Bioadhesive drug formulations for oral transmucosal delivery

• US 8,865,211 B2
• Filed: 08/27/2012
• Issued: 10/21/2014
• 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, Hamel, Larry, Palmer, Pamela, Schreck, Thomas, Poutiatine, Andrew I.
• Primary Examiner(s): GULLEDGE, BRIAN M
• Application Number:
  US13/595,879
• Publication Number:
  US 20130156842A1
• Time in Patent Office: 785 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: A61J 7/00 Devices for administering medicines orally, e.g. spoons calibrated capacity measures for fluids or fluent solid material G01F19/00; weighing spoons G01G19/56; Pill counting devices; Arrangements for time indication or reminder for taking medicine
• CPC Class Codes: A61J 7/0023 Spoons
• CPC Class Codes: A61J 7/0046 Cups, bottles or bags
• CPC Class Codes: A61J 7/0053 Syringes, pipettes or oral dispensers
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• 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 25/00 Drugs for disorders of the nervous system

Abstract

Bioadhesive drug formulations that adhere to an oral mucosal membrane of a subject are provided together with single dose applicators and devices for delivering the drug formulations to the oral mucosa, and methods for using the same.

Claims

1. A method of treating pain in a subject, comprising administering a bioadhesive tablet to the oral mucosa of a subject,

wherein said tablet comprises:

(a) from about 2.5 to about 100 micrograms of sufentanil, expressed as the base; and

(b) a bioadhesive material, wherein said bioadhesive material provides for adherence to the oral mucosa of said subject, and

(c) said tablet has a volume of from about 0.1 microliters to about 50 microliters,

wherein after administration of said tablet to said subject, said tablet provides a minimal saliva response and minimal swallowing of sufentanil; and

more than 50% of drug delivery of sufentanil occurs via the oral transmucosal route.

2. The method according to claim 1, wherein said tablet forms a hydrogel upon contact with an aqueous fluid.

3. The method 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.

4. The method according to claim 1, wherein upon contact with an aqueous fluid said tablet disintegrates and forms a film.

5. The method according to claim 1, wherein dissolution of said tablet is independent of pH.

6. The method according to claim 5, wherein dissolution of said tablet is independent of pH over a pH range of about 4 to 8.

7. The method according to claim 1, wherein said tablet has a volume of from about 0.5 to about 10.0 microliters.

8. The method according to claim 1, wherein said tablet has a volume of from about 1.0 to about 25 microliters.

9. The method according to claim 1, wherein said tablet has a volume of from about 3.0 to about 15.0 microliters.

10. The method according to claim 1, wherein said tablet comprises 10 micrograms of sufentanil, expressed as the base.

11. The method according to claim 1, wherein said tablet comprises 15 micrograms of sufentanil, expressed as the base.

12. The method according to claim 1, wherein said tablet has a thickness of from 0.5 to 3.0 mm.

13. The method according to claim 1, wherein said tablet disintegrates over a period of 10-30 minutes following sublingual administration to said subject.

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

15. The method according to claim 1, wherein following administration, said tablet adheres to the oral mucosa of said subject throughout the period of drug delivery.

16. The method 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.

17. The method according to claim 1, wherein the amount of the drug in said tablet 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 bioadhesive tablet.

18. The method according to claim 17, wherein at least 55% of the total amount of drug in said formulation is absorbed via the oral transmucosal route.

19. The method according to claim 17, wherein at least 60% of the total amount of drug in said formulation is absorbed via the oral transmucosal route.

20. The method according to claim 1, wherein said tablet is administered using a single dose applicator (SDA).

21. The method according to claim 20, wherein said SDA is effective to accurately place said tablet in the sublingual space.

22. The method according to claim 21, wherein said tablet remains dry in said SDA prior to dispensing, at which point a single tablet is dispensed from the SDA into the mouth of said subject.

23. The method according to claim 1, wherein said tablet is administered using a drug dispensing device, wherein said drug dispensing device is effective to check user identification and provide a lockout period between dose dispenses.

24. The method according to claim 23, wherein said drug dispensing device is effective to accurately place said tablet in the sublingual area.

25. The method according to claim 24, wherein said tablet remains dry in the drug dispensing device prior to dispensing, at which point a single tablet is dispensed from the drug dispensing device into the mouth of said subject.

26. The method according to claim 24, wherein said drug dispensing device further comprises a user interface wherein dosage history can be transferred to another device, computer or network.