Modified release dosage forms of skeletal muscle relaxants

• US 9,399,025 B2
• Filed: 12/08/2014
• Issued: 07/26/2016
• Est. Priority Date: 11/14/2003
• Status: Expired due to Fees

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Adare Pharmaceuticals, Inc.
• Inventors: Venkatesh, Gopi M., Clevenger, James M.
• Primary Examiner(s): WORSHAM, JESSICA N
• Application Number:
  US14/563,580
• Publication Number:
  US 20150093436A1
• Time in Patent Office: 596 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: Y10T 29/49826 Assembling or joining

Abstract

A unit dosage form, such as a capsule or the like, for delivering a skeletal muscle relaxant, such as cyclobenzaprine hydrochloride, into the body in an extended or sustained release fashion comprising one or more populations of drug-containing particles (beads, pellets, granules, etc.) is disclosed. At least one bead population exhibits a pre-designed sustained release profile. Such a drug delivery system is designed for once-daily oral administration to maintain an adequate plasma concentration—time profile, thereby providing relief of muscle spasm associated with painful musculoskeletal conditions over a 24 hour period.

Claims

1. A dosage form comprising a plurality of active-containing particles comprising cyclobenzaprine hydrochloride and a dissolution rate controlling polymer granulated together,

wherein the dissolution rate controlling polymer is selected from the group consisting of ethers of cellulose and esters of cellulose;

wherein the dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1N HCl at 37°

C. exhibits a drug release profile substantially corresponding to the following pattern;

after 2 hours, no more than about 40% of the total active is released;

after 4 hours, from about 40-65% of the total active is released; and

after 8 hours, from about 60-85% of the total active is released; and

wherein the dosage form provides a therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions.

2. The dosage form of claim 1, wherein the particles are selected from the group consisting of pellets, beads, granules, and mini-tablets.

3. The dosage form of claim 1, wherein the particles are pellets.

4. The dosage form of claim 1, wherein the particles are beads.

5. The dosage form of claim 1, wherein the particles are granules.

6. The dosage form of claim 1, wherein the particles are mini-tablets.

7. The dosage form of claim 1, wherein the pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine hydrochloride following oral administration of a single 30 mg cyclobenzaprine dose.

8. The dosage form of claim 1, wherein the pharmaceutical dosage form provides an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL following oral administration of a single 30 mg cyclobenzaprine dose.

9. The dosage form of claim 1, wherein said pharmaceutical dosage form provides a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

10. The dosage form of claim 1, wherein the pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine hydrochloride, an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL, and a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

11. The dosage form of claim 6, wherein the pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine HCl, an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL, and a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

12. A capsule filled with the dosage form of claim 1.

13. A capsule filled with the dosage form of claim 6.

14. The dosage form of claim 1, comprising 15 or 30 mg of cyclobenzaprine hydrochloride.

15. The dosage form of claim 6, comprising 15 or 30 mg of cyclobenzaprine hydrochloride.

16. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 1 to the patient.

17. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 6 to the patient.

18. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 10 to said patient.

19. A dosage form comprising a plurality of active-containing particles comprising cyclobenzaprine hydrochloride and a dissolution rate controlling polymer, granulated together;

wherein the dissolution rate controlling polymer is selected from the group consisting of ethers of cellulose and esters of cellulose;

wherein said dosage form comprises 30 mg of cyclobenzaprine hydrochloride and provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine hydrochloride following oral administration of a single 30 mg cyclobenzaprine dose; and

wherein said dosage form provides a therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions.

20. The dosage form of claim 19, wherein the pharmaceutical dosage form provides an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL following oral administration of a single 30 mg cyclobenzaprine dose.

21. The dosage form of claim 20, wherein said pharmaceutical dosage form provides a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

22. The dosage form of claim 19, wherein the particles are selected from the group consisting of pellets, beads, granules, or mini-tablets.

23. The dosage form of claim 19, wherein the particles are pellets.

24. The dosage form of claim 19, wherein the particles are beads.

25. The dosage form of claim 19, wherein the particles are granules.

26. The dosage form of claim 19, wherein the particles are mini-tablets.

27. A capsule filled with the dosage form of claim 19.

28. A capsule filled with the dosage form of claim 26.

29. The dosage form of claim 26, wherein the pharmaceutical dosage form provides an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL and a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

30. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 19 to the patient.

31. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 26 to the patient.

