Film formulations containing dexmedetomidine and methods of producing them
Disclosed herein is a self-supporting, dissolvable, film containing dexmedetomidine or a pharmaceutically acceptable salt thereof. The film is administered orally to treat various conditions, particularly agitation, by transmucosal delivery of the active agent.
1. A self-supporting, dissolvable, mucoadhesive film for sublingual administration comprising:
(i) dexmedetomidine or a pharmaceutically acceptable salt thereof;
(ii) a first water-soluble hydroxypropyl cellulose polymer having a molecular weight of about 40,000 daltons;
(iii) a second water-soluble hydroxypropyl cellulose polymer having a molecular weight of about 140,000 daltons;
(iv) a third water-soluble hydroxypropyl cellulose polymer having a molecular weight of about 370,000 daltons; and
(v) a water-soluble polyethylene oxide polymer having a molecular weight of about 600,000 daltons;
wherein: the only polymers present in the film are water-soluble hydroxypropyl cellulose and water-soluble polyethylene oxide polymers; said first water-soluble hydroxypropyl cellulose polymer having a molecular weight of about 40,000 daltons is present at about 3% to about 8% w/w of the total film weight; said second hydroxypropyl cellulose polymer having a molecular weight of about 140,000 daltons is present at about 3% to about 8% w/w of the total film weight and said third water-soluble hydroxypropyl cellulose polymers having a molecular weight of about 370,000 daltons is present at about 20% to about 40% w/w of the total film weight; said water-soluble polyethylene oxide polymer having a molecular weight of about 600,000 daltons is present at about 50% to about 60% w/w of the total film weight; the polymers in (ii), (iii), (iv) and (v) above together form a single layer film substrate; and
dexmedetomidine or a pharmaceutically acceptable salt thereof is present on one surface of said single layer film substrate.
2. The film according to claim 1 , wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride which is present at a weight ratio of about 0.05 mcg to about 3 mcg for each 100 mcg of total weight of film.
3. A self-supporting, dissolvable, mucoadhesive film for sublingual administration consisting of:
(a) a composition comprising:
(i) dexmedetomidine hydrochloride;
(ii) hydroxypropyl cellulose having a molecular weight of about 40,000 daltons; and
(iii) hydroxypropyl cellulose having a molecular weight of about 140,000 daltons; and
(b) a film substrate comprising:
(i) hydroxypropyl cellulose having a molecular weight of about 40,000 daltons;
(ii) hydroxypropyl cellulose having a molecular weight of about 140,000 daltons;
(iii) hydroxypropyl cellulose having a molecular weight of about 370,000 daltons; and
(iv) polyethylene oxide having a molecular weight of about 600,000 daltons;
wherein the only polymers present in the film are water-soluble hydroxypropyl cellulose and water-soluble polyethylene oxide polymers; hydroxypropyl cellulose having a molecular weight of about 40,000 daltons is present at about 3% to about 8% w/w of the total film weight hydroxypropyl cellulose having a molecular weight of about 140,000 daltons is present at about 3% to about 8% w/w of the total film weight hydroxypropyl cellulose having a molecular weight of about 370,000 daltons is present at about 20% to about 40% w/w of the total film weight and polyethylene oxide having a molecular weight of about 600,000 daltons is present at about 50% to about 60% w/w of the total film weight; and the composition of part (a) is present on the surface of the film substrate (b).
4. The film according to claim 3 , wherein the composition of part (a) constitutes about 0.1% to about 10% w/w of the total film weight.
5. The film according to claim 3 , wherein dexmedetomidine hydrochloride is present at about 0.05% to about 3% w/w of the total film weight.
6. The film according to claim 3 , wherein dexmedetomidine hydrochloride is present at about 0.1% to about 0.2% w/w of the total film weight, hydroxypropyl cellulose having a molecular weight of about 40,000 daltons is present at about 5% w/w of the total film weight and hydroxypropyl cellulose having a molecular weight of about 140,000 daltons is present at about 5% w/w of the total film weight.
7. The film according to claim 3 , wherein the composition of part (a) comprises a colorant and the film substrate of part (b) comprises a colorant, wherein the colorant in part (a) is a different color from the colorant in part (b).
8. The film according to claim 3 , wherein the composition of part (a) covers a portion of the surface of the film substrate of part (b).
9. The film according to claim 1 , wherein the film has a thickness of about 20 micrometers to about 200 micrometers.
10. The film according to claim 1 , wherein the film has a thickness of about 20 micrometers to about 200 micrometers and covers an area (width×length) of about 100 mm 2 to about 300 mm 2 .
11. The film according to claim 1 , wherein the film has a disintegration time of about −14 60 seconds to about 180 seconds.
12. The film according to claim 1 , wherein the film has a mucoadhesion force of about 1000 g to about 2000 g.
13. The film according to claim 1 , wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 10 micrograms.
14. The film according to claim 1 , wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 20 micrograms.
15. The film according to claim 1 , wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 4-0 micrograms.
16. The film according to claim 1 , wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 60 micrograms.
17. A method of treating agitation comprising administering sublingually to the agitated subject a film according to claim 1 .
18. The film according to claim 1 , wherein the film is completely dissolvable in oral mucosal fluid in about 1 minute to about 5 minutes.
19. The film according to claim 1 , wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 90 micrograms.
20. The film according to claim 1 , wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 120 micrograms.
21. The film according to claim 1 , wherein said film is administered in one or more units to provide a total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof of about 120 micrograms.
22. The film according to claim 1 , wherein said film is administered in one or more units to provide a total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof of about 180 micrograms.
23. The film according to claim 3 , wherein said film is administered in one or more units to provide a total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof of about 120 micrograms.
24. The film according to claim 3 , wherein said film is administered in one or more units to provide a total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof of about 180 micrograms.
25. The film according to claim 1 , wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present on one surface of said film substrate and covers a portion of the surface of said film substrate at more than one isolated surface locations.
26. The film according to claim 3 , wherein said composition of part (a) is present on the surface of the film substrate (h) and covers a portion of the surface of said film substrate at more than one isolated surface locations.