Modified Release Dosage Forms of Skeletal Muscle Relaxants

• US 20090017127A1
• Filed: 09/24/2008
• Published: 01/15/2009
• Est. Priority Date: 11/14/2003
• Status: Active Grant

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Eurand Incorporated (Abbvie Incorporated)
• Inventors: Venkatesh, Gopi, Clevenger, James M.
• Granted Patent: US 7,790,199 B2
• Time in Patent Office: Days
• US Class Current: 424/497
• 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 pharmaceutical dosage form of a skeletal muscle relaxant providing a modified release profile comprising a population of extended release (ER) beads,

wherein said ER beads comprise

an active-containing core particle (IR (immediate release) bead) comprising a skeletal muscle relaxant;

and

an ER (extended release) coating comprising a water insoluble polymer membrane surrounding said core,

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; and

after 12 hours, from about 75- 85% of the total active is released;

thereby providing therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions in humans.

2. A pharmaceutical dosage form as defined in claim 1, wherein said skeletal muscle relaxant is selected from the group consisting of cyclobenzaprine, dantrolene, methocarbamol, metaxalone, carisoprodol, diazepam, pharmaceutically acceptable salts or derivatives thereof and mixtures thereof.

3. A pharmaceutical dosage form as defined in claim 2 wherein said skeletal muscle relaxant is cyclobenzaprine hydrochloride and 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 HCl MR Capsule.

4. A pharmaceutical dosage form as defined in claim 3 wherein the adjusted mean ratio of CMR 30 mg/CMR 15 mg is greater than about 2 for each of AUC_0-168 (p<

0.001), AUC_0-∞

(p<

0.001), and C_max (p<

0.001).

5. A pharmaceutical dosage form as defined in claim 1 further comprising an immediate release (IR) bead population, wherein said IR beads when tested in a USP Type 2 Apparatus at 50 rpm in 900 ml 0.1 N HCl at 37°

C. release at least about 70% of the active within 30 minutes.

6. A pharmaceutical dosage form as defined in claim 1, wherein said dosage form comprises only one extended release bead population.

7. A pharmaceutical dosage form as defined in claim 1, wherein said water insoluble polymer is selected from the group consisting of ethers and esters of cellulose, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof.

8. A pharmaceutical dosage form as defined in claim 7, wherein said extended release coating further comprises a plasticizer.

9. A pharmaceutical dosage form as defined in claim 8, wherein said plasticizer is selected from the group of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and di-glycerides and mixtures thereof.

10. A pharmaceutical dosage form as defined in claim 1, wherein said water insoluble polymer membrane on the drug cores comprises from about 7% to 12% by weight of the coated beads.

11. A pharmaceutical dosage form as defined in claim 7, wherein said extended release coating further comprises a water soluble polymer selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyethylene glycol polyvinylpyrrolidone and mixtures thereof.

22. A method of providing a patient with an oral dosage form, which comprises administering to said patient a sufficient amount of a dosage form of claim 3 to provide a total dose of 15 or 30 mg of cyclobenzaprine hydrochloride once a day.

12. A method for the preparation of an oral once-daily drug delivery system comprising a skeletal muscle relaxant, comprising the steps of:

a. preparing an active-containing core to form IR beads;

b. coating the IR beads with an extended release coating comprising a plasticized water insoluble polymer to form ER (extended release) beads; and

c. filling capsules with ER beads and optionally IR Beads at a ratio from about 70;

30 to 100;

0;

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; and

after 12 hours, from about 75- 85% of the total active is released.

13. The method of claim 12, wherein said step of preparing an active-containing core comprises coating a particle selected from the group consisting of non-pareil seeds, acidic buffer crystals and alkaline buffer crystals with a water soluble film-forming composition comprising a muscle relaxant.

14. The method of claim 13 wherein said water soluble film-forming composition further comprises a polymeric binder.

15. The method of claim 12, wherein said step of preparing an active-containing core comprises granulating and milling and/or extruding and spheronizing a polymer composition containing a muscle relaxant.

16. The method of claim 12, wherein said extended release coating on the drug cores comprises from about 7% to 12% by weight of the coated beads.

17. The method of claim 12, wherein said muscle relaxant is selected from the group consisting of cyclobenzaprine, dantrolene, methocarbamol, metaxalone, carisoprodol, diazepam, pharmaceutically acceptable salts or derivatives thereof and mixtures thereof.

18. The method of claim 12, wherein the muscle relaxant comprises cyclobenzaprine hydrochloride.

19. The method of claim 18 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, 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 5 administration of a single 30 mg cyclobenzaprine HCl MR Capsule.

20. The method of claim 12 wherein said extended release coating further comprises a plasticizer selected from the group consisting of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil and acetylated mono- and di-glycerides and mixtures thereof.

21. The method of claim 12, wherein said extended release coating comprises ethylcellulose plasticized with diethyl phthalate.