Small-volume oral transmucosal dosage forms

• US 8,202,535 B2
• Filed: 01/05/2007
• Issued: 06/19/2012
• Est. Priority Date: 01/06/2006
• Status: Active Grant

• Current Assignee: Vertical Pharmaceuticals LLC (Vertical/Trigen Holdings LLC)
• Original Assignee: AcelRx Pharmaceuticals Incorporated
• Inventors: Palmer, Pamela, Schreck, Thomas, Tzannis, Stelios, Hamel, Larry, Poutiatine, Andrew I.
• Primary Examiner(s): BARHAM, BETHANY P
• Application Number:
  US11/650,174
• Publication Number:
  US 20100256190A1
• Time in Patent Office: 1,992 Days
• Field of Search: None
• US Class Current: 424/464
• CPC Class Codes: A61J 2200/30 Compliance analysis for taking medication
• CPC Class Codes: A61J 7/0038 Straws
• CPC Class Codes: A61J 7/0053 Syringes, pipettes or oral dispensers
• CPC Class Codes: A61J 7/0418 with electronic history memory
• CPC Class Codes: A61J 7/0445 for preventing drug dispensing during a predetermined time period
• CPC Class Codes: A61J 7/0481 working on a schedule basis
• 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 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• 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: A61M 15/00 Inhalators drug delivery in endotracheal tubes A61M16/04
• CPC Class Codes: A61M 15/008 Electronic counters
• CPC Class Codes: A61M 15/0081 Locking means
• CPC Class Codes: A61M 15/0083 Timers
• CPC Class Codes: A61M 2205/276 preventing unwanted use
• CPC Class Codes: A61M 2205/3561 local, e.g. within room or hospital
• CPC Class Codes: A61M 2205/3584 using modem, internet or bluetooth
• CPC Class Codes: A61M 2205/3592 : using telemetric means, e.g. radio or optical transmission
• CPC Class Codes: A61M 2205/52 : with memories providing a history of measured variating parameters of apparatus or patient
• CPC Class Codes: A61M 2205/583 : by visual feedback
• CPC Class Codes: A61M 2205/6054 : Magnetic identification systems
• CPC Class Codes: A61M 2205/609 : Biometric patient identification means
• CPC Class Codes: A61M 2209/086 : Docking stations
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: G07C 9/22 : in combination with an identity check of the pass holder
• CPC Class Codes: G07F 17/0092 : for assembling and dispensing of pharmaceutical articles medical dispensers for private use, A61J7/00
• CPC Class Codes: H01Q 1/2208 : associated with components used in interrogation type services, i.e. in systems for information exchange between an interrogator/reader and a tag/transponder, e.g. in Radio Frequency Identification [RFID] systems methods or arrangements for sensing record carriers, e.g. for reading patterns G06K7/00; record carrier for use with machines and with at least a part designed to carry digital markings G06K19/00

Abstract

Small-volume oral transmucosal dosage forms or NanoTabs® comprising a predetermined amount of a pharmaceutically active drug are provided. Exemplary applications include use of the NanoTabs® to administer a drug for the treatment of acute, post-operative or breakthrough pain.

Claims

1. A method of treating pain in a subject, comprising administering a small volume substantially homogeneous solid tablet by adhering said tablet to the oral mucosa of said subject, wherein:

a) said tablet has a volume of from about 3 microliters (mcl) to about 15 mcl;

b) said tablet comprises from about 2 to about 200 micrograms (mcg) of sufentanil and a bioadhesive material;

c) said bioadhesive material provides for adherence of said tablet to the oral mucosa substantially throughout during the period of drug delivery;

d) said tablet generates a minimal saliva response and minimal swallowing of drug;

e) at least 50% of drug delivery occurs via the oral transmucosal route; and

f) administration of said tablet to said subject results in a T_max of from about 19.8 minutes to about 60 minutes.

2. The method according to claim 1, wherein said oral mucosal membrane is a sublingual membrane.

3. The method according to claim 1, wherein said oral mucosal membrane is a buccal membrane.

4. The method according to claim 1, wherein said tablet has a volume of less than 10 mcl.

5. The method according to claim 1, wherein said tablet comprises a dose of sufentanil selected from the group consisting of 5 mcg, 10 mcg, 15 mcg, 20 mcg, 40 mcg, 60 mcg, and 80 mcg, and 100 mcg.

6. The method according to claim 1, wherein oral transmucosal administration of said tablet to said subject results in a bioavailability of greater than 65%.

7. The method according to claim 1, wherein oral transmucosal administration of said tablet to said subject results in a bioavailability of greater than 75%.

8. The method according to claim 1, wherein oral transmucosal administration of said tablet to said subject results in a bioavailability of greater than 85%.

9. The method according to claim 1, wherein oral transmucosal administration of said drug tablet to said subject results in a T_max with a coefficient of variation of less than 40%.

10. The method according to claim 1, wherein repeated oral transmucosal administration of said tablet to said subject, results in a T_max that is shorter than the T_max following a single oral transmucosal administration to said subject.

11. The method according to claim 1, wherein oral transmucosal administration of said tablet results in a therapeutic time ratio of from about 0.5 to about 2.0.

12. The method according to claim 1, wherein an amount of drug 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 total amount of drug in said tablet is absorbed via the oral transmucosal route.

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

14. The method according to claim 1, wherein said tablet is administered using a device.

15. The method according to claim 1, wherein said tablet is self-administered.

16. The method according to claim 14, wherein said tablet is administered using a single-does applicator.

17. The method of treating pain according to claim 1, wherein following said administering, pain relief is evident in said subject.

18. The method of claim 1, wherein said pain is acute pain, breakthrough pain or post-operative pain.

19. The method according to claim 18, wherein said pain is acute pain.

20. The method according to claim 19, wherein said subject is treated by a paramedic or military medic.

21. The method according to claim 19, wherein said subject is treated in the field.

22. The method according to claim 19, wherein said subject is treated under non-sterile conditions.

23. The method according to claim 5, wherein said tablet comprises 20 mcg of sufentanil.

24. The method according to claim 1, wherein said tablet comprises 30 mcg of sufentanil.

25. The method according to claim 1, wherein a single oral mucosal administration of said subject results in an average T_max of 40.8±

13.2 minutes.

26. The method of claim 1, wherein repeated administrations result in an area under the curve (AUC) with a coefficient of variation of less than 30%.

27. The method according to claim 1, wherein complete erosion of said tablet is evident by visual examination after a time selected from the group consisting of about 5 minutes, about 10 minutes and about 15 minutes following administration.