Pharmaceutical formulations of tropomyosin related kinase (TRK) inhibitors

Patent metadata

Field	Value
Publication number	US-12527737-B2
Application number	US-202318491503-A
Country	US
Kind code	B2
Filing date	Oct 20, 2023
Priority date	Dec 18, 2014
Publication date	Jan 20, 2026
Grant date	Jan 20, 2026

Abstract

Pharmaceutical formulations with a tropomyosin-related kinase inhibitor (“Trk inhibitor”) are disclosed. The pharmaceutical formulations comprise 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5b-]pyridin-2-amine in microcrystalline suspension formulations in its monohydrate form, which shows improved characteristics over the anhydrate form, and in extended release formulations. The extended release pharmaceutical formulations comprise 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine-loaded microspheres.

First claim

The invention claimed is:

1 . A method of treating pain in a patient, comprising administering to the patient 3-(3-methoxy-4-((4-methoxybenzyl)oxy) benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-2-amine monohydrate, to thereby treat pain.

2 . A method of treating pain in a patient, comprising administering to the patient a pharmaceutical composition comprising:
a. a compound according to the following structural formula:

and
b. a pharmaceutically acceptable excipient;

to thereby treat pain.

3 . The method of claim 2 , wherein the pharmaceutically acceptable excipient comprises a diluent.

4 . The method of claim 3 , wherein the diluent is selected from sunflower oil, ammonium alginate, calcium carbonate, calcium lactate, calcium phosphate dibasic anhydrous, calcium silicate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, confectioner's sugar, corn starch, pregelatinized starch, dextrin, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, inhalation lactose, isomalt, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, a medium-chain triglyceride, microcrystalline cellulose, polydextrose, a polymethacrylate, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sulfobutylether b-cyclodextrin, talc, tragacanth, trehalose, or xylitol.

5 . The method of claim 3 , wherein the diluent is sorbitol.

6 . The method of claim 2 , wherein the pharmaceutically acceptable excipient comprises a suspending agent.

7 . The method of claim 6 , wherein the suspending agent is selected from acacia, agar, alginic acid, bentonite, calcium stearate, carbomer, carrageenan, cellulose, colloidal silicone dioxide, dextrin, gelatin, guar gum, hectorite, hydrophobic colloidal silica, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, kaolin, magnesium aluminum silicate, a medium-chain triglyceride, methylcellulose, phenylmercuric borate, a phospholipid, poycarbophil, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester, povidone, propylene glycol alginate, saponite, sesame oil, sodium alginate, a sorbitan ester, sucrose, tragacanth, vitamin E polyethylene glycol succinate, or xanthan gum.

8 . The method of claim 6 , wherein the suspending agent is povidone.

9 . The method of claim 2 , wherein the pharmaceutically acceptable excipient comprises a diluent, a suspending agent, and a buffering agent.

10 . The method of claim 9 , wherein the diluent is sorbitol, the suspending agent is povidone, and the buffering agent is phosphoric acid.

11 . A method of inhibiting tropomyosin-related kinase A in a patient, comprising administering to the patient 3-(3-methoxy-4-((4-methoxybenzyl)oxy) benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-2-amine monohydrate, to thereby inhibit tropomyosin-related kinase A.

12 . A method of inhibiting tropomyosin-related kinase A in a patient, comprising administering to the patient a pharmaceutical composition comprising:
a. a compound according to the following structural formula:

and
b. a pharmaceutically acceptable excipient;

to thereby inhibit tropomyosin-related kinase A.

13 . The method of claim 12 , wherein the pharmaceutically acceptable excipient comprises a diluent.

14 . The method of claim 13 , wherein the diluent is selected from sunflower oil, ammonium alginate, calcium carbonate, calcium lactate, calcium phosphate dibasic anhydrous, calcium silicate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, confectioner's sugar, corn starch, pregelatinized starch, dextrin, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, inhalation lactose, isomalt, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, a medium-chain triglyceride, microcrystalline cellulose, polydextrose, a polymethacrylate, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sulfobutylether b-cyclodextrin, talc, tragacanth, trehalose, or xylitol.

15 . The method of claim 13 , wherein the diluent is sorbitol.

16 . The method of claim 12 , wherein the pharmaceutically acceptable excipient comprises a suspending agent.

17 . The method of claim 16 , wherein the suspending agent is selected from acacia, agar, alginic acid, bentonite, calcium stearate, carbomer, carrageenan, cellulose, colloidal silicone dioxide, dextrin, gelatin, guar gum, hectorite, hydrophobic colloidal silica, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, kaolin, magnesium aluminum silicate, a medium-chain triglyceride, methylcellulose, phenylmercuric borate, a phospholipid, poycarbophil, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester, povidone, propylene glycol alginate, saponite, sesame oil, sodium alginate, a sorbitan ester, sucrose, tragacanth, vitamin E polyethylene glycol succinate, or xanthan gum.

18 . The method of claim 16 , wherein the suspending agent is povidone.

19 . The method of claim 12 , wherein the pharmaceutically acceptable excipient comprises a diluent, a suspending agent, and a buffering agent.

20 . The method of claim 19 , wherein the diluent is sorbitol, the suspending agent is povidone, and the buffering agent is phosphoric acid.

Assignees

• Genzyme Corp

Inventors

• Lieberman Harvey
• Yang Donglai
• Philbrook C Michael
• Santos Michael
• Ho Chris

Classifications

• A61K31/00

  Medicinal preparations containing organic active ingredients · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K9/5026

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K9/1694

  resulting in granules or microspheres of the matrix type containing more than 5% of excipient · CPC title