SUBLINGUAL APOMORPHINE

• US 20110111011A1
• Filed: 06/11/2010
• Published: 05/12/2011
• Est. Priority Date: 06/12/2009
• Status: Active Grant

• Current Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Original Assignee: Cynapsus Therapeutics Inc. (Sumitomo Pharma America, Inc.)
• Inventors: Giovinazzo, Anthony John, Bryson, Nathan John, Hedden, David Bruce, de Somer, Marc L.
• Granted Patent: US 9,044,475 B2
• Time in Patent Office: Days
• US Class Current: 424/443
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

The invention features sublingual formulations of apomorphine and apomorphine prodrugs, and methods of treating Parkinson'"'"'s disease, sexual dysfunction, and depressive disorders therewith.

Claims

1. A pharmaceutical composition in unit dosage form formulated for sublingual administration, said unit dosage form having a first portion comprising an acid addition salt of apomorphine, or an apomorphine prodrug, and a second portion comprising a pH neutralizing agent.

2. The pharmaceutical composition of claim 1, wherein said unit dosage form is a lozenge, a pill, a tablet, a film, or a strip.

3. The pharmaceutical composition of claim 1, wherein said pH neutralizing agent is selected from polyamines, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, calcium carbonate, iron carbonate, magnesium carbonate, zinc carbonate, sodium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, and mixtures thereof.

4. The pharmaceutical composition of claim 1, wherein said unit dosage form is a film or a strip and wherein said unit dosage form comprises a mucoadhesive polymer.

5. The pharmaceutical composition of claim 1, wherein said acid addition salt of apomorphine, or an apomorphine prodrug, is apomorphine hydrochloride.

6. The pharmaceutical composition of claim 1, wherein said acid addition salt of apomorphine, or an apomorphine prodrug, is protonated apomorphine complexed to an anionic polyelectrolyte.

7. The pharmaceutical composition of claim 6, wherein said anionic polyelectrolyte is selected from alginates, carrageenan, xanthan gum, polyacrylate, and carboxymethylcellulose.

8. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is a film or a strip, wherein said first portion is a first layer and said second portion is a second layer, said first layer being acidic and comprising said acid addition salt of apomorphine, or an apomorphine prodrug, and said second layer comprising said pH neutralizing agent.

9. The pharmaceutical composition of claim 1, further comprising an antioxidant.

10. The pharmaceutical composition of claim 1, wherein said first portion is a film comprising a solid solution of an acid addition salt of apomorphine, or an apomorphine prodrug, and said second portion is a particulate base on or within said unit dosage form.

11. The pharmaceutical composition of claim 10, wherein said particulate base comprises sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, or a mixture thereof.

12. The pharmaceutical composition of claim 1, wherein said first portion is separated from said second portion by a barrier.

13. The pharmaceutical composition of claim 12, wherein said barrier is a film or a coating.

36. The pharmaceutical composition of any of claim 1, 14, 28, or 33, wherein said pharmaceutical composition is in a unit dosage form comprising from 2 to 40 mg of apomorphine, an apomorphine prodrug, or an acid addition salt thereof.

37. The pharmaceutical composition of any of claim 1, 14, 28, or 33, wherein said unit dosage form when placed in 1 mL of unbuffered water at pH 7 results in a solution having a pH of between 7.4 and 9.1.

38. The pharmaceutical composition of any of claim 1, 14, 28, or 33, wherein following sublingual administration to a subject said unit dosage form produces an average circulating concentration of at least 3 ng/mL within a period of from 5 to 15 minutes.

39. A method of treating Parkinson'"'"'s disease in a mammal, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to treat said mammal.

40. A method for alleviating dyskinesia in a mammal afflicted with Parkinson'"'"'s disease, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to alleviate said dyskinesia.

41. A method for alleviating akinesia in a mammal afflicted with Parkinson'"'"'s disease, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to alleviate said akinesia.

