Sublingual apomorphine

• US 9,669,020 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:
  US14/963,971
• Publication Number:
  US 20160089328A1
• 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

The invention features mucoadhesive sublingual films containing a pH neutralizing agent and apomorphine particles containing an acid addition salt of apomorphine. The pH neutralizing agent in these films can be sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, or a mixture thereof.

Claims

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, wherein said pH neutralizing agent is sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, or a mixture thereof.

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

3. The pharmaceutical composition of claim 1, wherein said mucoadhesive film further comprises an antioxidant.

4. The pharmaceutical composition of claim 3, 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.

5. The pharmaceutical composition of claim 4, wherein said antioxidant is sodium metabisulfite.

6. The pharmaceutical composition of claim 4, wherein said antioxidant is a metal chelator.

7. The pharmaceutical composition of claim 6, wherein said metal chelators is EDTA.

8. The pharmaceutical composition of claim 1, wherein said mucoadhesive film further comprises 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.

9. The pharmaceutical composition of claim 8, wherein said plasticizer is glycerol.

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

11. The pharmaceutical composition of claim 10, wherein said mucoadhesive film comprises 10±

3 mg of said acid addition salt of apomorphine.

12. The pharmaceutical composition of claim 10, wherein said mucoadhesive film comprises 15±

3 mg of said acid addition salt of apomorphine.

13. The pharmaceutical composition of claim 10, wherein said mucoadhesive film comprises 22±

4 mg of said acid addition salt of apomorphine.

14. The pharmaceutical composition of claim 10, wherein said mucoadhesive film comprises 27±

4 mg of said acid addition salt of apomorphine.

15. The pharmaceutical composition of claim 10, wherein said mucoadhesive film comprises 30±

5 mg of said acid addition salt of apomorphine.

16. The pharmaceutical composition of claim 10, wherein said mucoadhesive film comprises 35±

5 mg of said acid addition salt of apomorphine.

17. 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.

18. The method of claim 17, wherein said administering alleviates “

off”

symptoms of Parkinson'"'"'s disease.

19. 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.

20. The pharmaceutical composition of claim 1, wherein said first portion is a first layer and said second portion is a second layer.

21. The pharmaceutical composition of claim 1, wherein said unit dosage form is a non-effervescent unit dosage form.

22. 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.

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

24. The pharmaceutical composition of claim 21, wherein said acid addition salt of apomorphine is apomorphine hydrochloride.

25. The pharmaceutical composition of claim 17, wherein the film comprises 12 to 30 mg of an acid addition salt of apomorphine.

26. The pharmaceutical composition of claim 23, wherein said acid addition salt of apomorphine is apomorphine hydrochloride.