Sustained release aminopyridine composition

Abstract

A pharmaceutical composition which comprises a therapeutically effective amount of a aminopyridine dispersed in a release matrix, including, for example, a composition that can be formulated into a stable, sustained-release oral dosage formulation, such as a tablet which provides, upon administration to a patient, a therapeutically effective plasma level of the aminopyridine for a period of at least 12 hours, preferably 24 hours or more and the use of the composition to treat various neurological diseases.

1 . A sustained release 4-aminopyridine tablet, comprising:
 10 mg of 4-aminopyridine particles distributed substantially uniformly throughout a rate controlling polymer release matrix,   the sustained release 4-aminopyridine tablet providing a mean maximum plasma concentration of 4-aminopyridine of from about 15 ng/ml to about 180 ng/ml, and a mean T max  of 4-aminopyridine of about 2 hours to about 5 hours after administration of the tablet, and   the sustained release 4-aminopyridine tablet being the product of a method consisting essentially of the steps of
 (a) imparting a particle size distribution to particles of 4-aminopyridine by milling the particles of 4-aminopyridine such that 90% of the particles are smaller than 1.5 mm, 50% of the particles are smaller than 1 mm, and 10% of the particles are smaller than 500 mm; 
 (b) blending the 4-aminopyridine particles imparted with the particle size distribution produced in step (a) with the rate controlling polymer release matrix, thereby producing a blend with the 4-aminopyridine particles distributed substantially uniformly throughout the release matrix; and 
 (c) compressing the blend produced in step (b) to form a tablet, thereby producing the sustained release 4-aminopyridine tablet. 
   
     
     
         2 . The sustained release 4-aminopyridine tablet of  claim 1 , wherein the particle size distribution imparted in step (a) is such that 90% of the particles are smaller than 300 mm, 50% of the particles are smaller than 150 mm, and 10% of the particles are smaller than 50 mm. 
     
     
         3 . The sustained release 4-aminopyridine tablet of  claim 1 , wherein in step (b), the 4-aminopyridine particles imparted with the particle size distribution produced in step (a) are blended with the rate controlling polymer release matrix for about 10 minutes to about 55 minutes. 
     
     
         4 . The sustained release 4-aminopyridine tablet of  claim 1 , having a hardness in the range of from 150 N to 300 N. 
     
     
         5 . The sustained release 4-aminopyridine tablet of  claim 4 , having a hardness in the range of from 245 N to 255 N. 
     
     
         6 . The sustained release 4-aminopyridine tablet of  claim 1 , wherein the tablet is monolithic. 
     
     
         7 . The sustained release 4-aminopyridine tablet of  claim 1 , which provides a mean maximum plasma concentration of 4-aminopyridine of from 18.6 ng/ml to 36.8 ng/ml. 
     
     
         8 . The sustained release 4-aminopyridine tablet of  claim 1 , which provides a mean T max  of 4-aminopyridine of 3 hours to 4 hours after administration of the tablet. 
     
     
         9 . A sustained release 4-aminopyridine tablet, comprising:
 10 mg of 4-aminopyridine particles distributed substantially uniformly throughout a rate controlling polymer release matrix,   the sustained release 4-aminopyridine tablet having a hardness in the range of from 150 N to 300 N, and   the sustained release 4-aminopyridine tablet being the product of a method consisting essentially of the steps of
 (a) imparting a particle size distribution to particles of 4-aminopyridine by milling the particles of 4-aminopyridine such that 90% of the particles are smaller than 1.5 mm, 50% of the particles are smaller than 1 mm, and 10% of the particles are smaller than 500 mm; 
 (b) blending the 4-aminopyridine particles imparted with the particle size distribution produced in step (a) with the rate controlling polymer release matrix, thereby producing a blend with the 4-aminopyridine particles distributed substantially uniformly throughout the release matrix; and 
 (c) compressing the blend produced in step (b) to form a tablet, thereby producing the sustained release 4-aminopyridine tablet. 
   
     
     
         10 . The sustained release 4-aminopyridine tablet of  claim 9 , wherein the particle size distribution imparted in step (a) is such that 90% of the particles are smaller than 300 mm, 50% of the particles are smaller than 150 mm, and 10% of the particles are smaller than 50 mm. 
     
     
         11 . The sustained release 4-aminopyridine tablet of  claim 9 , wherein in step (b), the 4-aminopyridine particles imparted with the particle size distribution produced in step (a) are blended with the rate controlling polymer release matrix for about 10 minutes to about 55 minutes. 
     
     
         12 . The sustained release 4-aminopyridine tablet of  claim 9 , having a hardness in the range of from 245 N to 255 N. 
     
     
         13 . The sustained release 4-aminopyridine tablet of  claim 9 , wherein the tablet is monolithic. 
     
     
         14 . The sustained release 4-aminopyridine tablet of  claim 9 , which provides a mean maximum plasma concentration of 4-aminopyridine of from about 15 ng/ml to about 180 ng/ml, and a mean T max  of 4-aminopyridine of about 2 hours to about 5 hours after administration of the tablet. 
     
     
         15 . The sustained release 4-aminopyridine tablet of  claim 14 , which provides a mean maximum plasma concentration of 4-aminopyridine of from 18.6 ng/ml to 36.8 ng/ml. 
     
     
         16 . The sustained release 4-aminopyridine tablet of  claim 14 , which provides a mean T max  of 4-aminopyridine of 3 hours to 4 hours after administration of the tablet.