32. A dosage form comprising a plurality of active-containing particles comprising cyclobenzaprine hydrochloride and a dissolution rate controlling polymer surrounding the cyclobenzaprine hydrochloride,

wherein the dissolution rate controlling polymer is selected from the group consisting of ethers of cellulose and esters of cellulose;

wherein the dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1N HCl at 37°

C. exhibits a drug release profile substantially corresponding to the following pattern;

after 2 hours, no more than about 40% of the total active is released;

after 4 hours, from about 40-65% of the total active is released; and

after 8 hours, from about 60-85% of the total active is released; and

wherein the dosage form provides a therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions.

33. The dosage form of claim 32, wherein the particles are selected from the group consisting of pellets, beads, granules, and mini-tablets.

34. The dosage form of claim 32, wherein the particles are pellets.

35. The dosage form of claim 32, wherein the particles are beads.

36. The dosage form of claim 32, wherein the particles are granules.

37. The dosage form of claim 32, wherein the particles are mini-tablets.

38. The dosage form of claim 32, wherein the pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine hydrochloride following oral administration of a single 30 mg cyclobenzaprine dose.

39. The dosage form of claim 32, wherein the pharmaceutical dosage form provides an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL following oral administration of a single 30 mg cyclobenzaprine dose.

40. The dosage form of claim 32, wherein said pharmaceutical dosage form provides a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

41. The dosage form of claim 32, wherein the pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine hydrochloride, an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL, and a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

42. The dosage form of claim 37, wherein the pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine HCl, an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL, and a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

43. A capsule filled with the dosage form of claim 32.

44. A capsule filled with the dosage form of claim 37.

45. The dosage form of claim 32, comprising 15 or 30 mg of cyclobenzaprine hydrochloride.

46. The dosage form of claim 37, comprising 15 or 30 mg of cyclobenzaprine hydrochloride.

47. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 32 to the patient.

48. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 37 to the patient.

49. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 41 to said patient.

50. A dosage form comprising a plurality of active-containing particles comprising cyclobenzaprine hydrochloride and a dissolution rate controlling polymer surrounding the cyclobenzaprine hydrochloride;

wherein the dissolution rate controlling polymer is selected from the group consisting of ethers of cellulose and esters of cellulose;

wherein said dosage form comprises 30 mg of cyclobenzaprine hydrochloride and provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine hydrochloride following oral administration of a single 30 mg cyclobenzaprine dose; and

wherein said dosage form provides a therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions.

51. The dosage form of claim 50, wherein the pharmaceutical dosage form provides an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL following oral administration of a single 30 mg cyclobenzaprine dose.

52. The dosage form of claim 50, wherein said pharmaceutical dosage form provides a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

53. The dosage form of claim 50, wherein the particles are selected from the group consisting of pellets, beads, granules, or mini-tablets.

54. The dosage form of claim 50, wherein the particles are pellets.

55. The dosage form of claim 50, wherein the particles are beads.

56. The dosage form of claim 50, wherein the particles are granules.

57. The dosage form of claim 50, wherein the particles are mini-tablets.

58. A capsule filled with the dosage form of claim 50.

59. A capsule filled with the dosage form of claim 57.

60. The dosage form of claim 57, wherein the pharmaceutical dosage form provides an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL and a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose.

61. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 50 to the patient.

62. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 57 to the patient.

63. A dosage form comprising a plurality of active-containing particles comprising cyclobenzaprine hydrochloride and a dissolution rate controlling polymer, granulated together;

wherein the dissolution rate controlling polymer is selected from the group consisting of ethers of cellulose and esters of cellulose;

wherein said dosage form comprises 30 mg of cyclobenzaprine hydrochloride and provides a T_max within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine dose; and

wherein said dosage form provides a therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions.

64. The dosage form of claim 63, wherein the pharmaceutical dosage form provides an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL following oral administration of a single 30 mg cyclobenzaprine dose.

65. The dosage form of claim 63, wherein the particles are selected from the group consisting of pellets, beads, granules, or mini-tablets.

66. The dosage form of claim 63, wherein the particles are pellets.

67. The dosage form of claim 63, wherein the particles are beads.

68. The dosage form of claim 63, wherein the particles are granules.

69. The dosage form of claim 63, wherein the particles are mini-tablets.

70. A capsule filled with the dosage form of claim 63.

71. A capsule filled with the dosage form of claim 69.

72. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 63 to the patient.

73. A method of relieving muscle spasms in a patient in need thereof, comprising orally administering the dosage form of claim 69 to the patient.