Methods and dosage forms for controlled delivery of alprazolam

• US 20050260268A1
• Filed: 09/24/2004
• Published: 11/24/2005
• Est. Priority Date: 09/26/2003
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Seroff, Sonya M., Davar, Nipun, Gupta, Suneel K., Modi, Nishit B.
• Application Number:
  US10/949,900
• Publication Number:
  US 20050260268A1
• Time in Patent Office: Days
• US Class Current: 424/473
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• 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 25/22 Anxiolytics

Abstract

A dosage form for delivery of alprazolam is described. The sustained release dosage form provides via once-a-day dosing a therapeutically effective average steady-state plasma alprazolam concentration, where the maximum attained plasma concentration is achieved more than about 14 hours after administration. The slow, sustained release reduces side effects such as sedation and abuse potential.

Claims

1. A dosage form comprising a dose of alprazolam, said dosage form effective to provide a dissolution rate where between 25% and 60% of the dose is released 10 hours after exposure to an aqueous environment.

2. The dosage form of claim 1 effective to provide a dissolution rate where between 35% and 55% of the dose is released 10 hours after exposure to an aqueous environment.

3. The dosage form of claim 1 effective to provide a dissolution rate where less than 20% of the dose is released 2 hours after exposure to an aqueous environment.

7. The dosage form of claim 1, wherein the dosage form is an osmotic dosage form.

8. The dosage form of claim 7 comprised of (i) a push layer;

(ii) drug layer comprising alprazolam;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

9. The dosage form of claim 7 comprised of (i) a semipermeable wall provided around an osmotic formulation comprising an alprazolam formulation, an osmagent, and an osmopolymer;

and (ii) an exit.

13. The dosage form of claim 1, wherein the dosage form provides a total daily dose of between 0.25-25 mg.

14. The dosage form of claim 13, where in the dosage form provides a total daily dose of between 0.5 and 6 mg.

4. A dosage form comprising a dose of alprazolam, said dosage form effective to provide a dissolution rate where between 30% and 80% of the dose is released 12 hours after exposure to an aqueous environment.

5. The dosage form of claim 4 effective to provide a dissolution rate where between 40% and 70% of the dose is released 10 hours after exposure to an aqueous environment.

6. The dosage form of claim 4 effective to provide a dissolution rate where less than 20% of the dose is released 2 hours after exposure to an aqueous environment

10. The dosage form of claim 4, wherein the dosage form is an osmotic dosage form.

11. The dosage form of claim 10 comprised of (i) a push layer;

(ii) drug layer comprising alprazolam;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

12. The dosage form of claim 10 comprised of (i) a semipermeable wall provided around an osmotic formulation comprising an alprazolam formulation, an osmagent, and an osmopolymer;

and (ii) an exit.

15. A dosage form, comprising, a dose of alprazolam, said dosage form effective to provide an in vitro release profile where

(i) less than 20% of the dose is released 2 hours after exposure to an aqueous environment;

(ii) between 25% and 65% of the dose is released 10 hours after exposure to an aqueous environment; and

(iii) greater than 85% of the dose is released 24 hours after exposure to an aqueous environment.

16. A dosage form for delivery of alprazolam, comprising a dose of alprazolam, the dosage form being configured to release at least about 10% of the dose 16 hours after exposure to an aqueous environment.

17. The dosage form of claim 16, wherein at least about 15% of the dose is released 16 hours after exposure to an aqueous environment.

22. The dosage form of claim 16, wherein the dosage form is an osmotic dosage form.

25. The dosage form of claim 22 comprised of (i) a push layer;

(ii) drug layer comprising alprazolam;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

26. The dosage form of claim 22 comprised of (i) a semipermeable wall provided around an osmotic formulation comprising an alprazolam formulation, an osmagent, and an osmopolymer;

and (ii) an exit.

31. The dosage form of claim 16, wherein the dosage form provides a total daily dose of between 0.25-25 mg.

18. A dosage form for delivery of alprazolam, comprising a dose of alprazolam, the dosage form being configured to release at least about 15% of the dose 14 hours after exposure to an aqueous environment.

19. The dosage form of claim 18, wherein at least about 20% of the dose is released 14 hours after exposure to an aqueous environment.

23. The dosage form of claim 18, wherein the dosage form is an osmotic dosage form.

27. The dosage form of claim 23 comprised of (i) a push layer;

(ii) drug layer comprising alprazolam;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

28. The dosage form of claim 23 comprised of (i) a semipermeable wall provided around an osmotic formulation comprising an alprazolam formulation, an osmagent, and an osmopolymer;

and (ii) an exit.

32. The dosage form of claim 18, wherein the dosage form provides a total daily dose of between 0.25-25 mg.

20. A dosage form for delivery of alprazolam, comprising a dose of alprazolam, the dosage form being configured to release at least about 25% of the dose 12 hours after exposure to an aqueous environment.

21. The dosage form of claim 20, wherein at least about 30% of the dose is released 12 hours after exposure to an aqueous environment.

24. The dosage form of claim 20, wherein the dosage form is an osmotic dosage form.

29. The dosage form of claim 24 comprised of (i) a push layer;

(ii) drug layer comprising alprazolam;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

30. The dosage form of claim 24 comprised of (i) a semipermeable wall provided around an osmotic formulation comprising an alprazolam formulation, an osmagent, and an osmopolymer;

and (ii) an exit.

