Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/485—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to oral capsule compositions of a GLP-1 receptor agonist, 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5- dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H- l,2,4-oxadiazol-5-one, (herein, GLP1RA), or a pharmaceutically acceptable salt thereof.
• Compositions, disclosed herein, can be useful for the treatment of type 2 diabetes mellitus (T2D) and in weight management.
• Diabetes mellitus is a chronic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
• 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 frequently leads to declining health and quality of life for patients. Effective oral treatments to manage T2D and/or for use in weight management are desired.
• GLP1RA that is, 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4- fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2-oxoimidazol-l-yl]-4- methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l-yl]-2- methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, is described and claimed in US10,858,356.
• the US10,858,356 patent generally describes oral compositions.
• GLP1RA may be prepared as a pharmaceutically acceptable salt.
• One salt of GLP1RA is a hemi-calcium hydrate, 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate, (herein “GLP1RA- Ca”) with the structure as shown below.
• GLP1RA is a poorly permeable and poorly soluble weak acid with a pKa of 5.1.
• GLP1RA and its pharmaceutically acceptable salts have very low aqueous solubility across the physiologic pH range as well as in simulated physiological fluids. GLP1RA is observed to have a strong pH dependent solubility profile contributing to challenges such as variability in absorption and consequently in pharmacokinetic performance and potential food effects.
• GLP1RA including but not limited to, GLPIRA-Ca, capsule compositions providing reliable PK performance in a patient friendly dosage form, with minimal potential for drug-drug interactions and reduced or no food effects.
• a GLP1RA composition to enhance solubility and dissolution rate of the active substance in a capsule dosage form may be desired.
• a pharmaceutically elegant dosage form to deliver an effective amount of active GLP1RA to the targeted portion of the gastrointestinal tract, while small enough to facilitate patient swallowing is desired.
• compositions described herein provide desired properties.
• the use of a sprayed dried dispersion (SDD) of the GLP1RA, or a pharmaceutically acceptable salt thereof, together with a pH modifier, as described herein contributes to the desired properties.
• the specific particle sizes of the SDD and the particular compositions as described provide the desired properties.
• compositions disclosed herein provide desirable pharmacokinetic performances and deliver an effective amount of active GLP1RA to the targeted portion of the gastrointestinal tract.
• disclosed herein is an elegant dosage form that is convenient for patients to take without the limitation of food or water restrictions.
• Solid oral formulations provided herein can be useful for patients in need of treatment for T2D.
• Solid oral formulations provided herein can be useful for patients in need of treatment for chronic weight management.
• a pH modifier is selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and a mixture thereof.
• a pH modifier is sodium bicarbonate. In an embodiment, a pH modifier is sodium carbonate.
• a pH modifier is anhydrous.
• a pH modifier is anhydrous sodium bicarbonate.
• a pH modifier is anhydrous sodium carbonate.
• a capsule composition comprising 3-[(lS,2S)-l-[5-[(4S)-2,2- dimethyloxan-4-yl] -2- [(4 S)-2-(4-fluoro-3 , 5 -dimethylphenyl)-3 -[3 -(4-fluoro- 1 - methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and a pH modifier, wherein the pH modifier is anhydrous sodium bicarbonate.
• a capsule composition comprises 3-[(lS,2S)-l-[5-[(4S)-2,2- dimethyloxan-4-yl] -2- [(4 S)-2-(4-fluoro-3 , 5 -dimethylphenyl)-3 -[3 -(4-fluoro- 1 - methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one; and a pH modifier.
• a capsule composition comprising 3-[(lS,2S)-l-[5-[(4S)-2,2- dimethyloxan-4-yl] -2- [(4 S)-2-(4-fluoro-3 , 5 -dimethylphenyl)-3 -[3 -(4-fluoro- 1 - methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in the amount of about 0.5 to about 46 mg per capsule composition.
• composition comprising 3-[(lS,2S)-l-[5-[(4S)-2,2- dimethyloxan-4-yl] -2- [(4 S)-2-(4-fluoro-3 , 5 -dimethylphenyl)-3 -[3 -(4-fluoro- 1 - methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in the amount of about 46 mg per capsule composition.