42. A method of treating sexual dysfunction in a mammal, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to treat said mammal.

43. A method of treating a depressive disorder in a mammal, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to treat said mammal.

44. The method of any of claims 39, further comprising the administration of an effective amount of an anti-emetic agent.

45. The method of claim 44, wherein said anti-emetic agent is selected from nicotine, lobeline sulfate, pipamazine, oxypendyl hydrochloride, ondansetron, buclizine hydrochloride, cyclizine hydrochloride, dimenhydrinate, scopolamine, metopimazine, benzauinamine hydrochloride, and diphenidol hydrochloride.

14. A pharmaceutical composition formulated for sublingual administration comprising apomorphine particles having an effective particle size of from 20 nm to 10 μ

m, wherein said apomorphine particles comprise apomorphine, an apomorphine prodrug, or a salt thereof.

15. The pharmaceutical composition of claim 14, wherein said pharmaceutical composition is in a unit dosage form selected from a lozenge, a pill, a tablet, a film, or a strip.

16. The pharmaceutical composition of claim 14, wherein said pharmaceutical composition is a sublingual gel.

17. The pharmaceutical composition of claim 16, wherein said apomorphine particles having an effective particle size of from 1 μ

m to 10 μ

m.

18. The pharmaceutical composition of claim 17, wherein said apomorphine particles having an effective particle size of from 2 μ

m to 7 μ

m.

19. The pharmaceutical composition of claim 16, wherein said apomorphine particles having an effective particle size of from 20 nm to 1 μ

m.

20. The pharmaceutical composition of claim 19, wherein said apomorphine particles having an effective particle size of from 50 nm to 700 nm.

21. The pharmaceutical composition of claim 14, further comprising a mucoadhesive polymer.

22. The pharmaceutical composition of claim 14, wherein said apomorphine particles comprise an acid addition salt of apomorphine, or an apomorphine prodrug.

23. The pharmaceutical composition of claim 22, wherein said apomorphine particles comprise apomorphine hydrochloride.

24. The pharmaceutical composition of claim 14, wherein said unit dosage form is a film or a strip and wherein said unit dosage form comprises a mucoadhesive polymer.

25. The pharmaceutical composition of claim 24, wherein said pharmaceutical composition comprises a first layer and a second layer, said first layer being acidic and comprising said apomorphine particles and said second layer comprising a pH neutralizing agent.

26. The pharmaceutical composition of claim 25, wherein said pH neutralizing agent is selected from polyamines, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, calcium carbonate, iron carbonate, magnesium carbonate, zinc carbonate, sodium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, and mixtures thereof.

27. The pharmaceutical composition of claim 14, further comprising an antioxidant.

28. A pharmaceutical composition formulated for sublingual administration comprising protonated apomorphine, or an apomorphine prodrug, complexed to an anionic polyelectrolyte.

29. The pharmaceutical composition of claim 28, wherein said anionic polyelectrolyte is selected from alginates, carrageenan, xanthan gum, polyacrylate, and carboxymethylcellulose.

30. The pharmaceutical composition of claim 28, further comprising an antioxidant.

31. The pharmaceutical composition of claim 28, wherein said pharmaceutical composition is in a unit dosage form selected from a lozenge, a pill, a tablet, a film, or a strip.

32. The pharmaceutical composition of claim 28, wherein said pharmaceutical composition is a sublingual gel.

33. A pharmaceutical composition in unit dosage form formulated for sublingual administration, said unit dosage form comprising from 2 to 50 mg of an apomorphine prodrug.

34. The pharmaceutical composition of claim 33, wherein said unit dosage form is a lozenge, a pill, a tablet, a film, or strip comprising from 2 to 50 mg of an apomorphine prodrug in its free base form.

35. The pharmaceutical composition of claim 33, wherein said unit dosage form is a lozenge, a pill, a tablet, a film, or strip comprising a solid solution of an apomorphine prodrug in its free base form.