MODIFIED RELEASE OF 4-METHYL-3-[[4-(3-PYRIDINYL)-2-PYRIMIDINYL]AMINO]-N-[5-(4-METHYL-1H-IMIDAZOL-1-YL)-3-(TRIFLOUOROMETHYL)PHENYL] BENZAMIDE SOLUBILIZED USING ORGANIC ACIDS

• US 20150273070A1
• Filed: 06/13/2012
• Published: 10/01/2015
• Est. Priority Date: 06/14/2011
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Li, Shoufeng, Kumar, Saran, Kavimandan, Nikhil Javant, Lu, Enxian
• Application Number:
  US14/126,219
• Publication Number:
  US 20150273070A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

Soluble pharmaceutical compositions of nilotinib or a pharmaceutically acceptable salt thereof were invented using one or more organic acids that function as a solubilizing agent, increasing the bioavailability of nilotinib and supressing the food effect associated with certain compositions of nilotinib. The pharmaceutical compositions are in the form of solid oral dosage forms, including capsules and tablets.

Claims

1. An amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof.

5. A dosage form of claim 1 comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid, having a fed/fasted ratio of 0.8-1.5 for AUC and/or C_max.

14. The dosage form of claim 1, wherein the dosage form has water content of less than 10% w/w, preferably less than 5% w/w, particularly less than 2% w/w.

15. The dosage form of claim 1 further comprising excipients for solidifying the dosage form.

16. The dosage form of claim 1, wherein the dosage form is solid.

17. The dosage form of claim 16, wherein the dosage form is a tablet.

18. The dosage form of claim 16, wherein the dosage form is a capsule.

32. A dosage form of claim 1 for use as a medicine.

33. The dosage form of claim 32, wherein the medicine is stored under refrigeration at 2 to 8°

C.

2. A dosage form comprising amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof.

3. A dosage form of claim 2 comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid.

4. A dosage form of claim 2 comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid, having a fasted state bioavailability that exceeds 130% of a hard-gelatin capsule comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide.

6. The dosage form of claim 3, wherein said at least one organic acid is selected from acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid, maleic acid, hydroxymaleic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid and ascorbic acid.

7. The dosage form of claim 3, wherein the organic acid is citric acid.

8. The dosage form of claim 3, wherein the organic acid is lactic acid.

9. The dosage form of claim 3, wherein the organic acid is acetic acid.

10. The dosage form of claim 3 further comprising a surfactant or an anionic polymer.

11. The dosage form of claim 10, wherein the surfactant or the anionic polymer is CYP3A4 or Pg-P inhibitor.

12. The dosage form of claim 10, wherein the surfactant is Poloxamer 407 and/or Vitamin E TPGS.

13. The dosage form of claim 10, wherein the polymer is Eudragid L100-55.

19. A method for preparing amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof, comprising the step of adding at least one organic acid.

20. A method for preparing a dosage form comprising amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid, comprising the step of melt extruding 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and the at least one organic acid.

21. A method of claim 20, wherein 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid are mixed and melt extruded together.

24. The method of claim 20 further comprising a step of adding a surfactant or an anionic polymer.

25. The method of claim 24, wherein the surfactant or the anionic polymer is CYP3A4 or Pg-P inhibitor.

26. The method of claim 24, wherein the surfactant is Poloxamer 407 and/or Vitamin E TPGS.

27. The method of claim 24, wherein the polymer is Eudragid L100-55.

28. The method of claim 20 comprising a further step of obtaining a solid dosage form.

29. The method of claim 28, wherein the solid dosage form is a tablet or a capsule.

22. A method of preparing a dosage form comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid comprising the step of spray drying at least partly dissolved of 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and adding the at least one organic acid.

23. The method of claim 22, wherein the 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and the at least one organic acid together are in a solution or suspension for spray drying.

30. Use of organic acid for increasing of bioavailability of nilotinib.

31. Use of organic acid for supressing the food effect associated with pharmaceutical composition comprising nilotinib or a pharmaceutically acceptable salt thereof.