a glidant silicone oil or silicon dioxide in an amount of about 1 mg to about 5 mg;

[0127] The total weight of the composition is about 260 mg.

[0128] In one embodiment, a composition comprises:

[0129] SDD of about 30 wt % 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5Ca hydrate in an amount of about 16 mg (based on the free acid);

[0130] a pH adjuster, sodium bicarbonate, in an amount of about 200 mg;

[0131] A filler, MCC PH-102, in an amount of about 7 mg; and

[0132] A glidant silicone oil or silicon dioxide in an amount of about 2.6 mg;

[0133] The total weight of the composition is about 260 mg.

[0134] In one embodiment, a composition comprises:

[0135] 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, about 30 wt % in an amount of about 6 mg based on the free acid; and SDD of PVP-VA, about 70 wt % in an amount of about 14 mg;

[0136] a pH adjuster, sodium bicarbonate, in an amount of about 600 mg; and

[0137] The glidant silicone oil is in an amount of about 1 mg to about 10 mg.

[0138] In one embodiment, a composition comprises:

[0139] 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, about 30 wt % in an amount of about 6 mg (based on the free acid); and SDD of PVP-VA, about 70 wt % in an amount of about 14 mg;

[0140] a pH adjuster, sodium bicarbonate, in an amount of about 600 mg; and

[0141] The amount of the glidant silicone oil or silicon dioxide is about 6 mg.

[0142] In one embodiment, a 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, 0.5Ca hydrate, about 30 wt % in an amount of about 12 mg based on the free acid; and SDD of PVP-VA, about 70 wt % in an amount of about 28 mg;

[0144] a pH adjuster, sodium bicarbonate, in an amount of about 600 mg; and

[0145] The glidant silicone oil is in an amount of about 1 mg to about 10 mg.

[0146] In one embodiment, a composition comprises:

[0147] 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, about 30 wt % in an amount of about 12 mg (based on the free acid); and SDD of PVP-VA, about 70 wt % in an amount of about 28 mg;

[0148] a pH adjuster, sodium bicarbonate, in an amount of about 600 mg; and

[0149] The amount of the glidant silicone oil or silicon dioxide is about 6 mg.

[0150] In one embodiment, a composition comprises:

[0151] 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, about 30 wt % in an amount of about 36 mg based on the free acid; and SDD of PVP-VA, about 70 wt % in an amount of about 83 mg;

[0152] a pH adjuster, sodium bicarbonate, in an amount of about 600 mg; and

[0153] The glidant silicone oil is in an amount of about 1 mg to about 10 mg.

[0154] In one embodiment, a composition comprises:

[0155] 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, about 30 wt % in an amount of about 36 mg based on the free acid; and SDD of PVP-VA, about 70 wt % in an amount of about 83 mg;

[0156] a pH adjuster, sodium bicarbonate, in an amount of about 600 mg; and

[0157] The amount of the glidant silicone oil or silicon dioxide is about 6 mg.

[0158] In one embodiment, the above composition is encapsulated in a capsule shell. In one embodiment, the capsule shell is a HPMC capsule shell.

[0159] 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; “MeOH” means methanol or methyl alcohol; “rpm” means revolutions per minute; “PVP-VA” means polyvinylpyrrolidone / vinyl acetate copolymer; “SDD” means spray dried dispersion; “SIF” means simulated intestinal fluid; “T2D” means type 2 diabetes mellitus; “THF” means tetrahydrofuran; “USP” means United States Pharmacopoeia; “wt%” means mass of material desired / total mass; XRPD means X-ray powder diffraction. As used herein, "prep" refers to a preparation.

[0160] 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. In one embodiment, the product is amorphous, has the desired weight % of drug (30%) and PVP-VA (70%) as measured by XRPD, has a particle size that can be isolated and further processed, and is acceptably free of process-related impurities and excess residual solvent. In one embodiment, an amorphous solid dispersion can be used in the preparation method. In one embodiment, the particle size is about 5 to about 113 μm for preparing the composition.

[0161] Example 1

[0162] 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

[0163]

[0164] Example 1 can be prepared as described in WO 18 / 056453.

[0165] The title compound has aliases. For example, it is also known as the hemi-calcium salt hydrate of orforglipron.

[0166] 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.

[0167] Example 2

[0168] 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, prepared by SDD

[0169] 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 polyvinylpyrrolidone / vinyl acetate copolymer (PVP-VA, VA64) (18.7 g) was dissolved in EtOH (200 mL) to prepare 30% 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxane-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-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. After the solid was 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 with Buchi B290 / B295. 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.

[0170] SDD parameters

[0171] Table 1

[0172] 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℃

[0173] Alternative Embodiment 2

[0174] 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, prepared by SDD

[0175] 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 ethanol denatured with methanol (5% v / v or w / w). A solution of 20% w / w solids content was prepared with 30% w / w of the solid fraction consisting of the title compound (based on the free acid), and 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 ethanol 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.

