MODIFIED RELEASE DOSAGE FORMS OF SKELETAL MUSCLE RELAXANTS

• US 20150093436A1
• Filed: 12/08/2014
• Published: 04/02/2015
• Est. Priority Date: 11/14/2003
• Status: Active Grant

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Aptalis Pharmatech Incorporated
• Inventors: VENKATESH, Gopi M., CLEVENGER, James M.
• Granted Patent: US 9,399,025 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• 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

1-22. -22. (canceled)

23. A multi-particulate dosage form comprising a skeletal muscle relaxant and a dissolution rate controlling polymer, wherein said skeletal muscle relaxant is selected from the group consisting of cyclobenzaprine, pharmaceutically acceptable salts or derivatives thereof and mixtures thereof;

wherein said 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;

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

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.

24. The multi-particulate dosage form of claim 23, wherein the particles are selected from the group consisting of pellets, beads, granules, or mini-tablets.

25. The multi-particulate dosage form of claim 23, wherein the particles are pellets.

26. The multi-particulate dosage form of claim 23, wherein the particles are beads.

27. The multi-particulate dosage form of claim 23, wherein the particles are granules.

28. The multi-particulate dosage form of claim 23, wherein the particles are mini-tablets.

29. The multi-particulate dosage form of claim 23, wherein said 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 following oral administration of a single 30 mg cyclobenzaprine dose.

30. The multi-particulate dosage form of claim 23, wherein said 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.

31. The multi-particulate dosage form of claim 23, 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.

32. The multi-particulate dosage form of claim 23, wherein said 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, and an AUC_1-168 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.

33. The multi-particulate dosage form of claim 28, wherein said 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, and 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.

34. A capsule filled with the multi-particulate dosage form of claim 23.

35. A capsule filled with the multi-particulate dosage form of claim 28.

37. The multi-particulate dosage form of claim 28, comprising 15 or 30 mg of cyclobenzaprine HCl.

38. A method of relieving muscle spasms in a patient in need thereof, comprising administering the pharmaceutical dosage form of claim 23 to said patient.

39. A method of relieving muscle spasms in a patient in need thereof, comprising administering the pharmaceutical dosage form of claim 28 to said patient.

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

41. A multi-particulate dosage form comprising a skeletal muscle relaxant and a dissolution rate controlling polymer, wherein said skeletal muscle relaxant is selected from the group consisting of cyclobenzaprine, pharmaceutically acceptable salts or derivatives thereof and mixtures thereof;

wherein said 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, and 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 HCl 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.

42. The multi-particulate dosage form of claim 41, wherein the particles are selected from the group consisting of pellets, beads, granules, or mini-tablets.

43. The multi-particulate dosage form of claim 41, wherein the particles are pellets.

44. The multi-particulate dosage form of claim 41, wherein the particles are beads.

45. The multi-particulate dosage form of claim 41, wherein the particles are granules.

46. The multi-particulate dosage form of claim 41, wherein the particles are mini-tablets.

47. A capsule filled with the multi-particulate dosage form of claim 41.

48. A capsule filled with the multi-particulate dosage form of claim 46.

49. The multi-particulate dosage form of claim 41, comprising 30 mg of cyclobenzaprine HCl.

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

51. A method of relieving muscle spasms in a patient in need thereof, comprising administering the pharmaceutical dosage form of claim 46 to said patient.