• a process for preparing a capsule composition as disclosed herein comprising an amorphous dispersion process.
• a process for preparing a capsule composition as claimed herein comprising a spray dried dispersion (SDD) process.
• SDD spray dried dispersion
• GLP1RA or a pharmaceutically acceptable salt thereof, is prepared into a spray dried dispersion (SDD) for use as the active drug in a capsule composition.
• SDD spray dried dispersion
• an SDD of GLP1RA, or a pharmaceutically acceptable salt thereof is prepared under the conditions as described in Example 2 or Alternative Example 2.
• the GLP1RA 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]- 2- [(4 S)-2-(4-fluoro-3 , 5 -dimethylphenyl)-3 - [3 -(4-fluoro- 1 -methylindazol-5 -yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one) or GLPIRA-Ca ( 3-[(lS,2S)-l-[5- [(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[
• an SDD preparation disclosed herein comprises GLP1RA, or a pharmaceutically acceptable salt thereof, and a polymer to maintain an amorphous state of the GLP1RA, or a pharmaceutically acceptable salt thereof.
• the polymer is selected from the group consisting of polyvinyl pyrrolidone (also known as “povidone” or “PVP”) and polyvinyl pyrrolidone vinyl acetate (also known as “copovidone” or “PVP-VA”).
• the polymer is PVP-VA.
• the polymer is PVP.
• the balance component of the SDD is a polymer selected from PVP and PVP-VA, that is, the total weight percentage of the GLP1RA, or a pharmaceutically acceptable salt thereof, and the polymer is 100 wt%.
• the polymer is PVP-VA.
• the polymer is PVP.
• a small or trace amount of the processing solvent or solvents may be present in an SDD preparation.
• the SDD preparation comprises about 20 wt% to about 40 wt% of GLP1RA or GLPIRA-Ca and the balance is composed of PVP-VA. In an embodiment, the SDD preparation comprises about 30 wt% of GLP1RA or GLPIRA-Ca and the balance is composed of PVP-VA.
• the mean particle size of the GLP1RA or GLPIRA-Ca SDD is about 5 pm to about 150 pm in diameter. In an embodiment, the mean particle size of the SDD is about 5 pm to about 113 pm in diameter. In an embodiment, the mean particle size of the SDD is about 40 pm to about 65 pm in diameter. In an embodiment, the mean particle size of the SDD is about 40 pm to about 50 pm in diameter. In an embodiment, the mean particle size of the SDD is about 5 pm to about 25 pm in diameter.
• the SDD preparation comprises about 20 wt% to about 40 wt% of GLPIRA-Ca and the balance is composed of PVP-VA. In an embodiment, the SDD preparation comprises about 30 wt% of GLP1RA or GLPIRA-Ca and the balance is composed of PVP-VA.
• the mean particle size of the GLPIRA-Ca SDD is about 5 pm to about 150 pm in diameter. In an embodiment, the mean particle size of the SDD is about 5 pm to about 113 pm in diameter. In an embodiment, the mean particle size of the SDD is about 40 pm to about 65 pm in diameter. In an embodiment, the mean particle size of the SDD is about 40 pm to about 50 pm in diameter. In an embodiment, the mean particle size of the SDD is about 5 pm to about 25 pm in diameter.
• GLP1RA or a pharmaceutically acceptable salt thereof; a pH modifier selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide, and a mixture thereof; optionally, a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof; and optionally, a glidant selected from the group consisting of colloidal silicon dioxide, talc, magnesium carbonate, and a mixture thereof.
• GLP1RA or a pharmaceutically acceptable salt thereof; in an amount of about 0.7 mg to about 80 mg; a pH modifier selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide , and a mixture thereof; in an amount of about 20 mg to about 800 mg; a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof; in an amount of about 0.1 mg to about 400 mg; and optionally, a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof; in an amount of about 0 mg to about 20 mg.
