Sublingual apomorphine

Patent metadata

Field	Value
Publication number	US-9669019-B2
Application number	US-201514963910-A
Country	US
Kind code	B2
Filing date	Dec 9, 2015
Priority date	Jun 12, 2009
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

Disclosed are sublingual formulations of apomorphine in unit dosage form formulated for sublingual administration, where the unit dosage form is a mucoadhesive film containing a pH neutralizing agent and apomorphine particles containing an acid addition salt of apomorphine, and where the mucoadhesive film is formed by the steps of: (i) combining a film-forming mucoadhesive polymer, apomorphine particles comprising an acid addition salt of apomorphine, and a solvent to form a mixture; and (ii) pouring the mixture onto a surface and evaporating some of the solvent to form a first film comprising the apomorphine particles, where the steps further include contacting or impregnating the first film or mixture with a pH neutralizing agent to produce the mucoadhesive film containing the apomorphine particles and the pH neutralizing agent.

First claim

What is claimed is:

1. A pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein said unit dosage form is a mucoadhesive film comprising a pH neutralizing agent and apomorphine particles comprising an acid addition salt of apomorphine, and wherein said mucoadhesive film is formed by the steps of:
(i) combining a film-forming mucoadhesive polymer, apomorphine particles comprising an acid addition salt of apomorphine, and a solvent to form a mixture; and
(ii) pouring the mixture onto a surface and evaporating some of said solvent to form a first film comprising said apomorphine particles,
wherein said steps further comprise contacting or impregnating said first film or mixture with a pH neutralizing agent to produce said mucoadhesive film, said mucoadhesive film comprising said apomorphine particles and said pH neutralizing agent.

2. The pharmaceutical composition of claim 1 , wherein said pH neutralizing agent is an inorganic base.

3. The pharmaceutical composition of claim 2 , wherein said inorganic base is sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, or a mixture thereof.

4. The pharmaceutical composition of claim 1 , wherein said acid addition salt of apomorphine is apomorphine hydrochloride.

5. The pharmaceutical composition of claim 1 , wherein said combining further comprises adding an antioxidant.

6. The pharmaceutical composition of claim 5 , wherein said antioxidant is selected from the group consisting of thiols, sulphoximines, metal chelators, sodium metabisulfite, vitamins, phenols, benzoates, uric acid, mannose, propyl gallate, selenium, stilbenes, and combinations thereof.

7. The pharmaceutical composition of claim 6 , wherein said antioxidant is sodium metabisulfite.

8. The pharmaceutical composition of claim 6 , wherein said antioxidant is a metal chelator.

9. The pharmaceutical composition of claim 8 , wherein said metal chelator is EDTA.

10. The pharmaceutical composition of claim 1 , wherein said combining further comprises adding a plasticizer selected from the group consisting of glycerol, propylene glycol, fatty acid esters, sorbitan esters, citric acid esters, PEG 400, polyvinyl methyl ether, triacetin, mannitol, xylitol, and sorbitol.

11. The pharmaceutical composition of claim 10 , wherein said plasticizer is glycerol.

12. The pharmaceutical composition of claim 1 , wherein said mucoadhesive film comprises from 2 to 40 mg of said acid addition salt of apomorphine.

13. The pharmaceutical composition of claim 12 , wherein said mucoadhesive film comprises 10±3 mg of said acid addition salt of apomorphine.

14. The pharmaceutical composition of claim 12 , wherein said mucoadhesive film comprises 15±3 mg of said acid addition salt of apomorphine.

15. The pharmaceutical composition of claim 12 , wherein said mucoadhesive film comprises 22±4 mg of said acid addition salt of apomorphine.

16. The pharmaceutical composition of claim 12 , wherein said mucoadhesive film comprises 27±4 mg of said acid addition salt of apomorphine.

17. The pharmaceutical composition of claim 12 , wherein said mucoadhesive film comprises 30±5 mg of said acid addition salt of apomorphine.

18. The pharmaceutical composition of claim 12 , wherein said mucoadhesive film comprises 35±5 mg of said acid addition salt of apomorphine.

19. A method of treating a patient having Parkinson's disease comprising administering to said patient an effective amount of the pharmaceutical composition of claim 1 .

20. The method of claim 19 , wherein said administering alleviates “off” symptoms of Parkinson's disease.

21. The method of claim 1 , wherein said pH neutralizing agent is an organic base.

22. The pharmaceutical composition of claim 1 , wherein said mucoadhesive film comprises a first portion comprising apomorphine particles comprising said acid addition salt of apomorphine and a second portion comprising said pH neutralizing agent, and wherein said steps comprise contacting said first film with said pH neutralizing agent to produce said mucoadhesive film.

23. The pharmaceutical composition of claim 22 , wherein said first portion is a first layer, and said second portion is a second layer.

24. The pharmaceutical composition of claim 1 , wherein said mucoadhesive film is a non-effervescent, mucoadhesive film.

25. The pharmaceutical composition of claim 1 , wherein said mucoadhesive film produces an average circulating apomorphine plasma concentration of at least 3 ng/mL within 20 minutes following sublingual administration.

26. The pharmaceutical composition of claim 1 , wherein said mucoadhesive film further comprises a permeation enhancer.

27. The pharmaceutical composition of claim 1 , wherein said mucoadhesive film further comprises glycerol monostearate.

28. The pharmaceutical composition of claim 1 , wherein the film comprises 12 to 30 mg of an acid addition salt of apomorphine.

29. The pharmaceutical composition of claim 28 , wherein said acid addition salt of apomorphine is apomorphine hydrochloride.

30. The pharmaceutical composition of claim 22 , wherein the film comprises 12 to 30 mg of an acid addition salt of apomorphine.

31. The pharmaceutical composition of claim 30 , wherein said acid addition salt of apomorphine is apomorphine hydrochloride.

Assignees

• Sunovion Pharmaceuticals Inc

Inventors

• Giovinazzo Anthony John
• Hedden David Bruce
• De Somer Marc L
• Bryson Nathan John

Classifications

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P15/10

  for impotence · CPC title

• A61K47/10

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

• Y10T428/2982

  Particulate matter [e.g., sphere, flake, etc.] · CPC title

• A61K31/473

  ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines · CPC title