Solid dispersions containing kinase inhibitors

• US 8,557,995 B2
• Filed: 06/07/2011
• Issued: 10/15/2013
• Est. Priority Date: 06/09/2010
• Status: Expired due to Fees

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbvie Incorporated
• Inventors: Miller, Jonathan M., Schmitt, Eric A., Gao, Yi, Lafountaine, Justin, Dias, Lloyd, Gokhale, Rajeev
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US13/154,562
• Publication Number:
  US 20110306632A1
• Time in Patent Office: 861 Days
• Field of Search: 514/338, 546/114
• US Class Current: 546/114
• CPC Class Codes: A61K 31/4743 condensed with ring systems having sulfur as a ring hetero atom
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A solid dispersion comprises, in essentially non-crystalline form, a kinase inhibitory compound, e.g., N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a cancer.

Claims

1. A solid dispersion product comprising N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno [3,2-c]pyridin-3-yl}phenyl)-N′

-(3-fluorophenyl)urea or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable water-soluble polymeric carrier, and at least one pharmaceutically acceptable surfactant, wherein the N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′

-(3-fluorophenyl)urea is present in about 1% to about 40% by free base equivalent weight.

2. The solid dispersion product of claim 1, wherein solid dispersion product is amorphous.

3. The solid dispersion product of claim 1, comprising at least one acid.

4. The solid dispersion product of claim 3, wherein the at least one acid comprises from about 0.1 to about 10 equivalents with respect to N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno [3,2-c]pyridin-3-yl}phenyl)-N′

-(3-fluorophenyl)urea.

5. The solid dispersion product of claim 3, wherein the at least one acid is selected from the group consisting of acetic acid, ascorbic acid, benzenesulfonic acid, citric acid, ethanedisulfonic acid, 1-hydroxy-2-napthoic acid, hydrochloric acid, hydrobromic acid, lactic acid, maleic acid, malic acid, malonic acid, methanesulfonic acid, phosphoric acid, sulfuric acid, succinic acid, tartaric acid, and toluenesulfonic acid.

6. The solid dispersion product of claim 3, wherein the at least one acid is selected from the group consisting of citric acid, maleic acid, malic acid, malonic acid, succinic acid, and tartaric acid.

7. The solid dispersion product of claim 3, wherein the at least one acid is citric acid.

8. The solid dispersion product of claim 1, wherein the N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′

-(3-fluorophenyl)urea is present in about 5% to about 15% by free base equivalent weight.

9. The solid dispersion product of claim 1, wherein the N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′

-(3-fluorophenyl)urea is present in about 8% to about 12% by free base equivalent weight.

10. The solid dispersion product of claim 1, wherein the at least one polymeric carrier is present in an amount of about 40% to about 85% by weight and the at least one surfactant is present in an amount of about 5% to about 30% by weight.

11. The solid dispersion product of claim 1, wherein at least one polymeric carrier is selected from the group consisting of homopolymers and copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, high molecular weight polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, oligo- and polysaccharides, and mixtures thereof.

12. The solid dispersion product of claim 1, wherein the at least one polymeric carrier is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methylcellulose, and mixtures thereof.

13. The solid dispersion product of claim 1, wherein the at least one surfactant is selected from the group consisting of polyethylene glycol glyceride derivatives, polyoxyethylene castor oil derivatives, fatty acid monoesters of sorbitan, polysorbates, poloxamers, α

-tocopheryl polyethylene, glycol succinate, and mixtures thereof.

14. The solid dispersion product of claim 1, wherein the at least one surfactant is selected from the group consisting of polysorbates, polyoxyethylene castor oil derivatives, and mixtures thereof.

15. An orally deliverable pharmaceutical dosage form comprising the solid dispersion product of claim 1.

16. The dosage form of claim 15, containing at least one additive selected from the disintegrants, lubricants, and bulking agents.