• a pH modifier selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, magnesium hydroxide , and a mixture thereof
• a filler selected from the group consist
• composition comprising: GLP1RA, or a pharmaceutically acceptable salt thereof; in an amount of about 0.7 mg to about 50 mg; a pH modifier selected from the group consisting of sodium bicarbonate and sodium carbonate; in an amount of about 150 mg to about 700 mg; and a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof; in an amount of about 0.1 mg to about 10 mg.
• GLP1RA or a pharmaceutically acceptable salt thereof; in an amount of about 1 mg to about 45 mg; a pH modifier which is sodium bicarbonate; in an amount of about 150 mg to about 650 mg; a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof; in an amount of about 1 mg to about 150 mg; and a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof; in an amount of about 0.1 mg to about 5 mg.
• a pH modifier which is sodium bicarbonate
• a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof
• a glidant selected from the group consisting of silicon oil, silicon
• compositions as described above wherein the 3-[(lS,2S)-l- [5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro- l-methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one (“GLP1RA”), or a pharmaceutically acceptable salt thereof, is in the form of an SDD preparation.
• GLP1RA 3-[(lS,2S)-l- [5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-flu
• a capsule composition comprising: an SDD of about 20 wt% to about 40 wt% of GLP1RA, or a pharmaceutically acceptable salt thereof; and the balance of the SDD is composed of a polymer selected from PVP-VA and PVP; and a pH modifier; wherein the pH modifier is selected from the group consisting of calcium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, and anhydrous magnesium hydroxide.
• compositions as described above wherein the SDD comprises about 30 wt% to about 35 wt% of GLP1RA, or a pharmaceutically acceptable salt thereof; and the balance of the SDD is composed of PVP-VA; and a pH modifier; wherein the pH modifier is selected from the group consisting of sodium bicarbonate and sodium carbonate.
• compositions as described above wherein the SDD comprises about 30 wt% of GLP1RA, or a pharmaceutically acceptable salt thereof; and the balance is composed of PVP-VA; wherein the SDD has a mean particle size of about 5 pm to about 113 pm in diameter; and a pH modifier which is sodium bicarbonate.
• compositions as described above further comprising: a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof; and optionally, a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof.
• a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof
• a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof.
• GLP1RA or a pharmaceutically acceptable salt thereof; in an amount of about 0.7 mg to about 50 mg; a pH modifier which is sodium bicarbonate; in an amount of about 150 mg to about 650 mg; a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof; in an amount of about 0.1 mg to about 80 mg; and optionally, a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof; in an amount of about 0 mg to about 5 mg.
• a pH modifier which is sodium bicarbonate
• a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof
• a glidant selected from the group consisting
• composition comprising: an SDD of about 20 wt% to about 40 wt% of 3-[(l S,2S)-l-[5-[(4S)-2,2- dimethyloxan-4-yl] -2- [(4 S)-2-(4-fluoro-3 , 5 -dimethylphenyl)-3 -[3 -(4-fluoro- 1 - methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and the balance of the SDD is composed of a polymer selected from PVP-VA and PVP; and a pH modifier; wherein the pH modifier is selected from the group consisting of calcium carbon
• the SDD comprises about 30 wt% to about 35 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2- dimethyloxan-4-yl] -2- [(4 S)-2-(4-fluoro-3 , 5 -dimethylphenyl)-3 -[3 -(4-fluoro- 1 - methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and the balance of the SDD is composed of a polymer which is PVP-VA; and a pH modifier; wherein the pH modifier is selected from the group consisting of sodium bicarbonate and sodium
• the SDD comprises about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4- yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and the balance of the SDD is composed of PVP-VA; wherein the SDD has a mean particle size of about 5 pm to about 113 pm in diameter; and a pH modifier which is sodium bicarbonate.
• compositions further comprise: optionally, a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof; and optionally, a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof.
• a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof
• a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof.
