Oral pharmaceutical formulation in the form of an aqueous suspension of microcapsules for modified release of amoxicillin

Abstract

The invention concerns liquid pharmaceutical formulations, for oral delivery, with modified release of amoxicillin and consisting of suspensions of coated particles of amoxicillin (microcapsules). The microcapsules constituting the dispersed phase of the suspension are designed, according to the invention, to enable modified release of amoxicillin, in accordance with a profile which remains unaltered during the shelf life of the liquid suspension. Therefor, the invention consists in selecting a coating composition specific to the microcapsules consisting of at least four components enabling preservation of said microcapsules in water without altering their properties of modified release of amoxicillin, said liquid phase being furthermore saturated with amoxicillin.

1 . A suspension of microcapsules in an aqueous liquid phase, said suspension being intended for oral administration and allowing the modified release of amoxicillin, wherein said suspension comprises a plurality of microcapsules and an aqueous liquid phase, wherein the aqueous liquid phase is saturated or becomes saturated with active principle(s) on contact with the microcapsules, and wherein each microcapsule comprises
 (a) a core comprising amoxicillin and   (b) a film coating that: (i) is applied to the core, (ii) controls the modified release of the amoxicillin in gastrointestinal tract fluids, and (iii) comprises:   (1) at least one film-forming polymer insoluble in gastrointestinal tract fluids selected from the group consisting of:   water-insoluble cellulose derivatives,   water-insoluble acrylic polymers,   polyvinyl acetates,   and mixtures thereof;   (2) at least one water-soluble polymer selected from the group consisting of:   water-soluble cellulose derivatives,   polyacrylamides,   poly-N-vinylamides,   poly-N-vinyllactams,   polyvinyl alcohols (PVA),   polyoxyethylenes (POE),   polyvinylpyrrolidones (PVP),   and mixtures thereof;   (3) at least one plasticizer;   and wherein the in vitro release profile of the suspension of microcapsules in an aqueous liquid phase on day ten is similar to the release profile on day zero, as measured using a type II apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8, at a temperature of 37° C.   
     
     
         2 . The suspension according to  claim 1 , wherein
 the at least one plasticizer is selected from the group consisting of   glycerol, glycerol esters,   phthalates,   citrates,   sebacates,   adipates,   azelates,   benzoates,   vegetable oils,   fumarates,   malates,   oxalates,   succinates,   butyrates,   cetyl alcohol esters,   salicylic acid,   triacetin,   malonates,   cutin,   castor oil,   and mixtures thereof.   
     
     
         3 . The suspension according to  claim 1 , wherein the film coating consists of a single layer. 
     
     
         4 . The suspension according to  claim 1 , wherein said suspension comprises 30 to 95% by weight of liquid phase; and 5 to 70% by weight of microcapsules. 
     
     
         5 - 7 . (canceled) 
     
     
         8 . The suspension according to  claim 1 , wherein prior to the incorporation of the microcapsules into the aqueous liquid phase, the aqueous liquid phase is saturated with amoxicillin. 
     
     
         9 . The suspension according to  claim 1 , wherein the microcapsules have a particle size less than or equal to 1000 microns. 
     
     
         10 . The suspension according to  claim 1 , wherein the from 1 to 50% of the total weight of the coated microcapsules is film coating. 
     
     
         11 . The suspension according to  claim 1 , having an in vitro release profile obtained using a type II apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8 and at a temperature of 37° C., such that: the proportion PI of amoxicillin released during the first 15 minutes of the dissolution test is such that: PI≦15; and the remaining amoxicillin is released over a period such that the release time of 50% by weight of amoxicillin (t 1/2 ) is defined as follows (in hours): 0.5≦t 1/2 ≦30. 
     
     
         12 . The suspension according to  claim 1 , wherein the initial in vitro release profile Pfi obtained just after suspension of the microcapsules in the solvent (preferably aqueous liquid phase, measured using a type II apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8, at a temperature of 37° C., and the in vitro release profile Pf 10  obtained 10 days after suspension of the microcapsules in the aqueous liquid phase, measured using a type II apparatus according to the European Pharmacopoeia 3rd edition, in a phosphate buffer medium of pH 6.8, at a temperature of 37° C., are similar. 
     
     
         13 . The suspension according to  claim 1 , wherein the pH of the suspension is acidic or neutral. 
     
     
         14 . The suspension according to  claim 1 , wherein the suspension comprises at least one rheology modifier. 
     
     
         15 . The suspension according to  claim 1  wherein the suspension further comprises at least one agent for modifying the solubility of the amoxicillin in the aqueous liquid phase. 
     
     
         16 . The suspension according to  claim 1 , wherein the suspension further comprises at least one additive selected from the group consisting of: surfactants, colourants, dispersants, preservatives, taste improvers, flavourings, sweeteners, antioxidants, and mixtures thereof. 
     
     
         17 . (canceled) 
     
     
         18 . A kit for preparing the suspension according to  claim 1 , wherein said kit comprises:
 microcapsules for modified release in substantially dry form containing amoxicillin,   immediate-release uncoated amoxicillin in a necessary and sufficient dose to saturate the liquid phase with amoxicillin once the saturation dose of amoxicillin and the liquid phase have been brought into contact;   at least part of the ingredients useful for its preparation;   the protocol for preparation of the suspension.   
     
     
         19 . The suspension according to  claim 9  wherein the microcapsules have a particle size of between 200 and 800 microns. 
     
     
         20 . The suspension according to  claim 9  wherein the microcapsules have a particle size of between 200 and 600 microns. 
     
     
         21 . The suspension according to  claim 10 , wherein from 5 to 40% of the total weight of the coated microcapsules is film coating. 
     
     
         22 . The suspension according to  claim 11 , wherein the proportion PI of amoxicillin released during the first 15 minutes of the dissolution test is such that: PI≦5 and the remaining amoxicillin is released over a period such that the release time of 50% by weight of AP (t 1/2 ) is defined as follows (in hours): 0.5≦t 1/2 ≦20. 
     
     
         23 . The kit according to  claim 18 , wherein said kit further comprises the liquids useful for preparing the suspension.