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.

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 ammonia 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. 
     
     
         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 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. 
     
     
         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.