• a capsule composition comprises:
• the composition comprises: an SDD of about 30 wt% to about 35 wt% of 3-[(l S,2S)-l-[5-[(4S)-2,2- dimethyloxan-4-yl] -2- [(4 S)-2-(4-fluoro-3 , 5 -dimethylphenyl)-3 -[3 -(4-fluoro- 1 - methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3- c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 0.7 mg to about 45 mg, on a free acid basis; and the balance of the SDD is composed of PVP-VA; a pH modifier which is sodium bicarbonate
• the composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of between about 1 mg to about 36 mg, on a free acid basis; and the balance of the SDD is composed of PVP-VA; a pH modifier which is sodium bicarbonate; in an amount of about 200 mg to about 600 mg
• the SDD has a mean particle size of about 5 pm to about 113 pm in diameter.
• the filler when present, is MCC PH-102; in an amount of about 2 mg to about 25 mg; and the glidant, when present, is silicon oil or silicon dioxide; in an amount of about 0.1 mg to about 5 mg.
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 1 mg, on a free acid basis; a pH modifier which is sodium bicarbonate; in an amount of about 200 mg; a filler which is MCC PH-102; in an amount of about 40 mg to about 50 mg; and
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 1 mg (on a free acid basis); a pH modifier which is sodium bicarbonate; in an amount of about 200 mg; a filler which is MCC PH-102; in an amount of about 44 mg; and a glid
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 16 mg, on a free acid basis; a pH modifier which is sodium bicarbonate; in an amount of about 200 mg; a filler which is MCC PH-102; in an amount of about 5 mg to about 10 mg; and
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 16 mg (on a free acid basis); a pH modifier which is sodium bicarbonate; in an amount of about 200 mg; a filler which is MCC PH-102; in an amount of about 7 mg; and a glid
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 6 mg, on a free acid basis; and about 70 wt% of PVP-VA in an amount of about 14 mg; a pH modifier which is sodium bicarbonate; in an amount of about 600 mg; and a glidant
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 6 mg (on a free acid basis); and about 70 wt% of PVP-VA in an amount of about 14 mg; a pH modifier which is sodium bicarbonate; in an amount of about 600 mg; and a glidant
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 12 mg, on a free acid basis; and about 70 wt% of PVP-VA in an amount of about 28 mg; a pH modifier which is sodium bicarbonate; in an amount of about 600 mg; and a glidant
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 12 mg (on a free acid basis); and about 70 wt% of PVP-VA in an amount of about 28 mg; a pH modifier which is sodium bicarbonate; in an amount of about 600 mg; and a glidant
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2- oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l- yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 36 mg, on a free acid basis; and about 70 wt% of PVP-VA in an amount of about 83 mg; a pH modifier which is sodium bicarbonate; in an amount of about 600 mg; and a glid
• a composition comprises: an SDD of about 30 wt% of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)- 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2-oxoimidazol-l- yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l-yl]-2- methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 36 mg, on a free acid basis; and about 70 wt% of PVP-VA in an amount of about 83 mg; a pH modifier which is sodium bicarbonate; in an amount of about 600 mg; and a glid
• product is amorphous as measured by XRPD, of the desired wt% of drug (30%) and PVP- VA (70%), of a particle size that can be isolated and forward processed and is acceptably free of process related impurities and excessive residual solvents.
• amorphous solid dispersion may be used in the preparation process.
• the particle size is from about 5 to about 113 pm for use in preparing the composition for use in the preparing the composition.
• Example 1 may be prepared as described in WO18/056453.
• the title compound has alternative names.
• it is also known as the hemicalcium salt hydrate of orforglipron.
• the solution is spray dried on a conventional spray dryer with a pressure nozzle.
• the following parameters in Table 1 are used to create the dispersion with a Buchi B290/B295. Spray drying can begin when the spray dryer temperature is above 33 °C. Collect the material and dry under vacuum at 50 °C overnight to give the title compound (21.99 g, 7.0 g, 92% potency, 80% recovery) and observe via photomicroscopy that the material is microscopically non birefringent particles that are approximately 5-25 pm in diameter.
• a 20% w/w solids solution is prepared with 30% w/w of the solid fraction composed of the title compound (on a free acid basis) and the balance is composed of PVP-VA. This translates to 6% of the title compound (on a free acid basis), 14% PVP-VA and 80% of denatured ethanol SDA-3A - all fractions as w/w.
