Compositions and methods for treating middle-of-the-night insomnia

• US 20070123562A1
• Filed: 05/23/2006
• Published: 05/31/2007
• Est. Priority Date: 05/25/2005
• Status: Abandoned Application

• Current Assignee: Transcept Pharmaceuticals Incorporated
• Original Assignee: TransOral Pharmaceuticals, Inc.
• Inventors: Singh, Nikhilesh, Pather, Sathasivan
• Application Number:
  US11/439,884
• Publication Number:
  US 20070123562A1
• 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 for treating insomnia comprising zolpidem in an amount less than 5 mg and a binary buffer.

2. A pharmaceutical composition for treating insomnia comprising zolpidem in an amount less than 5 mg and a binary buffer, wherein the composition is formulated for delivery of zolpidem across the oral mucosa and the binary buffer produces a saliva pH of at least 8.5, irrespective of the starting saliva pH.

3. A pharmaceutical composition of claim 2, wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.

4. A pharmaceutical composition for delivery across the oral mucosa for treating insomnia comprising zolpidem in an amount less than 5 mg and a buffer.

5. A pharmaceutical composition of claim 4, wherein the buffer comprises a carbonate buffer.

6. A pharmaceutical composition of claim 4, wherein the buffer comprises a bicarbonate buffer.

7. A pharmaceutical composition of claim 4, wherein the buffer comprises a carbonate buffer and a bicarbonate buffer.

8. A pharmaceutical composition of claim 4, wherein the buffer comprises a binary buffer.

9. A pharmaceutical composition of claim 4, wherein the amount of zolpidem is less than 1.30×

10<sup>−

5</sup> moles of zolpidem.

10. A pharmaceutical composition of claim 4, wherein the amount of zolpidem is about 1.5 to about 2.5 mg of zolpidem hemitartrate.

11. A pharmaceutical composition of claim 4, wherein the amount of zolpidem is about 3.0 to about 3.75 mg of zolpidem hemitartrate.

12. A pharmaceutical composition comprising a dose of zolpidem hemitartrate in an amount of less than 5 mg and a binary buffer system capable of raising the pH of a subject'"'"'s saliva to a pH greater than about 8.5, irrespective of the starting pH of saliva, wherein the composition is formulated for delivery of zolpidem across the subject'"'"'s oral mucosa.

13. A pharmaceutical composition of claim 12, comprising from 1.5 to 2.5 mg of zolpidem hemitartrate.

14. A pharmaceutical composition of claim 12, comprising from 3.0 to 3.75 mg of zolpidem hemitartrate.

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

16. A pharmaceutical composition of claim 12, wherein said binary buffer system comprises a carbonate salt and a bicarbonate salt and said carbonate and bicarbonate are present in a carbonate:

bicarbonate ratio of about 1;

1.0 to about 1;

1.2 by weight.

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

administering a pharmaceutical composition comprising zolpidem in an amount less than 5 mg and a buffer, to a subject who awakens from sleep and desires to resume sleep for less than 5 hours,

wherein the pharmaceutical composition provides delivery of zolpidem across the subject'"'"'s oral mucosa, and wherein a blood level of zolpidem is achieved in the subject of between about 25 ng/ml and about 50 ng/ml within about 20 minutes of administration.

18. A method in accordance with claim 17, wherein the blood level of zolpidem in the subject is less than about 20 ng/ml at about 4 hours after administration.

19. A method in accordance with claim 17, wherein the composition is a solid pharmaceutical composition which dissolves or disintegrates in the subject'"'"'s mouth in about 2 minutes or less.

20. A method in accordance with claim 17, wherein the composition is a solid pharmaceutical composition which dissolves or disintegrates in the subject'"'"'s mouth in about 3 to about 6 minutes.

21. A method in accordance with claim 17, wherein the buffer is a binary buffer.

22. A method in accordance with claim 21, wherein the binary buffer comprises a carbonate buffer and a bicarbonate buffer.

23. A method in accordance with claim 17, wherein the buffer raises the pH of saliva in the subject'"'"'s mouth to a pH greater than about 9.0.

24. A method in accordance with claim 23, wherein the pH of the saliva is raised above 9.0 for at least about 2 minutes.

25. A method in accordance with claim 17, wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.

26. A method of treating insomnia, said method comprising:

administering a pharmaceutical composition comprising zolpidem in an amount less than 5 mg and a binary buffer, to a subject who awakens from sleep and desires to resume sleep for less than 5 hours,

wherein the pharmaceutical composition provides delivery of zolpidem across the subject'"'"'s oral mucosa, and wherein the binary buffer raises the pH of saliva in the subject'"'"'s mouth to a pH greater than about 9.0.

27. A method in accordance with claim 26, wherein the pH of the saliva is raised above 9.0 for at least about 2 minutes.

28. A method in accordance with claim 26, wherein the binary buffer comprises a carbonate buffer and a bicarbonate buffer.

29. A method in accordance with claim 26, wherein a blood level of zolpidem in the subject is between about 25 ng/ml and about 50 ng/ml within about 20 minutes of administration.

30. A method in accordance with claim 26, wherein the blood level of zolpidem in the subject is less than about 20 ng/ml at about 4 hours after administration.

31. A method in accordance with claim 26, wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.

32. A method of treating insomnia, said method comprising the steps of:

providing a pharmaceutical composition comprising zolpidem in an amount less than 5 mg and a buffer to a patient who awakens from sleep and desires to resume sleep for less than 5 hours; and

administering the pharmaceutical composition to the patient for delivery of the zolpidem across the patient'"'"'s oral mucosa,

wherein a blood level of zolpidem in the patient is between about 25 ng/ml and about 50 ng/ml within about 20 minutes of administration.

33. A method in accordance with claim 32, wherein the blood level of zolpidem in the patient is less than about 20 ng/ml at about 4 hours after administration.

34. A method in accordance with claim 32, wherein the buffer is a binary buffer.

35. A method in accordance with claim 34, wherein the binary buffer comprises a carbonate buffer and a bicarbonate buffer.

36. A method in accordance with claim 32, wherein the buffer raises the pH of saliva in the patient'"'"'s mouth to a pH greater than about 9.0.

37. A method in accordance with claim 36, wherein the pH of the saliva is raised above 9.0 for at least about 2 minutes.

38. A method in accordance with claim 32, wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.

39. A method of treating insomnia, said method comprising the steps of:

providing a pharmaceutical composition comprising zolpidem in an amount less than 5 mg and a binary buffer to a patient who awakens from sleep and desires to resume sleep for less than 5 hours; and

administering the pharmaceutical composition to the patient for delivery of the zolpidem across the patient'"'"'s oral mucosa,

wherein the binary buffer raises the pH of saliva in the patient'"'"'s mouth to a pH greater than about 9.0.

40. A method in accordance with claim 39, wherein the pH of the saliva is raised above 9.0 for at least about 2 minutes.

41. A method in accordance with claim 39, wherein the binary buffer comprises a carbonate buffer and a bicarbonate buffer.

42. A method in accordance with claim 39, wherein a blood level of zolpidem in the patient is between about 25 ng/ml and about 50 ng/ml within about 20 minutes of administration.

43. A method in accordance with claim 39, wherein the blood level of zolpidem in the patient is less than about 20 ng/ml at about 4 hours after administration.

44. A method in accordance with claim 39, wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.

45. A method in accordance with claim 39, wherein the zolpidem is zolpidem hemitartrate.