Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt

Abstract

An extended release pellet comprising an active ingredient selected from pramipexole and the pharmaceutically acceptable salts thereof, and at least one release-modifying excipient.

1 . An extended release pellet comprising pramipexole or a pharmaceutically acceptable salt thereof, and at least one release-modifying excipient. 
   
   
       2 . The extended release pellet according to  claim 1 , wherein the pramipexole or the pharmaceutically acceptable salt thereof is embedded within a matrix formed by at least one release-modifying excipient. 
   
   
       3 . The extended release pellet according to  claim 1 , wherein at least one of the release-modifying excipients is a lipid, wax, or water-insoluble polymer. 
   
   
       4 . The extended release pellet according to  claim 1 , comprising a core and a coating, wherein at least one release-modifying excipient is incorporated in the coating. 
   
   
       5 . The extended release pellet according to  claim 4 , wherein the pramipexole or the pharmaceutically acceptable salt thereof is incorporated in the core. 
   
   
       6 . The extended release pellet according to  claim 4 , wherein the coating comprises at least a first layer and a second layer surrounding the first layer, wherein the first layer comprises the pramipexole or the pharmaceutically acceptable salt thereof, and wherein the second layer comprises at least one release-modifying excipient. 
   
   
       7 . The extended release pellet according to  claim 6 , wherein at least one release-modifying excipient is ethyl cellulose, cellulose acetate, polyvinylacetate, polyacrylate, polymethacrylate, or ammonio methacrylate copolymer. 
   
   
       8 . The extended release pellet according to  claim 7 , wherein the second layer further comprises at least one water-soluble excipient. 
   
   
       9 . The extended release pellet according to  claim 8 , wherein at least one water-soluble excipient is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and polyethylene glycol. 
   
   
       10 . The extended release pellet according to  claim 7 , wherein the second layer further comprises an enteric coating polymer. 
   
   
       11 . The extended release pellet according to  claim 8 , wherein enteric coating polymer is methacrylic acid copolymers type A and B. 
   
   
       12 . The extended release pellet according to  claim 10 , wherein the second layer comprises from about 10 to about 85 wt.-% of the enteric coating polymer and from about 15 to about 75 wt.-% of the water-insoluble polymer. 
   
   
       13 . The extended release pellet according to  claim 6 , wherein the core comprises a saccharide. 
   
   
       14 . The extended release pellet according to  claim 13 , wherein the saccharide is saccharose, starch, cellulose, or a cellulose derivative. 
   
   
       15 . The extended release pellet according to  claim 14 , wherein the saccharide is microcrystalline cellulose. 
   
   
       16 . An extended release pellet comprising:
 (1) an inert pellet core;   (2) a first layer comprising pramipexole or a pharmaceutically acceptable salt thereof; and   (3) a second layer provided on the first layer, the second layer being an extended release coating comprising:
 (a) at least one water-insoluble polymer and optionally a pore former, the resulting pellet having a pH-independent in vitro release characteristic, or 
 (b) a mixture of a pH-dependent enteric-coating polymer and a pH-independently water swelling polymer, 
   
     wherein the extended release pellet has a close to zero order in vitro release characteristic at acidic pH values up to pH 6.8, an accelerated release above pH 6.8, and a more accelerated release above pH 7.3. 
   
   
       17 . The extended release pellet according to  claim 16 , wherein the first layer further comprises one or more wet binders and further excipients. 
   
   
       18 . The extended release pellet according to  claim 16 , wherein the inert pellet core comprises polysaccharides, cellulose, a cellulose derivative, starch, and/or waxes. 
   
   
       19 . The extended release pellet according to  claim 16 , wherein the inert pellet core comprises saccharose and/or microcrystalline cellulose. 
   
   
       20 . The extended release pellet according to  claim 16 , wherein the water-insoluble polymer is ethyl cellulose, cellulose acetate, polyvinylacetate, or polyacrylates and derivatives thereof. 
   
   
       21 . The extended release pellet according to  claim 16 , wherein the pH-dependent enteric-coating polymer is an anionic carboxylic acrylic polymer soluble above a pH value of 5.5. 
   
   
       22 . The extended release pellet according to  claim 21 , wherein the pH-dependent enteric-coating polymer is soluble above a pH value of 7.0. 
   
