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) a first layer comprising:
(i) from 10 to 75% (w/w) apomorphine hydrochloride;
(ii) from 0.5 to 10% (w/w) 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; and
(iii) from 4 to 35% (w/w) 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, and
(B) a second layer comprising:
(iv) from 6 to 65% (w/w) a pH neutralizing agent that is an organic base having a pKa of 5±2, and
(v) from 15 to 50% (w/w) of 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,
wherein said first layer comprises from 2 to 60 mg of apomorphine hydrochloride,
wherein, following sublingual administration to subjects, said unit dosage form produces an average circulating concentration of 3 to 6 ng/mL within a period of from 7 to 20 minutes, and
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 6.5.
2. The pharmaceutical composition of claim 1 , wherein said film further comprises from 3 to 12% (w/w) plasticizing agent.
3. The pharmaceutical composition of claim 2 , wherein said plasticizing agent is a polyol, oleic acid, or triacetin.
4. The pharmaceutical composition of claim 3 , wherein said plasticizing agent is a polyol selected from sorbitol, mannitol, maltitol, xylitol, glycerol, propylene glycol, and polyethylene glycol.
5. The pharmaceutical composition of claim 1 , wherein said film comprises from 1 to 50% (w/w) hydrolyzed starch.
6. The pharmaceutical composition of claim 5 , wherein said hydrolyzed starch is a dextrin or a maltodextrin.
7. The pharmaceutical composition of claim 1 , wherein said film further comprises an antioxidant.
8. The pharmaceutical composition of claim 7 , wherein said film further comprises from 0.05 to 2.5% (w/w) metabisulfite.
9. The pharmaceutical composition of claim 1 , wherein said film further comprises from 0.2 to 5% (w/w) of a permeation enhancer.
10. The pharmaceutical composition of claim 9 , wherein said permeation enhancer is glycerol monostearate.
11. The pharmaceutical composition of claim 1 , wherein said low molecular weight polymer is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, or hydroxyethyl cellulose.
12. The pharmaceutical composition of claim 11 , wherein said hydroxypropyl methylcellulose has about 20% to about 35% methoxyl substitution and about 5% to about 15% hydroxypropyl substitution.
13. The pharmaceutical composition of claim 1 , wherein said high molecular weight polymer is hydroxypropyl methyl cellulose or hydroxyethyl cellulose.
14. The pharmaceutical composition of claim 13 , wherein said high molecular weight polymer is hydroxypropyl methyl cellulose having about 20% to about 35% methoxyl substitution and about 5% to about 15% hydroxypropyl substitution.
15. The pharmaceutical composition of claim 13 , wherein said high molecular weight polymer is hydroxyethyl cellulose having a weight average molecular weight of from 60 KDa to 1,000 KDa.
16. The pharmaceutical composition of claim 1 , wherein said organic base selected from pyridoxine, citrate, acetate, and histidine.
17. The pharmaceutical composition of claim 1 , wherein following sublingual administration to a subject said unit dosage form produces an average circulating concentration of at least 3 ng/mL within a period of from 5 to 15 minutes.
18. 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.
19. The pharmaceutical composition of claim 16 , wherein said organic base is pyridoxine.
20. The pharmaceutical composition of claim 1 , wherein said unit dosage form comprises 12±3 mg of apomorphine hydrochloride.
21. The pharmaceutical composition of claim 1 , wherein said unit dosage form comprises 22±4 mg of apomorphine hydrochloride.
22. The pharmaceutical composition of claim 1 , wherein said unit dosage form comprises 30±5 mg of apomorphine hydrochloride.
23. The pharmaceutical composition of claim 1 , wherein said unit dosage form comprises 35±5 mg of apomorphine hydrochloride.