Bioadhesive drug formulations for oral transmucosal delivery

• US 8,252,328 B2
• Filed: 01/05/2007
• Issued: 08/28/2012
• Est. Priority Date: 01/06/2006
• Status: Active Grant

• Current Assignee: Vertical Pharmaceuticals LLC (Vertical/Trigen Holdings LLC)
• Original Assignee: AcelRx Pharmaceuticals Incorporated
• Inventors: Tzannis, Stelios, Palmer, Pamela, Schreck, Thomas, Hamel, Larry, Poutiatine, Andrew I.
• Primary Examiner(s): GULLEDGE, BRIAN M
• Application Number:
  US11/650,227
• Publication Number:
  US 20070207207A1
• Time in Patent Office: 2,062 Days
• Field of Search: None
• US Class Current: 424/464
• CPC Class Codes: A61J 3/005 Coating of tablets or the like coating of sweetmeats or confectionery A23G3/20; coating of granules in general B01J2/006
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

Formulations for controlled delivery of oral transmucosal medications are provided. The formulations are characterized as hydrogel-forming or eroding-types which are bioadhesive and provide for controlled and sustained release of the medication such that enhanced bioavailability and efficacy is provided.

Claims

1. A bioadhesive tablet, comprising:

from about 2.5 to about 100 micrograms of sufentanil, a bioadhesive material and pharmaceutically acceptable excipients, wherein said bioadhesive tablet;

(i) provides for adherence to the oral mucosa of said subject during the period of drug delivery such that the majority of drug is delivered across the oral mucosa, (ii) generates a minimal saliva response and minimal swallowing of drug, and (iii) said bioadhesive tablet is a substantially homogeneous composition with a volume of from about 3.0 to about 15.0 microliters (mcl).

2. The bioadhesive tablet according to claim 1, wherein complete erosion of said tablet is evident by visual examination in about 30 seconds up to about 15 minutes following administration.

3. The bioadhesive tablet according to claim 1, comprising from about 2.5 to 40 micrograms of sufentanil.

4. The bioadhesive tablet according to claim 1, wherein said tablet becomes a hydrogel upon contact with an aqueous fluid.

5. The bioadhesive tablet according to claim 1, wherein said tablet is an eroding tablet wherein upon contact with an aqueous fluid, the surface of the tablet hydrates and erodes, without formation of a hydrogel.

6. The bioadhesive tablet according to claim 1, wherein a single or repeated oral transmucosal administration to a subject results in a bioavailability of greater than 70%.

7. The bioadhesive tablet according to claim 1, wherein a single or repeated oral transmucosal administration to a subject results in a bioavailability of greater than 75%.

8. The bioadhesive tablet according to claim 1, wherein a single or repeated oral transmucosal administration to a subject results in a bioavailability of greater than 85%.

9. The bioadhesive tablet according to claim 1, wherein a single oral transmucosal administration to a subject results in a plasma level that reaches 50% of C_max in from about 10 minutes to about 30 minutes.

10. The bioadhesive tablet according to claim 1, wherein a single oral transmucosal administration to a subject results in a therapeutic time ratio of from about 0.5 to about 2.0.

11. The bioadhesive tablet according to claim 1, wherein the amount of the drug in said formulation absorbed via the oral mucosa is selected from the group consisting of at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% and at least 99% of the drug in said tablet.

12. The bioadhesive tablet according to claim 1, wherein at least 60% of the total amount of drug in said formulation is absorbed via the oral transmucosal route.

13. The bioadhesive tablet according to claim 1, wherein said tablet has a disintegration time of from about 30 seconds to about 30 minutes and oral transmucosal administration results in a plasma level that reaches 50% of C_max in a time of from about 10 minutes to about 30 minutes.

14. The bioadhesive tablet according to claim 1, wherein said tablet has a disintegration time of from about 15 minutes to about 8 hours and oral transmucosal administration results in a plasma level that reaches 50% of C_max in a time of from about 10 minutes to about 100 minutes.

15. The bioadhesive tablet according to claim 1, wherein said tablet has a disintegration time of from about 15 minutes to about 8 hours and oral transmucosal administration results in a therapeutic time ratio of from about 0.3 to about 2.0.

16. The bioadhesive tablet according to claim 1, wherein said tablet comprises from about 2.5 to about 15.0 micrograms of sufentanil.

17. The bioadhesive tablet according to claim 2, wherein said tablet comprises from about 2.5 to about 15.0 micrograms of sufentanil.

18. The bioadhesive tablet according to claim 1, wherein a single or repeated oral transmucosal administration to a subject results in a bioavailability with a coefficient of variation of less than 40%.

19. The bioadhesive tablet according to claim 1, wherein a single oral transmucosal administration to a subject results in a Tonset of from about 3 minutes to about 30 minutes.

20. The bioadhesive tablet according to claim 11, wherein at least 65% of the total amount of drug in said formulation is absorbed via the oral transmucosal route.

21. The bioadhesive tablet according to claim 1, wherein a single or repeated oral transmucosal administration to a subject results in a half life of from 30 minutes to 4 hours.

22. The bioadhesive tablet according to claim 1, wherein a single or repeated oral transmucosal administration to a subject results in a half life of from 100 to 300 minutes.

23. The bioadhesive tablet according to claim 1, wherein oral administration to a subject results in an average bioavailability of 12.2%.

24. The bioadhesive tablet according to claim 23, wherein said tablet comprises 10 micrograms of sufentanil.

25. The bioadhesive tablet according to claim 23, wherein said tablet comprises 15 micrograms of sufentanil.

26. The bioadhesive tablet according to claim 1, wherein following administration, said tablet adheres to the oral mucosa of said subject for the period of drug delivery.

27. The bioadhesive tablet according to claim 1, wherein said tablet further comprises one or more excipients that affect both tablet disintegration kinetics and drug release from said tablet.

28. The bioadhesive tablet according to claim 27, wherein said one or more excipients that affect tablet disintegration kinetics and drug release from said tablet is crosslinked sodium carboxy methylcellulose.

29. The bioadhesive tablet according to claim 1, wherein a single or repeated oral transmucosal administration to a subject results in a bioavailability of greater than 90%.

30. The bioadhesive tablet according to claim 1, wherein said tablet further comprises one or more excipients that affect both tablet disintegration kinetics and drug release from said tablet.

31. The bioadhesive tablet according to claim 30, wherein said one or more excipients that affect tablet disintegration kinetics and drug release from said tablet is crosslinked sodium carboxy methylcellulose.

32. The bioadhesive tablet according to claim 31, wherein a single or repeated oral transmucosal administration to a subject results in a bioavailability of greater than 70%.

33. The bioadhesive tablet according to claim 1, wherein said tablet comprises between 1% and 40% bioadhesive material on a w/w basis.

34. The bioadhesive tablet according to claim 1, wherein said tablet exhibits an attachment force of from 0.03 to 0.18 N/cm² to a porcine mucosa substrate in vitro.

35. The bioadhesive tablet according to claim 34, wherein said tablet comprises between 1% and 40% bioadhesive material on a w/w basis.