Claims for Patent: 9,375,410

Summary for Patent: 9,375,410

Title:	Modified release dosage forms of skeletal muscle relaxants
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.
Inventor(s):	Venkatesh; Gopi M. (Vandalia, OH), Clevenger; James M. (Vandalia, OH)
Assignee:	ADARE PHARMACEUTICALS, INC. (Lawrenceville, NJ)
Application Number:	14/496,890
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,375,410
Patent Claims:	1. A method of relieving muscle spasms in a patient in need thereof, comprising administering a multi-particulate dosage form comprising a plurality of active-containing particles comprising about 30 mg of cyclobenzaprine or pharmaceutically acceptable salts thereof and a dissolution rate controlling polymer surrounding the cyclobenzaprine or pharmaceutically acceptable salts thereof; wherein said dissolution rate controlling polymer is 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; wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a maximum blood plasma concentration (C.sub.max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine HCl, and an AUC.sub.0-168 within the range of about 80% to 125% of about 740 nghr/mL, and a T.sub.max within the range of 80% to 125% of about 7 hours; and wherein following a single oral administration of the multi-particulate dosage form, 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 method of claim 1, wherein the active-containing particles comprise cyclobenzaprine hydrochloride. 3. The method of claim 1, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a C.sub.max of 19.851.+-.5.8765 ng/mL of cyclobenzaprine HCl and an AUC.sub.0-168 of 736.60.+-.259.414 nghr/mL. 4. The method of claim 1, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a T.sub.max of 7.1.+-.1.59 hours. 5. The method of claim 1, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a C.sub.max of 19.851.+-.5.8765 ng/mL of cyclobenzaprine HCl and an AUC.sub.0-.infin. of 779.889.+-.277.6349 nghr/mL. 6. The method of claim 1, wherein said multi-particulate dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1N HCl at 37.degree. 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. 7. A method of relieving muscle spasms in a patient in need thereof, comprising administering a multi-particulate dosage form comprising a plurality of active-containing particles comprising about 15 mg of cyclobenzaprine or pharmaceutically acceptable salts thereof and a dissolution rate controlling polymer surrounding the cyclobenzaprine or pharmaceutically acceptable salts thereof; wherein said dissolution rate controlling polymer is 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; wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a maximum blood plasma concentration (C.sub.max) of 8.315.+-.2.1635 ng/mL of cyclobenzaprine HCl and an AUC.sub.0-168 of 318.30.+-.114.657 nghr/mL; and wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions. 8. A method of relieving muscle spasms in a patient in need thereof, comprising administering a multi-particulate dosage form comprising a plurality of active-containing particles comprising about 15 mg of cyclobenzaprine or pharmaceutically acceptable salts thereof and a dissolution rate controlling polymer surrounding the cyclobenzaprine or pharmaceutically acceptable salts thereof; wherein said dissolution rate controlling polymer is 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; wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a maximum blood plasma concentration (C.sub.max) of 8.315.+-.2.1635 ng/mL of cyclobenzaprine HCl and an AUC.sub.0-.infin. of 354.075.+-.119.8037 nghr/mL; and wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions. 9. The method of claim 7 or 8, wherein the active-containing particles comprise cyclobenzaprine hydrochloride. 10. The method of claim 7 or 8, wherein said multi-particulate dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1N HCl at 37.degree. 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. 11. The method of claim 7 or 8, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a T.sub.max of 8.1.+-.2.94 hours. 12. A method of relieving muscle spasms in a patient in need thereof, comprising administering a multi-particulate dosage form comprising a plurality of active-containing particles comprising about 30 mg of cyclobenzaprine or pharmaceutically acceptable salts thereof and a dissolution rate controlling polymer surrounding the cyclobenzaprine or pharmaceutically acceptable salts thereof; wherein said dissolution rate controlling polymer is 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; wherein said multi-particulate dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1N HCl at 37.degree. 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 following a single oral administration of the multi-particulate dosage form, the dosage form provides a therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions. 13. The method of claim 12, wherein the active-containing particles comprise cyclobenzaprine hydrochloride. 14. The method of claim 12, wherein the multi-particulate dosage form provides a maximum blood plasma concentration (C.sub.max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine HCl following a single oral administration. 15. The method of claim 12, wherein the multi-particulate dosage form provides an AUC.sub.0-168 within the range of about 80% to 125% of about 740 nghr/mL following a single oral administration. 16. The method of claim 12, wherein the multi-particulate dosage form provides a T.sub.max within the range of 80% to 125% of about 7 hours following a single oral administration. 17. The method of claim 12, wherein the multi-particulate dosage form provides a maximum blood plasma concentration (C.sub.max) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine HCl, and an AUC.sub.0-168 within the range of about 80% to 125% of about 740 nghr/mL, and a T.sub.max within the range of 80% to 125% of about 7 hours following a single oral administration. 18. The method of claim 12, 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 12, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a C.sub.max of 19.851.+-.5.8765 ng/mL of cyclobenzaprine HCl, and an AUC.sub.0-168 of 736.60.+-.259.414 nghr/mL. 20. The method of claim 12, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a T.sub.max of 7.1.+-.1.59 hours. 21. The method of claim 12, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a C.sub.max of 19.851.+-.5.8765 ng/mL of cyclobenzaprine HCl and an AUC.sub.0-.infin. of 779.889.+-.277.6349 nghr/mL. 22. A method of relieving muscle spasms in a patient in need thereof, comprising administering a multi-particulate dosage form comprising a plurality of active-containing particles comprising about 15 mg of cyclobenzaprine or pharmaceutically acceptable salts thereof and a dissolution rate controlling polymer surrounding the cyclobenzaprine or pharmaceutically acceptable salts thereof; wherein said dissolution rate controlling polymer is 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; wherein said multi-particulate dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1N HCl at 37.degree. 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 following a single oral administration of the multi-particulate dosage form, the dosage form provides a therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions. 23. The method of claim 22, wherein the active-containing particles comprise cyclobenzaprine hydrochloride. 24. The method of claim 22, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a maximum blood plasma concentration (C.sub.max) of 8.315.+-.2.1635 ng/mL of cyclobenzaprine HCl and an AUC.sub.0-168 of 318.30.+-.114.657 nghr/mL. 25. The method of claim 22, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a maximum blood plasma concentration (C.sub.max) of 8.315.+-.2.1635 ng/mL of cyclobenzaprine HCl and an AUC.sub.0-.infin. of 354.075.+-.119.8037 nghr/mL. 26. The method of claim 22, wherein following a single oral administration of the multi-particulate dosage form, the dosage form provides a T.sub.max of 8.1.+-.2.94 hours. 27. The method of claim 22, 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. 28. The method of any one of claims 1, 7, 8, 12, and 22, wherein the dissolution rate controlling polymer is selected from the group consisting of cellulose ethers and cellulose acetate. 29. The method of any one of claims 1, 7, 8, 12, and 22, wherein said active-containing particles are prepared by granulating together the cyclobenzaprine or pharmaceutically acceptable salts thereof, the dissolution rate controlling polymer, and optionally other pharmaceutically acceptable excipients.