Once daily trospium chloride treatment method

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 method for treating a bladder dysfunction in a patient comprising orally administering to a patient suffering from a bladder dysfunction a therapeutically effective amount of a once-a-day dosage of a pharmaceutically acceptable salt of trospium (Tr + ) in a pharmaceutical composition comprising at least one component selected from the group consisting of an extended release (XR) and a delayed release (DR) component; wherein at least about 50% of the trospium salt is formulated for release in the lower gastrointestinal (GI) tract; which formulation provides an average C max  at steady state of less than 2400 pg/ml of Tr +  at a T max  of less than 6 hours; and wherein the bladder dysfunction is selected from the group consisting of urinary frequency, urgency, nocturia, urge-incontinence associated with detrusor instability, urge syndrome, and detrusor hyperreflexia. 
     
     
         79 . The method of  claim 78  in which the pharmaceutically acceptable salt of trospium is selected from the group consisting of a fluoride, chloride, bromide and iodide salt of trospium. 
     
     
         80 . The method of  claim 78  in which the pharmaceutically acceptable salt of trospium is trospium chloride. 
     
     
         81 . The method of  claim 78  which produces fewer incidents of one or more side effects, selected from the group of dry mouth, headache, constipation, dyspepsia, and abdominal pain, compared with the number of incidents of said one or more side effects observed after oral, twice daily administration of a 20 mg immediate release dosage formulation of trospium chloride. 
     
     
         82 . The method of  claim 78  in which said once-a-day formulation includes a mixture of a delayed release (DR) component and an extended release (XR) component. 
     
     
         83 . The method of  claim 82  in which the DR component and XR component each includes 30 mg of trospium chloride. 
     
     
         84 . The method of  claim 78 , wherein at least about 50% of the trospium salt in the pharmaceutical composition is targeted for release in the colon. 
     
     
         85 . The method of  claim 78 , wherein about 50% of the trospium salt in the pharmaceutical composition is targeted for release in the lower gastrointestinal tract. 
     
     
         86 . The method of  claim 78 , wherein about 50% of the trospium salt in the pharmaceutical composition is targeted for release in the colon. 
     
     
         87 . The method of  claim 78 , wherein 50% of the trospium salt in the pharmaceutical composition is targeted for release in the colon. 
     
     
         88 . A method for treating a bladder dysfunction in a patient comprising orally administering to a patient suffering from a bladder dysfunction a therapeutically effective amount of a once-a-day dosage formulation of a pharmaceutically acceptable salt of trospium (Tr + ) in a pharmaceutical composition, comprising at least one component selected from the group consisting of an extended release (XR) and a delayed release (DR) component, wherein at least about 50% of the trospium salt is formulated for release in the lower gastrointestinal (GI) tract; which formulation provides an average C max  at steady state of less than 2400 pg/ml of Tr +  at a T max  of less than 6 hours and which average steady state blood levels of Tr +  do not fall below 500 pg/ml; and wherein the bladder dysfunction is selected from the group consisting of urinary frequency, urgency, nocturia, urge-incontinence associated with detrusor instability, urge syndrome, and detrusor hyperreflexia. 
     
     
         89 . The method of  claim 88  in which the pharmaceutically acceptable salt of trospium is selected from the group consisting of a fluoride, chloride, bromide and iodide salt of trospium. 
     
     
         90 . The method of  claim 89  in which the pharmaceutically acceptable salt of trospium is trospium chloride. 
     
     
         91 . The method of  claim 88 , wherein at least about 50% of the trospium salt in the pharmaceutical composition is targeted for release in the colon. 
     
     
         92 . The method of  claim 88 , wherein about 50% of the trospium salt in the pharmaceutical composition is targeted for release in the lower gastrointestinal tract. 
     
     
         93 . The method of  claim 88 , wherein about 50% of the trospium salt in the pharmaceutical composition is targeted for release in the colon. 
     
     
         94 . The method of  claim 88 , wherein 50% of the trospium salt in the pharmaceutical composition is targeted for release in the colon. 
     
