Modified release dosage forms of skeletal muscle relaxants

• US 7,829,121 B2
• Filed: 09/24/2008
• Issued: 11/09/2010
• 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): Wax; Robert A
• Assistant Examiner(s): BARHAM, BETHANY P
• Application Number:
  US12/236,719
• Publication Number:
  US 20090017126A1
• Time in Patent Office: 776 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 multi-particulate pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise:

an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and

an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof;

wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 30 mg; and

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

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

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

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

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

wherein following a single oral administration, 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 and an AUC_0-168 within the range of about 80% to 125% of about 740 ng·

hr/mL.

3. The method of claim 1 or 2, wherein said extended release coating comprises from about 7% to 12% by weight of the extended release beads.

4. The method of claim 1 or 2, 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.

5. The method of claim 1 or 2, wherein said drug release profile substantially corresponds to the following pattern:

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

after 4 hours from about 40-65% of the total amount of the cyclobenzaprine hydrochloride is released;

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

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

6. The method of claim 1 or 2, wherein said water insoluble polymer membrane further comprises a plasticizer.

7. The method of claim 6, wherein said plasticizer is selected from the group consisting of triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and di-glycerides, and mixtures thereof.

8. The method of claim 6, wherein said extended release coating comprises about 10% to 25% by weight of said plasticizer.

9. The method of claim 7, wherein said plasticizer comprises about 10% to 25% by weight of said extended release coating.

10. The method of claim 1 or 2, wherein the multi-particulate pharmaceutical dosage form is in the form of a capsule.

11. The method of claim 1 or 2, wherein said extended release coating comprises about 1% to about 15% by weight of the extended release beads.

12. The method of claim 1 or 2, wherein said pharmaceutical dosage form further comprises a seal coating layer comprising hydroxypropyl methylcellulose or hydroxypropylcellulose.

2. A method of relieving muscle spasms in a patient in need thereof comprising administering a multi-particulate pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise:

an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and

an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH insensitive ammonio methacrylic acid copolymers, and mixtures thereof;

wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 15 mg;

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

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

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

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

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

wherein following a single oral administration, said pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 8 ng/mL of cyclobenzaprine and an AUC_0-168 within the range of about 80% to 125% of about 320 ng·

hr/mL.

13. A method of relieving muscle spasms in a patient in need thereof comprising administering a multi-particulate pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise:

an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and

an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH insensitive ammonio methacrylic acid copolymers, and mixtures thereof;

wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 15 mg;

wherein following a single oral administration, said pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) within the range of about 80% to 125% of about 8 ng/mL of cyclobenzaprine and an AUC_0-168 within the range of about 80% to 125% of about 320 ng·

hr/mL.

19. The method of any of claims 13-18, wherein said extended release coating comprises from about 7% to 12% by weight of the extended release beads.

20. The method of any of claims 13-18, 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 any of claims 13-18, wherein said drug release profile substantially corresponds to the following pattern:

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

after 4 hours from about 40-65% of the total amount of the cyclobenzaprine hydrochloride is released;

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

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

22. The method of any of claims 13-18, wherein said water insoluble polymer membrane further comprises a plasticizer.

23. The method of claim 22, wherein said plasticizer is selected from the group consisting of triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and di-glycerides, and mixtures thereof.

24. The method of claim 22, wherein said extended release coating comprises about 10% to 25% by weight of said plasticizer.

25. The method of claim 23, wherein said extended release coating comprises about 10% to 25% by weight of said plasticizer.

26. The method of any of claims 13-18, wherein the multi-particulate pharmaceutical dosage form is in the form of a capsule.

27. The method of any of claims 13-18, wherein said extended release coating comprises about 1% to about 15% by weight of the extended release beads.

28. The method of any of claims 13-18, wherein said pharmaceutical dosage form further comprise a seal coating layer comprising hydroxypropyl methylcellulose or hydroxypropylcellulose.

14. A method of relieving muscle spasms in a patient in need thereof comprising administering a multi-particulate pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise:

an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and

an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof;

wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 30 mg;

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 following a single oral administration thereof.

15. A method of relieving muscle spasms in a patient in need thereof comprising administering a multi-particulate pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise:

an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and

an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH insensitive ammonio methacrylic acid copolymers, and mixtures thereof;

wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 15 mg;

wherein said pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) of 8.315±

2.1635 ng/mL of cyclobenzaprine HCl and an AUC_0-168 of 318.30±

114.657 ng·

hr/mL following a single oral administration thereof.

16. A method of relieving muscle spasms in a patient in need thereof comprising administering a multi-particulate pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise:

an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and

an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH insensitive ammonio methacrylic acid copolymers, and mixtures thereof;

wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 30 mg;

wherein said pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) of 19.851±

5.8765 ng/mL of cyclobenzaprine HCl and an AUC_0-168 of 736.60±

259.414 ng·

hr/mL following a single oral administration thereof.

17. A method of relieving muscle spasms in a patient in need thereof comprising administering a multi-particulate pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise:

an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and

an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof

wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 30 mg;

wherein said pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) of 19.851±

5.8765 ng/mL of cyclobenzaprine HCl and an AUC_0-∞

of 779.889±

277.6349 ng·

hr/mL following a single oral administration thereof.

18. A method of relieving muscle spasms in administering to a patient in need thereof comprising administering a multi-particulate pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise:

an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and

an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH insensitive ammonio methacrylic acid copolymers, and mixtures thereof;

wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 15 mg;

wherein said pharmaceutical dosage form provides a maximum blood plasma concentration (C_max) of 8.315±

2.1635 ng/mL of cyclobenzaprine HCl and an AUC_0-∞

of 354.075±

119.8037 ng·

hr/mL following a single oral administration thereof.