Sublingual apomorphine

• US 9,669,018 B2
• Filed: 12/09/2015
• Issued: 06/06/2017
• Est. Priority Date: 06/12/2009
• Status: Active Grant

• Current Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Original Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Inventors: Giovinazzo, Anthony John, De Somer, Marc L., Bryson, Nathan John, Hedden, David Bruce
• Primary Examiner(s): Browe, David
• Application Number:
  US14/963,835
• Publication Number:
  US 20160089367A1
• Time in Patent Office: 545 Days
• 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

Disclosed are methods of preparing a pharmaceutical composition that is a mucoadhesive film by: (i) combining a film-forming mucoadhesive polymer, apomorphine particles containing 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 an intermediate film including the apomorphine particles; where the method further includes contacting or impregnating the intermediate film or mixture with a pH neutralizing agent to produce the mucoadhesive film containing the apomorphine particles and the pH neutralizing agent.

Claims

1. A method of preparing a pharmaceutical composition that is a mucoadhesive film comprising 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 method further comprises 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 method of claim 1, wherein said pH neutralizing agent is an inorganic base.

3. The method 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 method of claim 1, wherein said acid addition salt of apomorphine is apomorphine hydrochloride.

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

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

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

8. The method claim 6, wherein said antioxidant is a metal chelator.

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

10. The method 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 method of claim 10, wherein said plasticizer is glycerol.

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

13. The method of claim 12, wherein said mucoadhesive film comprises 10±

3 mg said acid addition salt of apomorphine.

14. The method of claim 12, wherein said mucoadhesive film comprises 5±

3 mg of said acid addition salt of apomorphine.

15. The method of claim 12, wherein said mucoadhesive film comprises 22±

4 mg of said acid addition salt of apomorphine.

16. The method of claim 12, wherein said mucoadhesive film comprises 27±

4 mg of said acid addition salt of apomorphine.

17. The method of claim 12, wherein said mucoadhesive film comprises 30±

5 mg of said acid addition salt of apomorphine.

18. The method of claim 12, herein said mucoadhesive film comprises 35±

5 mg of said acid addition salt of apomorphine.

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

20. The method 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 method comprises contacting said first film with said pH neutralizing agent to produce said mucoadhesive film.

21. The method of claim 20, wherein said first portion is a first layer, and said second portion is a second layer.

22. The method of claim 1, wherein said mucoadhesive film is a non-effervescent, mucoadhesive film.

23. The method 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.

24. The method of claim 1, wherein said mucoadhesive film further comprises a permeation enhancer.

25. The method of claim 1, wherein said mucoadhesive film further comprises glycerol monostearate.

26. The method of claim 1, wherein the film comprises 12 to 30 mg of an acid addition salt of apomorphine.

27. The method of claim 26, wherein said acid addition salt of apomorphine is apomorphine hydrochloride.

28. The method of claim 20, wherein the film comprise 12 to 30 mg of an acid addition salt of apomorphine.

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