Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof

• US 7,682,628 B2
• Filed: 08/03/2007
• Issued: 03/23/2010
• Est. Priority Date: 02/17/2004
• Status: Expired due to Fees

• Current Assignee: Paratek Pharmaceuticals Incorporated
• Original Assignee: Transcept Pharmaceuticals Incorporated
• Inventors: Singh, Nikhilesh N.
• Primary Examiner(s): Sheikh; Humera N
• Application Number:
  US11/833,323
• Publication Number:
  US 20080008753A1
• Time in Patent Office: 963 Days
• Field of Search: None
• US Class Current: 424/464
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/0058 Chewing gums non-medicinal aspects, preparing chewing gum A23G4/00; chewing gum for care of the teeth or oral cavity, e.g. with breath freshener A61Q11/00
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides novel compositions for the delivery of a hypnotic agent across the oral mucosa. In particular, the buffer system in the compositions of the present invention raises the pH of saliva to a pH greater than about 7.8, thereby facilitating the substantially complete conversion of the hypnotic agent from its ionized to its un-ionized form. As a result, the dose of hypnotic agent is rapidly and efficiently absorbed by the oral mucosa with surprisingly low inter-subject variability. Furthermore, delivery of the hypnotic agent across the oral mucosa advantageously bypasses hepatic first pass metabolism of the drug and avoids enzymatic degradation of the drug within the gastrointestinal tract. Methods for using the compositions of the present invention for treating sleep disorders such as insomnia are also provided.

Claims

1. A method for treating insomnia, comprising the steps of:

administering a solid pharmaceutical composition comprising zolpidem or a pharmaceutically acceptable salt thereof to a subject prone to insomnia, the pharmaceutical composition further comprising a buffer,

wherein the buffer raises the pH of saliva to a pH of about 7.8 or greater,

wherein zolpidem is absorbed across a permeable membrane of the subject'"'"'s oral mucosa, and

wherein at least 75% of the solid pharmaceutical composition dissolves within about 10 minutes or less within an oral cavity following administration.

2. The method of claim 1, wherein the solid pharmaceutical composition further comprises a binder and a disintegrating agent.

3. The method of claim 1, wherein the solid pharmaceutical composition dissolves within about 1-3 minutes within the oral cavity of the subject following administration.

4. The method of claim 1, wherein the solid pharmaceutical composition dissolves within about 2-3 minutes within the subject'"'"'s oral cavity following administration.

5. The method of claim 1, wherein the solid pharmaceutical composition is administered sublingually.

6. The method of claim 1, wherein the oral mucosa is selected from the group consisting of sublingual mucosa, buccal mucosa, gingival mucosa, palatal mucosa, and lining of the lips.

7. The method of claim 1, wherein a mean peak plasma concentration of zolpidem between about 20 to about 100 ng/mL is produced within about 30 minutes.

8. The method of claim 1, wherein a therapeutically effective amount of zolpidem enters the bloodstream within about 30 minutes.

9. The method of claim 1, wherein the buffer comprises a carbonate buffer and a bicarbonate buffer.

10. The method of claim 9, wherein the carbonate buffer and bicarbonate buffer are present in a carbonate:

bicarbonate weight ratio of about 1;

1 to about 1;

10.

11. The method of claim 1, wherein the solid pharmaceutical composition is a lozenge.

12. The method of claim 1, wherein the solid pharmaceutical composition is a tablet.

13. The method of claim 9, wherein the carbonate buffer and bicarbonate buffer are present in a carbonate:

bicarbonate weight ratio of about 1;

1 to about 1;

5.

14. The method of claim 1, wherein an average plasma concentration is from about 20 to about 300 ng/ml.

15. The method of claim 1, wherein the zolpidem or pharmaceutically acceptable salt is zolpidem tartrate.

16. The method of claim 1, wherein the zolpidem or pharmaceutically acceptable salt thereof is in an amount from about 1 mg to about 5 mg.

17. The method of claim 1, wherein the zolpidem or pharmaceutically acceptable salt thereof is in an amount from about 2 mg to about 5 mg.