Pramipexole once-daily dosage form

Abstract

An orally deliverable pharmaceutical composition comprises a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, said composition exhibiting at least one of (a) an in vitro release profile wherein on average no more than about 20% of the pramipexole is dissolved within 2 hours after placement of the composition in a standard dissolution test; and (b) an in vivo pramipexole absorption profile following single dose administration to healthy adult humans wherein the time to reach a mean of 20% absorption is greater than about 2 hours and/or the time to reach a mean of 40% absorption is greater than about 4 hours. The composition is useful for oral administration, not more than once daily, to a subject having a condition or disorder for which a dopamine receptor agonist is indicated.

What is claimed is: 
     
         1 . An orally deliverable pharmaceutical composition comprising a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, said composition exhibiting at least one of (a) an in vitro release profile wherein on average no more than about 20% of the pramipexole is dissolved within 2 hours after placement of the composition in a standard dissolution test; and (b) an in vivo pramipexole absorption profile following single dose oral administration to healthy adult humans wherein the time to reach a mean of 20% absorption is greater than about 2 hours and/or the time to reach a mean of 40% absorption is greater than about 4 hours. 
     
     
         2 . The composition of  claim 1  that exhibits an in vitro release profile wherein on average no more than about 20% of the pramipexole is dissolved within 2 hours after placement of the composition in a standard dissolution test conducted according to USP 24 using Apparatus 1 with a spindle rotation speed of 100 rpm and a dissolution medium of 0.05M phosphate buffer, pH 6.8, at 37° C., or a test substantially equivalent thereto. 
     
     
         3 . The composition of  claim 2  wherein no more than about 12% of the pramipexole dissolves within 1 hour in said test. 
     
     
         4 . The composition of  claim 2  wherein time to reach 50% dissolution is at least about 4 hours. 
     
     
         5 . The composition of  claim 2  wherein time to reach 50% dissolution is at least about 6 hours. 
     
     
         6 . The composition of  claim 2  wherein time to reach 50% dissolution is at least about 8 hours. 
     
     
         7 . The composition of  claim 2  wherein time to reach 50% dissolution is at least about 12 hours. 
     
     
         8 . The composition of  claim 1  that exhibits an in vivo pramipexole absorption profile following single dose oral administration to healthy adult humans wherein the time to reach a mean of 20% absorption is greater than about 2 hours and/or the time to reach a mean of 40% absorption is greater than about 4 hours. 
     
     
         9 . The composition of  claim 8  wherein the time to reach a mean of 40% absorption is at least about 5 hours. 
     
     
         10 . The composition of  claim 8  wherein the time to reach a mean of 40% absorption is at least about 6 hours. 
     
     
         11 . The composition of  claim 1  that, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release pramipexole dihydrochloride reference formulation, administered three times a day. 
     
     
         12 . The composition of  claim 1  that, following single dose administration of 0.375 mg, expressed as pramipexole dihydrochloride monohydrate equivalent, exhibits a maximum plasma concentration (C max ) of pramipexole that is not greater than about 0.3 ng/ml. 
     
     
         13 . The composition of  claim 1  that exhibits a time to reach maximum plasma concentration (T max ) of pramipexole that is at least about 6 hours following administration of the composition. 
     
     
         14 . The composition of  claim 1  that exhibits a time to reach maximum plasma concentration (T max ) of pramipexole that is at least about 8 hours following administration of the composition. 
     
     
         15 . The composition of  claim 1  that exhibits a pharmacokinetic profile consistent with steady-state plasma concentrations having a fluctuation ratio that is not substantially greater than that of an equal daily dose of an immediate-release pramipexole dihydrochloride reference formulation, administered three times a day. 
     
     
         16 . The composition of  claim 1  that comprises release-modifying means effective to provide said in vitro release profile and/or said in vivo pramipexole absorption profile. 
     
     
         17 . The composition of  claim 16  wherein said release-modifying means is selected from the group consisting of a polymer matrix wherein the pramipexole is dispersed; a release-controlling layer or coating; and an osmotic pump. 
     
     
         18 . The composition of  claim 1  wherein the pramipexole is in a form of a pharmaceutically acceptable salt thereof having moderate to high solubility in water. 
     
     
         19 . The composition of  claim 18  wherein said salt is pramipexole dihydrochloride. 
     
     
         20 . The composition of  claim 1  that is in the form of discrete dosage units. 
     
     
         21 . The composition of  claim 20  wherein the amount of pramipexole in each dosage unit is sufficient to provide a daily dose in one to a small plurality of dosage units administered at one time. 
     
     
         22 . The composition of  claim 20  wherein a full daily dose is contained in a single dosage unit. 
     
     
         23 . The composition of  claim 20  that comprises about 0.1 to about 10 mg pramipexole, expressed as pramipexole dihydrochloride monohydrate equivalent, per dosage unit. 
     
     
         24 . The composition of  claim 20  that comprises about 0.2 to about 6 mg pramipexole, expressed as pramipexole dihydrochloride monohydrate equivalent, per dosage unit. 
     
     
         25 . The composition of  claim 20  that comprises about 0.3 to about 5 mg pramipexole, expressed as pramipexole dihydrochloride monohydrate equivalent, per dosage unit. 
     
     
         26 . A method of treatment of a subject having a condition or disorder for which a dopamine receptor agonist is indicated, the method comprising orally administering to the subject, not more than once daily, the composition of any of the preceding claims. 
     
     
         27 . The method of  claim 26  wherein the condition or disorder is Parkinson's disease or a complication associated therewith.