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:
(i) 30 to 75% (w/w) of an acid addition salt of apomorphine,
(ii) 0.5 to 10% (w/w) of a low molecular weight polymer having a weight average molecular weight of 5 kDa to 50 kDa selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and
(iii) 4 to 20±6% (w/w) of a high molecular weight polymer having a weight average molecular weight of greater than 60 kDa selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose; and
wherein said film is a bilayer film comprising a first layer comprising said acid addition salt of apomorphine and a second layer comprising a pH neutralizing agent that is pyridoxine.
2. The pharmaceutical composition of claim 1 , further comprising from 0.2 to 5% (w/w) of permeation enhancer.
3. The pharmaceutical composition of claim 1 , further comprising from 0.2 to 5% (w/w) of glycerol monostearate.
4. The pharmaceutical composition of claim 1 , further comprising from 3 to 12% (w/w) of plasticizing agent.
5. The pharmaceutical composition of claim 4 , wherein said plasticizing agent is a polyol, oleic acid, or triacetin.
6. The pharmaceutical composition of claim 5 , wherein said plasticizing agent is a polyol selected from the group consisting of sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, and polyethylene glycol.
7. The pharmaceutical composition of claim 1 , further comprising from 1 to 50% (w/w) of a hydrolyzed starch.
8. The pharmaceutical composition of claim 7 , wherein said hydrolyzed starch is a dextrin.
9. The pharmaceutical composition of claim 7 , wherein said hydrolyzed starch is a maltodextrin.
10. The pharmaceutical composition of claim 1 , further comprising an antioxidant.
11. The pharmaceutical composition of claim 1 , further comprising said pharmaceutical composition further comprises from 0.05 to 2.5% (w/w) of a metabisulfite.
12. The pharmaceutical composition of claim 1 , wherein said unit dosage form is stable for a period of at least 2 months at 40° C., when packaged in a sealed plastic-lined aluminum foil.
13. The pharmaceutical composition of claim 1 , wherein said film comprises particles of said acid addition salt of apomorphine.
14. The pharmaceutical composition of claim 13 , wherein said acid addition salt of apomorphine is apomorphine hydrochloride.
15. The pharmaceutical composition of claim 13 , wherein said particles have an effective particle size of from 20 nm to 10 μm.
16. 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 4.5 and 8.5.
17. The pharmaceutical composition of claim 1 , wherein said film comprises 12±3 mg of apomorphine hydrochloride.
18. The pharmaceutical composition of claim 1 , wherein said film comprises 22±4 mg of apomorphine hydrochloride.
19. The pharmaceutical composition of claim 1 , wherein said film comprises 30±5 mg of apomorphine hydrochloride.
20. 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.
21. The method of claim 20 , wherein said treating comprises alleviating an OFF episode associated with Parkinson's disease in said subject.