Pharmaceutical formulations of tropomyosin related kinase (TRK) inhibitors

Patent metadata

Field	Value
Publication number	US-11110055-B2
Application number	US-201916239904-A
Country	US
Kind code	B2
Filing date	Jan 4, 2019
Priority date	Dec 18, 2014
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

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[4,5-b]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 manufacturing a crystalline form of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine comprising:
a. Mixing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H -pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine with a solvent to form a suspension;
b. Stirring the suspension;
c. Collecting the solids in the suspension by filtration; and
d. Drying the solids.

2. The method according to claim 1 , wherein the solvent comprises a mixture of acetone and water.

3. The method according to claim 1 , wherein the suspension is stirred overnight.

4. The method according to claim 1 , wherein the solids are air dried.

5. The method according to claim 1 , wherein the solvent comprises a mixture of acetone and water, the suspension is stirred overnight, and the solids are air dried.

6. A method of manufacturing a monohydrate form of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine comprising:
a. Mixing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H -pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine with a solvent to form a suspension;
b. Stirring the suspension;
c. Collecting the solids in the suspension by filtration; and
d. Drying the solids.

7. The method according to claim 6 , wherein the solvent is a mixture of acetone and water.

8. The method according to claim 6 , wherein the suspension is stirred overnight.

9. The method according to claim 6 , wherein the solids are air dried.

10. The method according to claim 6 , wherein the solvent is a mixture of acetone and water, the suspension is stirred overnight, and the solids are air dried.

11. A method of manufacturing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine-loaded microcapsules by solvent extraction, comprising:
a. Dissolving the 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine in an organic solvent to form a drug solution;
b. Adding a polymer to the drug solution to form a polymer/3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine solution;
c. Mixing the polymer/3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine solution into an aqueous solution to form an emulsion;
d. Adding deionized water to the emulsion;
e. Forming microspheres from the emulsion by solvent extraction; and
f. Sieving the resulting microspheres using a surfactant solution.

12. The method according to claim 11 , wherein the organic solvent comprises (i) dichloromethane and methanol, (ii) dichloromethane, (iii) benzyl alcohol and methanol, (iv) dichloromethane and benzyl alcohol, (v) chloroform, (vi) chloroform and methanol, or (vii) chloroform and benzyl alcohol.

13. The method according to claim 12 , wherein the organic solvent comprises dichloromethane and methanol.

14. The method according to claim 12 , wherein the organic solvent comprises dichloromethane, benzyl alcohol and methanol.

15. The method according to claim 12 , wherein the organic solvent comprises dichloromethane and benzyl alcohol.

16. The method according to claim 11 , wherein the polymer comprises poly(D,L-lactide).

17. The method according to claim 11 , wherein the polymer comprises poly(D,L-lactide-co-glycolide).

18. The method according to claim 11 , wherein the polymer comprises poly(D,L-lactide) and poly(D,L-lactide-co-glycolide).

19. The method according to claim 11 , wherein the aqueous solution comprises polyvinyl alcohol in water.

20. The method according to claim 11 , wherein the surfactant solution comprises poloxamer 407 in water, polysorbate 80 in water, or polysorbate 20 in water.

21. The method according to claim 20 , wherein the surfactant solution comprises poloxamer 407 in water.

22. A method of manufacturing 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine-loaded microcapsules by solvent extraction, comprising:
a. Dispersing the 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine in an organic solvent to form a drug suspension;
b. Adding a polymer to the drug suspension to form a polymer/3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine dispersion;
c. Mixing the polymer/3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine dispersion with an aqueous solution to form an emulsion;
d. Adding deionized water to the emulsion;
e. Forming microspheres from the emulsion by solvent extraction; and
f. Sieving the resulting microspheres using a surfactant solution.

23. The method according to claim 22 , wherein the organic solvent comprises (i) ethyl acetate, (ii) dichloromethane, (iii) chloroform, (iv) ethyl acetate and dichloromethane, (v) ethyl acetate and chloroform, (vi) dichloromethane and chloroform or (vii) ethyl acetate, dichloromethane and chloroform.

24. The method according to claim 23 , wherein the organic solvent comprises ethyl acetate.

25. The method according to claim 23 , wherein the organic solvent comprises dichloromethane.

26. The method according to claim 23 , wherein the organic solvent comprises dichloromethane and ethyl acetate.

27. The method according to claim 22 , wherein the polymer comprises poly(D,L-lactide).

28. The method according to claim 22 , wherein the polymer comprises poly(D,L-lactide-co-glycolide).

29. The method according to claim 22 , wherein the polymer comprises poly(D,L-lactide) and poly(D,L-lactide-co-glycolide).

30. The method according to claim 22 , wherein the aqueous solution comprises polyvinyl alcohol in water.

31. The method according to claim 22 , wherein the surfactant solution comprises poloxamer 407 in water, polysorbate 80 in water, or polysorbate 20 in water.

32. The method according to claim 31 , wherein the surfactant solution comprises poloxamer 407 in water.

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

• A61K9/0019 Primary

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title