[0176] Alternative Example 2 Formulation of SDD

[0177] Table 2

[0178] Solution (mass fraction) Amorphous SDD (mass fraction) Title compound 6％ 30.0％ PVP-VA 14％ 70.0％ EtOHSDA-3A 80％ EtOH 76％ MeOH 4％

[0179] 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.

[0180] Example 3

[0181] Capsule preparation

[0182] 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, 1 mg and 15 mg capsules

[0183] SDD, NaHCO3, microcrystalline cellulose (MCC PH-102) and SiO2 are distributed in separate low density polyethylene (LDPE) bags. NaHCO3 and MCC PH-102 are passed through a sieve (30 mesh) into separate LDPE bags in sequence. 25% of the sieved NaHCO3 is added to a 10L mixing box. The sieved MCC is added to the bag containing SDD and mixed manually for at least two minutes. Then SiO2 is added to the MCC and SDD blend and mixed manually for at least another two minutes. The blend is sieved into the box through a 30 mesh screen. The blend LDPE bag is rinsed with the remaining NaHCO3 and sieved into the box through a 30 mesh screen. Blend for 15 minutes at 20RPM. The blend is sieved through a 30 mesh screen and blended again for 15 minutes at 20RPM. The blend is filled into size 0 empty capsule shells to the target fill weight using a semi-automatic filling machine (eg, Dott-Bonapace).

[0184]

[0185] *As described herein, the conversion factor for 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.

[0186] Example 4

[0187] Capsule preparation

[0188] 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)

[0189] Capsule preparation

[0190] Capsules were prepared by first adding sodium bicarbonate (600 mg) to size 0 hypromellose (abbreviation for hydroxypropyl methylcellulose (HPMC)) capsules and then adding 10 mg SDD to give a 3 mg active portion strength capsule.

[0191] In vitro dissolution test of capsules

[0192] In vitro dissolution of the capsules was performed using USP Apparatus II under the following conditions: 50 rpm paddle speed until 60 minutes, and 250 rpm paddle speed from 60 to 90 minutes, 900 mL of 0.01 N hydrochloric acid maintained at 37°C, and a sinker basket was used to reduce capsule buoyancy. Six replicates were tested, and samples were taken from the dissolution vessel at 10, 15, 20, 30, 45, 60, and 90 minutes and detected using conventional HPLC with UV detection for the amount of dissolved drug relative to the label claim. The results can be seen in the table below.

[0193]

[0194] Clinical research results

[0195] Surprisingly, despite relatively poor dissolution in 0.01 N HCl, capsules prepared with SDD and sodium bicarbonate demonstrated an increase in Cmax and AUC compared to capsules containing SDD alone when tested in clinical study GZGA.

[0196]

[0197] Example 4

[0198] Capsule preparation

[0199] 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

[0200] GLP-1RA unit formulation (1-8mg)

[0201]

[0202] A The amount of GLP1RA-0.5Ca hydrate can be adjusted based on release potency to maintain target concentration in the SDD. The conversion factor of GLP1RA / GLP1RA hemi-calcium is approximately 0.98.

[0203] B During the drying process, ethanol and methanol are removed to residual levels.

[0204] C If necessary, the amount of SDD can be adjusted to account for the assay. Adjust the total capsule fill weight accordingly.

[0205] GLP-1RA capsule unit formulation (12–45 mg)

[0206]

[0207]

[0208] A The amount of GLP1RA-0.5Ca hydrate can be adjusted based on release potency to maintain target concentration in the SDD. The conversion factor of GLP1RA / GLP1RA hemi-calcium is approximately 0.98.

[0209] B During the drying process, ethanol and methanol are removed to residual levels.

[0210] C If necessary, the amount of SDD can be adjusted to account for the assay. Adjust the total capsule fill weight accordingly.

[0211] Example 5

[0212] Particle size measurement

[0213] 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.

[0214] The SDD of Example 2 and Alternative Example 2 had an average particle size of about 40 to about 65 μm in diameter, or more specifically, about 40 to about 50 μm in diameter, as measured by the method described above.

[0215] Manufacturing method

[0216] An amorphous solid dispersion consisting of 30 wt% GLP1RA free acid was separately made using a spray drying process. GLP1RA-Ca and PVP / VA were dissolved in a solvent mixture containing ethanol and methanol. The mixture was spray dried with a nitrogen stream at an elevated temperature to remove the solvent. This process resulted in the drug substance being an amorphous solid dispersion of GLP1RA-Ca in a PVP / VA matrix. The GLP1RA-Ca SDD can be dried to further reduce residual solvent levels.

[0217] For the encapsulation process, as the first fill in the secondary filling method, GLP1RA-Ca SDD is filled into capsules using automated equipment. As the second fill, sodium bicarbonate containing 1% silicone is filled into capsules using automated equipment. Sodium bicarbonate containing 1% silicone is manufactured separately using a liquid addition blending method such as a high shear annular mixer, a liquid capable tumble bin with an I-bar, continuous twin-screw wet granulation, or belt blending. The dual powder filling strategy addresses powder segregation that may occur at extremely low drug loads, particle size and density differences between GLP1RA-Ca SDD and sodium bicarbonate. This packaging method enables batches as small as 12 capsules, while accommodating significantly larger batch sizes, such as but not limited to more than 100,000 capsules per batch.