     
         95 . A method of treating a bladder dysfunction in a mammal comprising an oral administration to said mammal of a therapeutically effective amount of a once-daily dose of 25 to 80 mg of trospium chloride in a pharmaceutical composition for at least a time sufficient to ameliorate said dysfunction, wherein at least part of the trospium chloride is contained in an extended release (XR) component or in a delayed release (DR) component, wherein said composition comprises at least one polymer selected from enteric polymers, release controlling polymers, or combinations thereof, wherein at least about 50% of the trospium chloride is formulated for release in the lower gastrointestinal (GI) tract, wherein said administration provides steady state blood levels of trospium of a minimum of about 0.5 ng/ml and a maximum of about 6.0 ng/ml, and results in minimizing the occurrence of side effects as compared to twice daily administration of 20 mg of immediate release trospium chloride tablets; and wherein said bladder dysfunction is selected from the group consisting of urinary frequency, urgency, nocturia, and urge-incontinence due to detrusor instability, urge syndrome, and detrusor hyperreflexia. 
     
     
         96 . The method of  claim 95 , wherein said administration results in steady state blood levels of trospium which are comparable to steady state blood levels of trospium achieved with twice daily administration of 20 mg of immediate release trospium chloride tablets. 
     
     
         97 . The method of  claim 95 , wherein said XR component comprises at least one release controlling polymer selected from copolymers of acrylic and methacrylic acid esters, ethylcellulose aqueous dispersions, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyethylene glycols and combinations thereof. 
     
     
         98 . The method of  claim 95 , wherein said DR component comprises at least one enteric polymer selected from cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride, ethyl methacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, zein, shellac, copal collophorium, carboxymethyl ethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters and combinations thereof. 
     
     
         99 . The method of  claim 95 , wherein said composition additionally comprises an immediate release (IR) trospium component. 
     
     
         100 . The method of  claim 99 , wherein the IR component contains not more than about 20 mg of trospium chloride. 
     
     
         101 . The method of  claim 99 , wherein said composition is a combination of an IR trospium chloride component and a DR trospium chloride component. 
     
     
         102 . The method of  claim 99 , wherein said composition is a combination of an IR trospium chloride component and an XR trospium chloride component. 
     
     
         103 . The method of  claim 99 , wherein said composition is a combination of an IR trospium chloride component, an XR trospium chloride component, and a DR trospium component. 
     
     
         104 . The method of  claim 95 , wherein said composition is a combination of an XR trospium chloride component and a DR trospium chloride component. 
     
     
         105 . The method of  claim 104 , wherein the DR component comprises trospium chloride and an enteric polymer, and the XR component comprises trospium chloride and a release controlling polymer. 
     
     
         106 . The method of  claim 105 , wherein each one of XR component and DR component is in the form of pellets. 
     
     
         107 . The method of  claim 106 , wherein said DR component is composed of DR pellets consisting essentially of trospium chloride, a sugar core, hydroxypropyl methylcellulose, a coating of the enteric polymer that delays release of the trospium chloride from the pellet for a period of time after administration, triethyl citrate, a protective overcoating, and talc; and wherein said XR component is composed of XR pellets consisting essentially of trospium chloride, a sugar core, hydroxypropyl methylcellulose, a surface coating that controls a release profile of the trospium chloride from the pellet after administration, a protective overcoating, and talc. 
     
     
         108 . The method of  claim 107 , wherein the XR component contains about 30 mg of trospium chloride, and the DR component contains about 30 mg of trospium chloride. 
     
     
         109 . The method of  claim 95 , wherein said DR component releases trospium chloride at a pH of about 7.0. 
     
     
         110 . The method of  claim 95 , wherein at least about 50% of the trospium chloride in the pharmaceutical composition is targeted for release in the colon. 
     
     
         111 . The method of  claim 95 , wherein about 50% of the trospium chloride in the pharmaceutical composition is targeted for release in the lower gastrointestinal tract. 
     
     
         112 . The method of  claim 95 , wherein about 50% of the trospium chloride in the pharmaceutical composition is targeted for release in the colon. 
     
