Pharmaceutical formulations of tropomyosin related kinase (Trk) inhibitors

Patent metadata

Field	Value
Publication number	US-10219998-B2
Application number	US-201515536544-A
Country	US
Kind code	B2
Filing date	Dec 17, 2015
Priority date	Dec 18, 2014
Publication date	Mar 5, 2019
Grant date	Mar 5, 2019

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 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, wherein the x-ray powder diffraction pattern contains the following 2θ peaks measured using CuK α radiation: 3.6 , 7.1, 8.9, 10.4, 10.7, 12.4, 12.7 and 14.3.

2. A pharmaceutical formulation comprising the 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 according to claim 1 and a pharmaceutically acceptable excipient.

3. A composition comprising:

4. A pharmaceutical formulation comprising:
a. a compound according to the following structural formula:

and
b. a pharmaceutically acceptable excipient.

5. The pharmaceutical formulation according to claim 4 , wherein the pharmaceutically acceptable excipient comprises a diluent.

6. The pharmaceutical formulation according to claim 5 , wherein the diluent is selected from: malitol, sunflower oil, ammonium alginate, calcium carbonate, calcium lactate, calcium phosphatedibasic anhydrous, dibasic dihydrate, tribasic, calcium silicate, calcium sulfate, cellulose (powdered, silicified microcrystalline), cellulose acetate, compressible sugar, confectioner's sugar, corn starch and pregelatinized starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, inhalation lactose, isomalt, kaolin, lactitol, lactose (anhydrous, monohydrate and corn starch, monohydrate and microcrystalline cellulose, spray dried), magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium-chain triglycerides, microcrystalline cellulose, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch (pregelatinized, sterilizable maize), sucrose, sugar spheres, sulfobutylether b-cyclodextrin, talc, tragacanth, trehalose, xylitol.

7. The pharmaceutical formulation according to claim 4 , wherein the pharmaceutically acceptable excipient comprises a suspending agent.

8. The pharmaceutical formulation according to claim 7 , wherein the suspending agent is selected from: acacia, agar, alginic acid, bentonite, calcium stearate, carbomer, carboxymethylcellulose (calcium and sodium), carrageenan, cellulose (microcrystalline, microcyrstalline and carboxymethylcellulose sodium, powdered), colloidal silicone dioxide, destrin, gelatin, guar gum, hectorite, hydrophobic colloidal silica, hydroxyethyl cellulose, hydroxymethyl celluslose, hydroxypropyl cellulose, hypromellose, kaolin, magnesium aluminum silicate, maltitol solutions, medium-chain triglycerides, methylcellulose, phenylmercuric borate, phospholipids, poycarbophil, polyethylene glycol, polyoxyethylene sorbitan fatty acid esters, povidone (polyvinylpyrrrolidone), propylene glycol alginate, saponite, sesame oil, sodium alginate, sorbitan esters, sucrose, tragacanth, vitamin E polyethylene glycol succinate, and xanthan gum.

9. The pharmaceutical formulation according to claim 4 , wherein the pharmaceutically acceptable excipient comprises a buffering agent.

10. The pharmaceutical formulation according to claim 9 , wherein the buffering agent is selected from: adipic acid, ammonia solution, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic, citric acid monohydrate, dibasic sodium phosphate, diethanolamine, glycine, maleic Acid, malic acid, methionine, monobasic sodium phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate, and triethanolamine.

11. The pharmaceutical formulation according to claim 2 for use in the treatment of osteoarthritis.

12. The pharmaceutical formulation according to claim 2 for use in the treatment of pain.

13. The pharmaceutical formulation according to claim 2 for use in the treatment of pain associated with osteoarthritis.

14. An extended release pharmaceutical formulation comprising 3-(3-methoxy-4((4-methoxybenzyl)oxy)benzyI)-6-(1-methyl-1H-pyrazol-4-yl) -H-imidazo[4, 5-b]pyridin-2-amine-loaded microspheres.

15. The extended release pharmaceutical formulation according to claim 14 , wherein the microspheres comprise a polymer.

16. The extended release pharmaceutical formulation according to claim 15 , wherein the polymer comprises poly(D,L-lactide).

17. The extended release pharmaceutical formulation according to claim 15 , wherein the polymer comprises poly(D,L-lactide-co-glycolide).

18. The extended release pharmaceutical formulation according to claim 15 , wherein the polymer comprises poly(D,L-lactide) and poly(D,L-lactide-co-glycolide).

19. The extended release pharmaceutical formulation according to claim 16 , wherein the poly(D,L-lactide) has an inherent viscosity of 0.16-0.35 dL/g.

20. The extended release pharmaceutical formulation according to claim 17 , wherein the poly(D,L-lactide-co-glycolide) has an inherent viscosity of 0.14-0.24 dL/g.

21. The extended release pharmaceutical formulation according to claim 18 , wherein the poly(D,L-lactide) has an inherent viscosity of 0.16-0.35 dL/g and the poly(D,L-lactide-co-glycolide) has an inherent viscosity of 0.14-0.24 dL/g.

22. The extended release pharmaceutical formulation according to claim 18 , wherein the microspheres comprise a 9:1 ratio of poly(D,L-lactide) and poly(D,L-lactide-co-glycolide).

23. The extended release pharmaceutical formulation according to claim 18 , wherein the microspheres comprise a 9.5:0.5 ratio of poly(D,L-lactide) and poly(D,L-lactide-co-glycolide).

24. The extended release pharmaceutical formulation according to claim 14 , wherein the microspheres are loaded with 1% w/w to 99% w/w 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-im idazo[4,5-b]pyridin-2-amine.

25. The extended release pharmaceutical formulation according to claim 14 for use in the treatment of osteoarthritis.

26. The extended release pharmaceutical formulation according to claim 14 for use in the treatment of pain.

27. The extended release pharmaceutical formulation according to claim 14 for use in the treatment of pain associated with osteoarthritis.

Assignees

• Genzyme Corp

Inventors

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

Classifications

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/02

  without antiinflammatory effect · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title