Modified release dosage forms of skeletal muscle relaxants

• US 7,544,372 B2
• Filed: 02/06/2008
• Issued: 06/09/2009
• Est. Priority Date: 11/14/2003
• Status: Expired due to Fees

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Eurand Incorporated (Abbvie Incorporated)
• Inventors: Venkatesh, Gopi, Clevenger, James M.
• Primary Examiner(s): Woodward; M P
• Assistant Examiner(s): Barham; Bethany
• Application Number:
  US12/026,887
• Publication Number:
  US 20080124399A1
• Time in Patent Office: 489 Days
• Field of Search: None
• US Class Current: 424/489
• 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 method of relieving muscle spasms in a patient in need thereof comprising administering a pharmaceutical dosage form of a skeletal muscle relaxant comprising a population of extended release beads,

wherein said extended release beads comprise:

an active-containing core particle comprising a skeletal muscle relaxant selected from the group consisting of cyclobenzaprine, pharmaceutically acceptable salts or derivatives thereof and mixtures thereof; and

an 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;

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; and

wherein said water insoluble polymer membrane comprises a water insoluble polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethylacrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof;

and 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, acetylated mono- and di-glycerides and mixtures thereof.

2. The method of claim 1, wherein said skeletal muscle relaxant comprises cyclobenzaprine hydrochloride.

3. The method of claim 2 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 a single oral administration a pharmaceutical dosage form comprising 30 mg of cyclobenzaprine HCl.

4. The method of claim 3, wherein the adjusted mean ratio of said pharmaceutical dosage form comprising 30 mg of cyclobenzaprine to a pharmaceutical dosage form comprising 15 mg of cyclobenzaprine 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. The method of claim 1, wherein said pharmaceutical dosage form comprises only one extended release bead population.

6. The method of claim 1, wherein said active-containing core particles comprise from about 7% to about 12% by weight of the water insoluble polymer membrane.

7. The method of claim 1, 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.

8. The method of claim 1, wherein said skeletal muscle relaxant comprises cyclobenzaprine.

9. The method of claim 1, wherein said drug release profile substantially corresponds 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.

10. The method of claim 1, 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.

11. The method of claim 1, wherein the water insoluble polymer membrane comprises ethyl cellulose.

12. The method of claim 11, wherein said plasticizer is diethyl phthalate.

13. The method of claim 11, wherein the 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.

14. The method of claim 12, wherein the 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.

15. The method of claim 14, wherein the water soluble polymer is hydroxypropyl methylcellulose.

16. The method of claim 15, wherein the skeletal muscle relaxant is cyclobenzaprine hydrochloride.

17. The method of claim 16, wherein the water insoluble polymer membrane comprises from about 7% to 12% by weight of the extended release beads.

18. The method of claim 17, wherein the drug release profile substantially corresponds 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.

19. The method of claim 1, wherein said water insoluble polymer membrane comprises a water insoluble polymer selected from the group consisting of ethers of cellulose, esters of cellulose, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof.

20. The method of claim 19, 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.

21. The method of claim 1, wherein said pharmaceutical dosage form comprises a sufficient amount of cyclobenzaprine hydrochloride to provide a total dose of 15 mg or 30 mg of cyclobenzaprine hydrochloride once a day.