   
       23 . The extended release pellet according to  claim 21 , wherein the pH-dependent enteric-coating polymer is a partly methyl esterified methacrylic acid polymer. 
   
   
       24 . The extended release pellet according to  claim 16 , wherein the pH-independently water swelling polymer is a quaternary ammonium substituted acrylic polymer. 
   
   
       25 . The extended release pellet according to  claim 24 , wherein the quaternary ammonium substituted acrylic polymer has an ammonium substitution of about 5 to about 10 percent by weight. 
   
   
       26 . The extended release pellet according to  claim 16 , wherein the pH-dependent enteric-coating polymer is present in an amount of 10 to 85% by weight of the coating and the pH-independently water swelling polymer is present in an amount of 15 to 75% by weight of the coating. 
   
   
       27 . The extended release pellet according to  claim 21 , wherein the pH-dependent enteric-coating polymer is present in an amount of 10 to 85% by weight of the coating and the pH-independently water swelling polymer is present in an amount of 15 to 75% by weight of the coating. 
   
   
       28 . The extended release pellet according to  claim 24 , wherein the pH-dependent enteric-coating polymer is present in an amount of 10 to 85% by weight of the coating and the pH-independently water swelling polymer is present in an amount of 15 to 75% by weight of the coating. 
   
   
       29 . The extended release pellet according to  claim 16 , comprising:
 (1) an inert pellet core;   (2) a first layer comprising pramipexole or a pharmaceutically acceptable salt thereof; and   (3) a second layer provided on the first layer, the second layer being an extended release coating comprising a mixture of:
 (i) a pH-dependent enteric-coating polymer, 
 (ii) a pH-independently water swelling polymer, and 
 (iii) a pore-forming component, 
   
     wherein the extended release pellet has a close to zero order in vitro release characteristic at acidic pH values up to pH 6.8, an accelerated release above pH 6.8, and a more accelerated release above pH 7.3. 
   
   
       30 . The extended release pellet according to  claim 29 , wherein the pore-forming component is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, or polyethylene glycol. 
   
   
       31 . An extended release pellet comprising pramipexole or a pharmaceutically acceptable salt thereof prepared by wet or melt extrusion or melt granulation using excipients achieving extended release without a further diffusion membrane. 
   
   
       32 . A method of manufacturing extended release pellets, the method comprising the steps of:
 (1) providing an inert starter pellet core;   (2) applying a solution or dispersion of a first coating composition comprising pramipexole or a pharmaceutically acceptable salt thereof, at least a binder, and optionally excipient(s) onto the inert starter pellet core, wherein the pramipexole or a pharmaceutically acceptable salt thereof is used as unmilled material dissolved/dispersed in a solvent together with the binder(s) and optional excipient(s), and subsequently drying the first coated pellet;   (3) applying a solution or dispersion of a second coating composition as functional coating composition onto the first coated pellet obtained in step (2), wherein the coating composition comprises (a) at least one water-insoluble polymer and optionally a pore former or (b) a mixture of a pH-dependent enteric-coating polymer and a pH-independently water swelling polymer, and optional excipient(s), and a solvent, and subsequently drying the obtained extended release pellet.   
   
   
       33 . The method according to  claim 32 , further comprising performing manual screening after step (2) and/or step (3) in order to remove agglomerates. 
   
   
       34 . The method according to  claim 32 , wherein the applying the first coating composition of step (2) is done by spraying the solution or dispersion of the first coating composition onto the inert starter pellet core. 
   
   
       35 . The method according to  claim 32 , wherein the applying the second coating composition of step (3) is done by spraying the solution or dispersion of the second coating composition onto the first coated pellet. 
   
   
       36 . A capsule containing extended release pellets according to  claim 1 . 
   
   
       37 . A capsule containing extended release pellets according to  claim 16 . 
   
   
       38 . The capsule according to  claim 36 , wherein the capsule contains an amount of extended release pellets sufficient to provide an effective daily dose of pramipexole or a pharmaceutically acceptable salt thereof. 
   
   
       39 . The capsule according to  claim 37 , wherein the capsule contains an amount of extended release pellets sufficient to provide an effective daily dose of pramipexole or a pharmaceutically acceptable salt thereof.