Pharmaceutical Composition For Once-A-Day Administration of Trospium Chloride

Abstract

A pharmaceutical composition of a pharmaceutically acceptable trospium salt, with upon administration to a human patient generates an average steady state blood levels of trospium with a minimum (C min ) and maximum (C max ) blood levels of about 0.5-2.5 ng/ml and about 2.0-6.0 ng/ml, respectively.

1 - 77 . (canceled) 
     
     
         78 . A pharmaceutical composition suitable for a once-a-day oral administration of trospium chloride to a human, the composition comprising:
 a first plurality of particulates comprising trospium chloride, said first plurality of particulates further comprising a first polymer,   said first plurality of particulates having an in vitro release profile at 37° C. characterized by having less than about 10% of said trospium chloride released in a solution below about pH 4.5 within 2 hours and more than about 80% of said trospium chloride released in buffer media having a pH of at least 6.8 within 1 hour;   a second plurality of particulates comprising trospium chloride, said second plurality of particulates further comprising a second polymer,   said second plurality of particulates having an in vitro release profile at 37° C. in phosphate buffer (pH 7.5) dissolution medium characterized by about 0-40% of said trospium chloride released in about 1 hour, about 20-85% of said trospium chloride released in about 4 hours, and greater than 70% of said trospium chloride released in 12 hours.   
     
     
         79 . The pharmaceutical composition of  claim 78 , wherein the second polymer comprises ethylcellulose. 
     
     
         80 . The pharmaceutical composition of  claim 78 , wherein the first polymer comprises a methacrylic acid copolymer. 
     
     
         81 . The pharmaceutical composition of  claim 80 , wherein the second polymer comprises ethylcellulose. 
     
     
         82 . The pharmaceutical composition of  claim 81 , wherein said first plurality of particulates comprises about 30 mg trospium chloride and said second plurality of particulates comprises about 30 mg trospium chloride. 
     
     
         83 . The pharmaceutical composition of  claim 82 , wherein the particulates are substantially spherical. 
     
     
         84 . The pharmaceutical composition of  claim 82 , wherein upon once daily oral administration to a subject in need thereof provides therapeutically effective amounts of trospium chloride to treat said subject's condition while reducing the occurrence of dry-mouth relative to oral, twice-daily administration of 20 mg immediate release trospium chloride tablets. 
     
     
         85 . The pharmaceutical composition of  claim 78 , wherein the first polymer is selected from the group consisting of a methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and polyvinyl acetate phthalate, and wherein the second polymer is selected from the group consisting of a copolymer of acrylic and methacrylic acid esters, a copolymer of polyvinylpyrrolidone and vinyl acetate, and cellulose derivatives. 
     
     
         86 . The pharmaceutical composition of  claim 78 , wherein once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium chloride less than about 6.0 ng/mL. 
     
     
         87 . The pharmaceutical composition of  claim 78 , wherein once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium chloride greater than about 0.5 ng/mL. 
     
     
         88 . The pharmaceutical composition of  claim 78 , whereby single-dosage administration of said pharmaceutical composition provides a plasma concentration versus time curve having an area under the curve (AUC 0-72 hrs ) of about 30,000 pg/ml*hr to about 80,000 pg/ml*hr. 
     
     
         89 . The pharmaceutical composition of  claim 78 , whereby single-dosage administration of said pharmaceutical composition provides blood levels of trospium chloride less than about 3.0 ng/mL. 
     
     
         90 . The pharmaceutical composition of  claim 85 , wherein once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium chloride less than about 6.0 ng/mL. 
     
     
         91 . The pharmaceutical composition of  claim 85 , wherein once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium chloride greater than about 0.5 ng/mL. 
     
     
         92 . The pharmaceutical composition of  claim 85 , whereby single-dosage administration of said pharmaceutical composition provides a plasma concentration versus time curve having an area under the curve (AUC 0-72 hrs ) of f about 30,000 pg/ml*hr to about 80,000 pg/ml*hr. 
     
     
         93 . The pharmaceutical composition of  claim 85 , whereby single-dosage administration of said pharmaceutical composition provides blood levels of trospium chloride less than about 3.0 ng/mL. 
     
     
         94 . The pharmaceutical composition of  claim 78 , wherein the first plurality of particulates has an in vitro release profile at 37° C. characterized by having less than about 10% of said trospium chloride released in an acidic solution below about pH 4.5 within 2 hours and more than about 80% of said trospium chloride released in a buffer media having a pH of at least 7.0 within 1 hour. 
     
     
         95 . The pharmaceutical composition of  claim 94 , wherein the first polymer is selected from the group consisting of a methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and polyvinyl acetate phthalate, and wherein the second polymer is selected from the group consisting of a copolymer of acrylic and methacrylic acid esters, a copolymer of polyvinylpyrrolidone and vinyl acetate, and cellulose derivatives. 
     
     
         96 . The pharmaceutical composition of  claim 95 , wherein once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium chloride less than about 6.0 ng/mL. 
     
     
         97 . The pharmaceutical composition of  claim 95 , wherein once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium chloride greater than about 0.5 ng/mL. 
     
     
         98 . The pharmaceutical composition of  claim 95 , whereby single-dosage administration of said pharmaceutical composition provides a plasma concentration versus time curve having an area under the curve (AUC 0-72 hrs ) of about 30,000 pg/ml*hr to about 80,000 pg/ml*hr. 
     
     
         99 . The pharmaceutical composition of  claim 95 , whereby single-dosage administration of said pharmaceutical composition provides blood levels of trospium chloride less than about 3.0 ng/mL.