Oral controlled release formulation for sedative and hypotnic agents

Abstract

The present invention relates to a novel controlled release dosage form that releases therapeutic amounts of a sedative or hypnotic agent rapidly after administration and maintains therapeutic levels for about eight hours after administration.

Description

BRIEF DESCRIPTIONS OF DRAWINGS

FIG. 1 is a graph depicting the dissolution profile of the formulation as described in Example 1 and of a commercially available AMBIEN CR product (Lot #WJ22) when tested in a USP apparatus 2 using 900 ml of 0.01N HCl at 50 rpms and 37° C.

FIG. 2 is a graph of the mean plasma concentration for 47 subjects for the tablet prepared in Example 1 under fasting conditions.

FIG. 3 is a graph of the mean plasma concentration for 48 subjects for the tablet prepared in Example 1 under non-fasting conditions.

FIG. 4 is a graph of the mean plasma concentration for 12 subjects for the tablet prepared in Example 2 under fasting conditions.

FIG. 5 is a graph of the mean plasma concentration for 12 subjects for the tablet prepared in Example 2 under non-fasting conditions.

FIG. 6 is a graph of the mean plasma concentration for 12 subjects for the tablet prepared in Examples 3 and 4 under fasting conditions.

Claims

1. A controlled release oral dosage form for sedatives and hypnotic agents that maintains therapeutic levels for about four to eight hours after administration to a patient and release less than 40% of the sedative or hypnotic agent within 30 minutes when tested according to the United States Pharmacopiea 29 using Apparatus II (paddles), 900 ml of 0.01 N HCl at 50 rpms and 37° C.

2. The controlled release oral dosage form for sedatives and hypnotic agents as defined in claim 1 wherein the dosage form releases not more than 35% of the sedative or hypnotic agent within 30 minutes when tested according to the United States Pharmacopiea 29 using Apparatus II (paddles), 900 ml of 0.01 N HCl at 50 rpms and 37° C.

3. The controlled release oral dosage form for sedatives and hypnotic agents as defined in claim 1 wherein the dosage form releases not more than 30% of the sedative or hypnotic agent within 30 minutes when tested according to the United States Pharmacopiea 29 using Apparatus II (paddles), 900 ml of 0.01 N HCl at 50 rpms and 37° C.

4. The controlled release dosage form as defined by claim 1 wherein the dosage form is a tablet.

5. The controlled release dosage form as defined by claim 4 wherein the dosage form is a matrix tablet coated with a pH dependent polymer.

6. The controlled release dosage form as defined by claim 1 wherein the dosage form is a capsule.

7. A controlled release oral dosage form for sedatives and hypnotic agents comprising: (a) a core comprising: (i) a sedative or a hypnotic agent;(ii) a matrix forming material; and(b) a coating surrounding the core comprising; (i) a pH dependent material;(ii) a pore forming material;

8. The controlled release dosage form as defined in claim 7 wherein the sedative or hypnotic agent is selected from the group consisting of pyrazolopyrimidines, cyclopyrrolones, phenothiazines, imidazopyridines or combinations of the foregoing.

9. The controlled release dosage form as defined in claim 7 wherein the sedative or hypnotic agent is selected from the group consisting of zaleplon, zopiclone, eszopiclone, alimemazine, zolpidem and combinations of the foregoing.

10. The controlled release dosage form as defined in claim 7 wherein the matrix forming material is a hydrophobic material.

11. The controlled release dosage form as defined in claim 7 wherein the matrix forming material is a hydrophilic material.

12. The controlled release dosage form as defined in claim 7 wherein the core further comprises a diluent.

13. The controlled release dosage form as defined in claim 12 wherein the diluent further comprises a mixture of water soluble material and water insoluble material.

14. The controlled release dosage form as defined in claim 7 wherein the pH dependent material is a polymer.

15. The controlled release dosage form as defined in claim 14 wherein the polymer is selected from the group consisting of zein, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof.

16. The controlled release dosage form as defined in claim 7 wherein the pH dependent material comprises about 10% or less of the total weight of the dosage form.

17. The controlled release dosage form as defined in claim 16 wherein the pH dependent material comprises about 7.5% or less of the total weight of the dosage form.

18. The controlled release dosage form as defined in claim 17 wherein the pH dependent material comprises about 5% or less of the total weight of the dosage form.

19. The controlled release dosage form as defined in claim 7 that exhibits the following dissolution profile when tested in a USP apparatus 2, using 900 ml of 0.01 N HCl at 50 rpms and 37° C.: not more than 35% of the sedative or hypnotic agent is released within 0.5 hours;not less than 45% of the sedative or hypnotic agent is released within 2 hours;and not less than 85% of the sedative or hypnotic agent is released within 8 hours.

20. The controlled release dosage form as defined in claim 19 that exhibits the following dissolution profile when tested in a USP apparatus 2, using 900 ml of 0.01 N HCl at 50 rpms and 37° C.: not more than 30% of the sedative or hypnotic agent is released within 0.5 hours;not less than 50% of the sedative or hypnotic agent is released within 2 hours;and not less than 90% of the sedative or hypnotic agent is released within 8 hours.

21. A controlled release oral dosage form comprising: (a) a core comprising:(i) a hypnotic agent is selected from the group consisting of zaleplon, zopiclone, eszopiclone, alimemazine, zolpidem and combinations of the foregoing;(ii) 1-50% based upon the total weight of the core of a matrix forming material;(iii) 1-95% based upon the total weight of the core of a diluent; and(b) a coating surrounding the core comprising;(i) about a pH dependent polymer;(ii) a pore forming material; and

22. The controlled release dosage form as defined in claim 21 wherein the matrix forming material is a hydrophobic material.

23. The controlled release dosage form as defined in claim 21 wherein the matrix forming material is a hydrophilic material.

24. The controlled release dosage form as defined in claim 21 wherein the diluent further comprises a mixture of water soluble material and water insoluble material.

25. The controlled release dosage form as defined in claim 21 wherein the pH dependent polymer is selected from the group consisting of zein, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof.

26. The controlled release dosage form as defined in claim 21 wherein the pH dependent material comprises about 10% or less of the total weight of the dosage form.

27. The controlled release dosage form as defined in claim 26 wherein the pH dependent material comprises about 7.5% or less of the total weight of the dosage form.

28. The controlled release dosage form as defined in claim 27 wherein the pH dependent material comprises about 5% or less of the total weight of the dosage form.

29. The controlled release dosage form as defined in claim 21 that exhibits the following dissolution profile when tested in a USP apparatus 2, using 900 ml of 0.01 N HCl at 50 rpms and 37° C.: not more than 30% of the sedative or hypnotic agent is released within 0.5 hours;not less than 50% of the sedative or hypnotic agent is released within 2 hours;and not less than 90% of the sedative or hypnotic agent is released within 8 hours.