     
         113 . The method of  claim 88 , wherein 50% of the trospim chloride in the pharmaceutical composition is targeted for release in the colon. 
     
     
         114 . The method of  claim 95 , wherein said side effects are selected from a group consisting of dry mouth, headache, constipation, dyspepsia, abdominal pain, and a combination thereof. 
     
     
         115 . The method of  claim 95 , wherein said composition is administered as an oral dosage form selected from a granule, tablet, pellet, beadlet, powder, sachet, capsule, gel, dispersion, solution or suspension. 
     
     
         116 . The method of  claim 115 , wherein said tablet is a rapidly dispersible tablet. 
     
     
         117 . The method of  claim 115 , wherein said tablet, pellet or beadlet is a layered tablet, pellet or beadlet comprising at least two trospium-containing layers, wherein each layer comprises at least one component selected from an XR component, a DR component or an immediate release (IR) component. 
     
     
         118 . The method of  claim 95 , wherein said oral administration is carried out without the intake of high-fat food. 
     
     
         119 . A method of treating a bladder dysfunction in a mammal comprising orally administering to said mammal a therapeutically effective amount of a once-daily dose of trospium chloride in a pharmaceutical composition comprising a combination of a DR component and an XR component, wherein at least about 50% of the trospium chloride is formulated for release in the lower gastrointestinal (GI) tract, wherein said DR component is composed of enteric coated pellets consisting essentially of: trospium chloride, a sugar core, hydroxypropyl methylcellulose, a coating of the enteric polymer that delays release of the trospium chloride from the pellet for a period of time after administration, triethyl citrate, a protective overcoating, and talc; and wherein said XR component is composed of extended release pellets consisting essentially of: trospium chloride, a sugar core, hydroxypropyl methylcellulose, a surface coating that controls a release profile of the trospium chloride from the pellet after administration, a protective overcoating, and talc, wherein said administration provides steady state blood levels of trospium of a minimum of about 0.5 ng/ml and a maximum of about 6.0 ng/ml and wherein the bladder dysfunction is selected from the group consisting of urinary frequency, urgency, nocturia, urge-incontinence associated with detrusor instability, urge syndrome, and detrusor hyperreflexia. 
     
     
         120 . A method of treating a bladder dysfunction in a mammal comprising orally administering to said mammal a therapeutically effective amount of a once-daily dose of a pharmaceutical composition comprising a mixture of enteric coated pellets and extended release pellets in a ratio of 1:1, the enteric coated pellets consisting essentially of trospium chloride, sugar spheres, hydroxypropyl methylcellulose, methacrylic acid copolymer, triethyl citrate, and talc and wherein the extended release pellets consist essentially of trospium chloride, sugar spheres, hydroxypropyl methylcellulose, ethyl cellulose, and talc, wherein at least about 50% of the trospium chloride is formulated for release in the lower gastrointestinal (GI) tract, wherein said administration provides steady state blood levels of trospium of a minimum of about 0.5 ng/ml and a maximum of about 6.0 ng/ml, and wherein the bladder dysfunction is selected from the group consisting of urinary frequency, urgency, nocturia, urge-incontinence associated with detrusor instability, urge syndrome, and detrusor hyperreflexia. 
     
     
         121 . The method of one of  claim 119  or  120 , wherein 60 mg of trospium chloride is in the pharmaceutical composition. 
     
     
         122 . The method of  claim 121 , wherein the 60 mg of trospium chloride is equally divided between the enteric coated pellets and extended release pellets. 
     
     
         123 . The method of  claim 119  or  120 , wherein at least about 50% of the trospium salt in the pharmaceutical composition is targeted for release in the colon. 
     
     
         124 . The method of  claim 119  or  120 , wherein about 50% of the trospium salt in the pharmaceutical composition is targeted for release in the lower gastrointestinal tract. 
     
     
         125 . The method of  claim 119  or  120 , wherein about 50% of the trospium salt in the pharmaceutical composition is targeted for release in the colon. 
     
     
         126 . The method of  claim 119  or  120 , wherein 50% of the trospium salt in the pharmaceutical composition is targeted for release in the colon.