33. The dosage form of claim 20, wherein the dosage form provides a total daily dose of between 0.25-25 mg.

34. A dosage form for delivering alprazolam comprising a drug formulation including a desired dose of alprazolam, wherein the dosage form is configured to release alprazolam at a rate that ranges between 2% of the total dose of alprazolam per hour to 7% of the total dose of alprazolam per hour over the period of between 2 and 20 hours after exposure to an aqueous environment.

35. The dosage form of claim 34 wherein the dosage form is configure to release alprazolam at a rate that ranges between 2% of the total dose of alprazolam per hour to 7% of the total dose of alprazolam per hour over the period of between 2 and 16 hours after exposure to an aqueous environment.

36. The dosage form of claim 34 wherein the dosage form is configure to release alprazolam at a rate that ranges between 2% of the total dose of alprazolam per hour to 7% of the total dose of alprazolam per hour over the period of between 2 and 12 hours after exposure to an aqueous environment.

37. A dosage form comprising a dose of alprazolam, said dosage form effective to provide cumulative amount of drug released in vivo of between 25% and 60% of the total dose 10 hours after oral delivery.

38. The dosage form of claim 37 effective to release between 35% and 55% of the dose 10 hours after oral delivery.

39. The dosage form of claim 37 effective to release less than 20% of the dose 2 hours after oral delivery.

43. The dosage form of claim 37, wherein the dosage form is an osmotic dosage form.

44. The dosage form of claim 43 comprised of (i) a push layer;

(ii) drug layer comprising alprazolam;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

45. The dosage form of claim 43 comprised of (i) a semipermeable wall provided around an osmotic formulation comprising an alprazolam formulation, an osmagent, and an osmopolymer;

and (ii) an exit.

49. The dosage form of claim 37, wherein the dosage form provides a total daily dose of between 0.25-25 mg.

50. The dosage form of claim 49, where in the dosage form provides a total daily dose of between 0.5 and 6 mg.

40. A dosage form comprising a dose of alprazolam, said dosage form effective to release between 30% and 80% of the dose 12 hours after oral delivery.

41. The dosage form of claim 40 effective to release between 40% and 70% of the dose 10 hours after oral delivery.

42. The dosage form of claim 40 effective to release less than 20% of the dose 2 hours after oral delivery.

46. The dosage form of claim 40, wherein the dosage form is an osmotic dosage form.

47. The dosage form of claim 46 comprised of (i) a push layer;

(ii) drug layer comprising alprazolam;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

48. The dosage form of claim 46 comprised of (i) a semipermeable wall provided around an osmotic formulation comprising an alprazolam formulation, an osmagent, and an osmopolymer;

and (ii) an exit.

51. A dosage form, comprising alprazolam, wherein the dosage form provides a maximum attained alprazolam plasma concentration (C_max) more than 14 hours after administration.

52. The dosage form of claim 51, wherein the Cmax occurs more than 16 hours after administration.

54. The dosage form of claim 51, wherein the dosage form provides a total daily dose of between 0.25-25 mg.

53. A dosage form comprised of a desired dose of alprazolam, said dosage form being effective to provide a dose normalized ratio of maximum attained alprazolam plasma concentration (Cmax) to time to reach maximum attained alprazolam plasma concentration (Tmax) of less than 0.5.

55. A dosage form comprising alprazolam, said dosage form providing a dose-normalized area under the curve of less than about 110 ng·

hr/mL·

mg.

56. The dosage form of claim 55, wherein said dose-normalized area under the curve is greater than 70 ng·

hr/mL·

mg.

57. The dosage form of claim 55, wherein said dosage form is an osmotic dosage form.

58. The dosage form of claim 57, comprised of (i) a push layer;

(ii) drug layer comprising alprazolam;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

59. The dosage form of claim 57, comprised of (i) a semipermeable wall provided around an osmotic formulation comprising an alprazolam formulation, an osmagent, and an osmopolymer;

and (ii) an exit.

60. A method for administering alprazolam to a human subject, comprising administering a dosage form effective to provide an in vitro release profile where between 25% and 60% of the dose is released 10 hours after exposure to an aqueous environment.

61. A method for administering alprazolam to a human subject, comprising administering a dosage form effective to provide a ratio of maximum attained alprazolam plasma concentration (Cmax) more than 14 hours after administration.

62. A method for administering alprazolam to a human subject, comprising administering a dosage form effective to provide a dose-normalized area under the curve of less than about 110 ng·

hr/mL·

mg.

63. A method of treating a condition responsive to alprazolam, comprising administering a dosage form effective to provide a dose-normalized area under the curve of less than about 110 ng·

hr/mL·

mg.

64. The method according to claim 63, wherein said administering comprises a once daily administration of a dose between 0.25-25 mg.

65. The method of claim 63, wherein said administering comprises administering an osmotic dosage form.

66. The method of claim 65, wherein said dosage form is comprised of (i) a push layer;

(ii) drug layer comprising alprazolam;

(iii) a semipermeable wall provided around the push layer and the drug layer; and

(iv) an exit.

67. The method of claim 65, wherein said dosage form is comprised of (i) a semipermeable wall provided around an osmotic formulation comprising an alprazolam formulation, an osmagent, and an osmopolymer;

and (ii) an exit.

68. The method of claim 63, wherein the condition responsive to alprazolam is an anxiety disorder.

69. The method of claim 68, wherein said anxiety disorder is selected from the group consisting of mood disorders, general anxiety disorder, panic disorder, bipolar disorder, social phobias, substance abuse disorders, sleep disorders, stress disorders, conduct disorders.