[0218] As an alternative encapsulation method, GLP1RA-Ca SDD can be first blended with a mixture of sodium bicarbonate and 1% silicone and then filled into capsules using automated equipment.

[0219] 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. An oral capsule composition comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof; and pH adjuster.

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

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

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

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

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

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; and Anhydrous sodium bicarbonate.

8. The composition according to any one of claims 1 to 6, 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.

9. The composition according to claim 8, 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 in an amount between about 1.2 and about 46 mg per capsule based on the free acid.

10. The composition according to claim 9, 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 in an amount of approximately 46 mg per capsule based on the free acid.

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

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

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

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

15. A composition comprising: 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 between about 0.7 mg and about 50 mg based on the free acid; and the balance of the SDD consists of PVP-VA; and A pH adjuster selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and mixtures thereof.

16. The composition according to claim 15, wherein the composition comprises: SDD of about 30 weight % of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a pharmaceutically acceptable salt thereof in an amount between about 0.7 mg and about 45 mg based on the free acid; a pH adjuster, sodium bicarbonate, in an amount from about 150 mg to about 650 mg; Optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, calcium hydrogen phosphate, and mixtures thereof in an amount of about 0 mg to about 200 mg; and Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof in an amount of about 0 mg to about 5 mg.

17. The composition according to claim 16, wherein the composition comprises: SDD of about 30 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, 0.5Ca hydrate in an amount between about 1 mg and about 36 mg based on the free acid; and the balance of the SDD consisting of PVP-VA; a pH adjuster, sodium bicarbonate, in an amount from about 200 mg to about 600 mg; Optionally, a filler selected from the group consisting of sugar alcohols, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, dibasic calcium phosphate, and mixtures thereof in an amount of about 0 mg to about 60 mg; and Optionally, a glidant selected from the group consisting of silicone oil, silicon dioxide, talc, magnesium carbonate, and mixtures thereof in an amount of about 0 mg to about 5 mg.

18. The composition according to claim 17, in: The filler is MCC PH-102; the amount thereof is from about 2 mg to about 25 mg; and The glidant is silicone oil or silicon dioxide; the amount thereof is about 0.1 mg to about 5 mg.

19. The composition according to claim 17, in: No fillers are present; and The glidant is silicone oil; the amount thereof is from about 0.1 mg to about 5 mg.

20. The composition of any one of claims 15-19, wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter.

21. The composition of claim 17, wherein the composition comprises: SDD of about 30 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, 0.5Ca hydrate in an amount of about 1 mg based on the free acid; a pH adjuster, sodium bicarbonate, in an amount of about 200 mg; filler MCC PH-102 in an amount of about 40 mg to about 50 mg; and a glidant silicone oil or silicon dioxide in an amount of about 1 mg to about 5 mg; The total weight of the composition is about 250 mg.

22. The composition of claim 17, wherein the composition comprises: SDD of about 30 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, 0.5Ca hydrate in an amount of about 16 mg based on the free acid; a pH adjuster, sodium bicarbonate, in an amount of about 200 mg; filler MCC PH-102 in an amount of about 5 mg to about 10 mg; and a glidant silicone oil or silicon dioxide in an amount of about 1 mg to about 5 mg; The total weight of the composition is about 260 mg.

23. The composition of claim 17, 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, 0.5Ca hydrate, about 30 wt % in an amount of about 6 mg based on the free acid; and SDD of PVP-VA, about 70 wt % in an amount of about 14 mg; a pH adjuster, sodium bicarbonate, in an amount of about 600 mg; and The glidant silicone oil is in an amount of about 1 mg to about 10 mg.

24. The composition of claim 17, 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, 0.5Ca hydrate, about 30 wt % in an amount of about 12 mg based on the free acid; and SDD of PVP-VA, about 70 wt % in an amount of about 28 mg; a pH adjuster, sodium bicarbonate, in an amount of about 600 mg; and The glidant silicone oil is in an amount of about 1 mg to about 10 mg.

25. The composition of claim 17, 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, 0.5Ca hydrate, about 30 wt % in an amount of about 36 mg based on the free acid; and SDD of PVP-VA, about 70 wt % in an amount of about 83 mg; a pH adjuster, sodium bicarbonate, in an amount of about 600 mg; and The glidant silicone oil is in an amount of about 1 mg to about 10 mg.

26. The composition of any one of claims 21-25, wherein the SDD has an average particle size of about 5 μm to about 113 μm in diameter.

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

28. The composition of any one of claims 27, wherein the composition is in a capsule shell.

29. The composition of any one of claim 28, wherein the capsule shell is a HPMC capsule shell.

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