• the solids that form are composed of 30% w/w of the solid fraction composed of the title compound (on a free acid basis) and the balance is composed of PVP-VA.
• the % values are shown in the Table 2 below.
• the solution is pumped to a spray dryer where the solution atomizes upon entry.
• Heated drying gas enters co-current to the atomized liquid at the top of the spray drying chamber at an approximate ratio of 0.044 kg/kg of spray solution to drying gas.
• 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 a cyclone as well as a filter housing on the gas stream.
• the gas passed over a condenser maintained at -3 °C, to remove (to a dewpoint of -3 °C) solvent.
• the gas is then heated to the inlet temperature and passed back to the spray dryer.
• Example 3 Capsule Formulation 3-[(lS,2S)-l-[5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)- 3-[3-(4-fluoro-l-methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-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 hydrate, 1 mg and 15 mg capsule formulation
• the conversion factor for GLPIRA/GLPIRA-Ca i.e., the hemicalcium salt hydrate of GLP1RA
• the exact conversion rate may change slightly depending on the actual content of the hydrate.
• Capsules are prepared by first adding sodium bicarbonate (600 mg) to a size 0 hypromellose, short for hydroxypropyl methylcellulose (HPMC), capsule followed by 10 mg of SDD to yield capsules of 3 mg strength of the active moiety.
• sodium bicarbonate 600 mg
• HPMC hydroxypropyl methylcellulose
• Example 4 Capsule Preparation 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3hou5- dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H- l,2,4-oxadiazol-5-one, 0.5 Ca hydrate
• GLPlRA-0.5Ca hydrate may be adjusted based on the release potency to maintain target concentration in the SDD.
• the conversion factor of GLP1RA/GLP1RA hemicalcium is about 0.98.
• GLPlRA-0.5Ca hydrate may be adjusted based on the release potency to maintain target concentration in the SDD.
• the conversion factor of GLP1RA/GLP1RA hemicalcium is about 0.98.
• B Ethanol and methanol are removed to residual levels during drying.
• the amount of SDD may be adjusted to account for assay.
• the total capsule fill weight will be adjusted accordingly.
• Particle size of the SDD was determined by laser diffraction utilizing wet dispersion on the Malvern Mastersizer 3000 equipped with the Hydro MV (medium volume) liquid disperser (Malvern Instruments Ltd. UK.). Optical model: Mie model, obscuration limits: 5-30%, general purpose model. The volume-based distribution was measured and the (D10, D50, D90) quantiles were reported.
• the SDDs of Example 2 and Alternate Example 2 have a mean particle size of about 40 to about 65 pm, or more specifically, about 40 to about 50 pm, in diameter as measured by the above method.
• the amorphous solid dispersion consisting of 30 wt% GLP1RA free acid, is manufactured separately using a spray drying process.
• GLPIRA-Ca and PVP/VA are dissolved in a solvent mixture containing ethanol and methanol.
• the mixture is spray dried at an elevated temperature with a stream of nitrogen to remove solvent.
• the process renders the drug substance as an amorphous solid dispersion of GLPIRA-Ca in a matrix of PVP/VA.
• the GLPIRA-Ca SDD may be dried for further reduction of residual solvent levels.
• GLPIRA-Ca SDD is filled into capsules using automated equipment as the first fill in a two-fill process.
• Sodium bicarbonate with silicone 1% is filled into capsules using automated equipment as the second fill.
• Sodium bicarbonate with silicone 1% is manufactured separately using a liquid addition blending process such as high shear ring layer mixer, liquid capable tumble bin with I-bar, continuous twin screw wet granulation, or ribbon blending.
• the dual powder fill strategy addresses powder segregation that may occur with very low drug load, difference in particle size and density between the GLPIRA-Ca SDD and sodium bicarbonate. This encapsulation process allows for batches as small as 12 capsules, while accommodating substantially larger batch size, for example, but not limited to, over one hundred thousand capsules per batch.
• GLPIRA-Ca SDD may be first blended with the mixture of sodium bicarbonate with silicone 1% and then filled into capsules using automated equipment.

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