Sublingual films
The invention features sublingual film formulations of dopamine agonists and methods of treating Parkinson's disease, tremors, restless leg syndrome, sexual dysfunction, and depressive disorders therewith.
1. A pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein said unit dosage form is a film comprising a first portion comprising apomorphine hydrochloride and a second portion comprising from 10±2 to 50±5% (w/w) of a pH neutralizing agent that is an organic base having a pKa of 5±2, wherein said unit dosage form comprises from 2 to 60 mg of apomorphine hydrochloride.
2. The pharmaceutical composition of claim 1 , wherein said unit dosage form further comprises a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose.
3. The pharmaceutical composition of claim 1 , wherein said unit dosage form further comprises a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose.
4. The pharmaceutical composition of claim 1 , wherein said pH neutralizing agent is pyridoxine.
5. The pharmaceutical composition of claim 1 , further comprising 1±0.5% (w/w) permeation enhancer.
6. The pharmaceutical composition of claim 5 , wherein said permeation enhancer is glycerol monosterate.
7. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition comprises from 3 to 15% (w/w) plasticizing agent.
8. The pharmaceutical composition of claim 1 , wherein said plasticizing agent is a polyol, oleic acid, or triacetin.
9. The pharmaceutical composition of claim 8 , wherein said plasticizing agent is a polyol selected from sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, and polyethylene glycol.
10. The pharmaceutical composition of any claim 1 , wherein said pharmaceutical composition further comprises from 1 to 50% (w/w) hydrolyzed starch.
11. The pharmaceutical composition of claim 10 , wherein said hydrolyzed starch is a dextrin.
12. The pharmaceutical composition of claim 11 , wherein said hydrolyzed starch is a maltodextrin.
13. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition further comprises an antioxidant.
14. The pharmaceutical composition of claim 13 , wherein said pharmaceutical composition further comprises from 0.05 to 2.5% (w/w) metabisulfite.
15. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition has a sublingual bioavailability of greater than 40%.
16. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition has a T max of from 10 to 25 minutes.
17. The pharmaceutical composition of claim 1 , wherein following sublingual administration to a subject said unit dosage form produces an average circulating apomorphine concentration of at least 3 ng/mL within a period of from 5 to 15 minutes.
18. The pharmaceutical composition of claim 1 , wherein said unit dosage form when administered sublingually to a subject is non-irritating.
19. The pharmaceutical composition of claim 1 , wherein said unit dosage form is an individual film packaged in a sealed plastic-lined aluminum foil, wherein said unit dosage form is stable for a period of at least 2 months at 40° C.
20. The pharmaceutical composition of claim 1 , wherein said film comprises a solid solution of apomorphine hydrochloride.
21. The pharmaceutical composition of claim 1 , wherein said film comprises particles of apomorphine hydrochloride.
22. The pharmaceutical composition of claim 21 , wherein said particles have an effective particle size of from 20 nm to 10 μm.
23. The pharmaceutical composition of claim 1 , 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 2.5 and 8.0.
24. A method of treating Parkinson's disease in a subject, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to treat said subject.
25. The pharmaceutical composition of claim 1 , wherein said unit dosage form comprises 12±3 mg of apomorphine hydrochloride.
26. The pharmaceutical composition of claim 1 , wherein said unit dosage form comprises 22±4 mg of apomorphine hydrochloride.
27. The pharmaceutical composition of claim 1 , wherein said unit dosage form comprises 30±5 mg of apomorphine hydrochloride.
28. The pharmaceutical composition of claim 1 , wherein each said portion is a layer.
29. A method of treating restless leg syndrome in a subject, said method comprising sublingual administration of a pharmaceutical composition of claim 1 in an amount effective to treat said subject.