Methods of treating middle-of-the-night insomnia

• US 20070066643A1
• Filed: 05/23/2006
• Published: 03/22/2007
• Est. Priority Date: 05/25/2005
• Status: Active Grant

• Current Assignee: Paratek Pharmaceuticals Incorporated
• Original Assignee: TransOral Pharmaceuticals, Inc.
• Inventors: Singh, Nikhilesh, Pather, Sathasivan
• Granted Patent: US 8,242,131 B2
• Time in Patent Office: Days
• US Class Current: 514/303
• 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 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 9/006 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: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives

Abstract

The present invention provides compositions and methods for treating middle-of-the-night insomnia without residual sedative effects upon awakening by administering low doses (about 5 mg or less) of zolpidem or a salt thereof.

Claims

1. A pharmaceutical composition suitable for absorption by the oral mucosa in the treatment of MOTN insomnia, said composition comprising from about 0.5 mg to about 4.0 mg of zolpidem or a salt thereof and a pharmaceutically acceptable excipient.

2. A pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises from about 0.5 to about 4.0 mg of zolpidem hemitartrate.

3. A pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises about 1.0 mg zolpidem.

4. A pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises about 1.75 mg zolpidem.

5. A pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises about 3.5 mg zolpidem.

6. A pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises a binary buffer system.

7. A pharmaceutical composition of claim 6, wherein said buffer system raises the pH of saliva to a pH greater than about 8.5, irrespective of the starting pH of saliva.

8. A pharmaceutical composition of claim 6, in the form of a quick-dissolving tablet or lozenge.

9. A pharmaceutical composition of claim 8, which provides complete buccal and/or sublingual dissolution in about 5 minutes or less following administration.

10. A pharmaceutical composition of claim 6, wherein said buffer system comprises a carbonate and a bicarbonate.

11. A pharmaceutical composition of claim 10, wherein said carbonate and bicarbonate are present in a carbonate:

bicarbonate ratio of about 1;

1.0 to about 1;

1.2 by weight.

12. A pharmaceutical composition of claim 10, wherein said buffer system comprises sodium carbonate and sodium bicarbonate.

13. A method of treating insomnia, said method comprising administering to a subject who awakens from sleep and desires return to sleep within 30 minutes and sleep for less than 5 hours, a single unit dosage composition comprising an effective amount of zolpidem or a salt thereof, formulated for delivery of zolpidem across the subject'"'"'s oral mucosa, wherein said effective amount is an amount of less than 1.30×

10<sup>−

5</sup> moles of zolpidem, and is an amount sufficient to produce a plasma concentration between about 25 ng/ml and about 50 ng/ml within 20 minutes of administration, when evaluated in an appropriate patient population.

14. A method in accordance with claim 13, wherein said composition is administered pro re nata.

15. A method in accordance with claim 13, wherein said composition is a quick-dissolving tablet or lozenge formulated for buccal and/or sublingual delivery of zolpidem.

16. A method in accordance with claim 13, wherein said composition comprises a binary buffer system that raises the pH of said subject'"'"'s saliva to a pH greater than about 8.5, irrespective of the starting pH of saliva.

17. A method in accordance with claim 13, wherein said composition comprises from 0.5 to 4.75 mg of zolpidem hemitartrate and a binary buffer system of sodium carbonate and sodium bicarbonate that raises the pH of said subject'"'"'s saliva to a pH greater than about 8.5, irrespective of the starting pH of saliva.

18. A method of treating MOTN insomnia in a subject, comprising:

administering to said subject a pharmaceutical composition comprising zolpidem or a salt thereof in an amount of less than 1.30×

10<sup>−

5</sup> moles of zolpidem,

wherein said administering is on an as-needed basis, and wherein delivery of zolpidem occurs across the subject'"'"'s oral mucosa to produce a blood level of zolpidem in said subject between about 25 ng/ml and about 50 ng/ml within about 20 minutes of administration and less than 20 ng/ml at a time 4 hours after administration.

19. A method in accordance with claim 18, wherein said composition comprises at least one pH-adjusting agent.

20. A method in accordance with claim 18, wherein said composition comprises a binary buffer system that raises the pH of said subject'"'"'s saliva to a pH greater than about 8.5, irrespective of the starting pH of saliva.

21. A method in accordance with claim 18, wherein said composition comprises zolpidem hemitartrate.

22. A method in accordance with claim 21, wherein said composition comprises from 0.5 to 4.75 mg of zolpidem hemitartrate.

23. A method in accordance with claim 21, wherein said composition comprises from 1.5 to 2.5 mg of zolpidem hemitartrate.

24. A method in accordance with claim 21, wherein said composition comprises from 3.0 to 3.75 mg of zolpidem hemitartrate.

25. A method in accordance with claim 18, wherein said composition provides 50% of the maximum plasma concentration (C_max) in 10 minutes or less following administration.

26. A method in accordance with claim 25, wherein said composition comprises less than a 5 mg dose of zolpidem hemitartrate and a binary buffer system consisting of a carbonate salt and a bicarbonate salt.

27. A method in accordance with claim 18, wherein said composition is in the form of a quick-dissolving sublingual tablet or lozenge.

28. A method in accordance with claim 18, wherein delivery of zolpidem occurs across at least one of the sublingual or buccal mucosa.

29. A method of treating insomnia in a subject, comprising:

administering to said subject a pharmaceutical composition comprising zolpidem or a salt thereof,

wherein said composition provides delivery of zolpidem across the subject'"'"'s oral mucosa, wherein said subject is a subject who awakens from sleep and desires to resume sleep for less than 5 hours, and wherein said composition produces sleep within 30 minutes of dosing and the dose is such that it does not produce residual sedative effects when said subject is awakened at a time 4 hours after dosing.

30. A method in accordance with claim 29, wherein said sleep is polysomnography stage 1 sleep at the onset of sleep.

31. A method in accordance with claim 29, wherein said composition produces a blood level of zolpidem in said subject between about 25 ng/ml and about 50 ng/ml within 20 minutes of administration.

32. A method in accordance with claim 29, wherein said composition produces a blood level of zolpidem in said subject less than 20 ng/ml at a time 4 hours after administration.

33. A method in accordance with claim 32, wherein said composition provides 50% of the maximum plasma concentration (C_max) in 10 minutes or less following administration.

34. A method in accordance with claim 29, wherein said composition comprises zolpidem hemitartrate.

35. A method in accordance with claim 29, wherein said composition comprises at least one pH-adjusting agent.

36. A method in accordance with claim 29, wherein said composition comprises a binary buffer system that raises the pH of said subject'"'"'s saliva to a pH greater than about 8.5, irrespective of the starting pH of saliva.

37. A method in accordance with any of claims 29 to 36, wherein said composition is a solid unit dosage form.

38. A method in accordance with claim 36, wherein said composition is in the form of a quick-dissolving sublingual tablet or lozenge.

39. A method in accordance with claim 36, wherein said composition comprises from 1.5 to 2.5 mg of zolpidem hemitartrate.

40. A method in accordance with claim 36, wherein said composition comprises from 3.0 to 3.75 mg of zolpidem hemitartrate.

41. A method in accordance with claim 36, wherein said composition comprises from 1.5 to 2.5 mg of zolpidem hemitartrate and said binary buffer system consists of sodium carbonate and sodium bicarbonate.

42. A method in accordance with claim 36, wherein said composition comprises from 3.0 to 3.75 mg of zolpidem hemitartrate and said binary buffer system consists of sodium carbonate and sodium bicarbonate.

43. A method in accordance with claim 29, wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.