Monolithic composition for dual-rate release with high drug loading

Abstract

The present document describes a process for the preparation of a low functionalization polysaccharide having carboxyl groups, comprising a) swelling of a polysaccharide granule in boiling water or a water/polyol mixture, to obtain a swollen polysaccharide; b) partial gelatinization of said swollen polysaccharide in an alkaline solvent mixture of water and alcohol and/or polyol, to obtain a partially gelatinized polysaccharide; and c) partial functionalization of said partially gelatinized polysaccharide with a functionalizing agent, to obtain the low functionalization polysaccharide.

1 . A monolithic solid dosage form for dual rate release of an active pharmaceutical ingredient, comprising
 a low functionalization polysaccharide obtained from:
 a) swelling of a polysaccharide granule in boiling water or a boiling water/polyol mixture, to obtain a swollen polysaccharide; 
 b) partial gelatinization of said swollen polysaccharide in an alkaline solvent mixture of water and alcohol and/or polyol, to obtain a suspension of a partially gelatinized polysaccharide; 
 c) low functionalization of said partially gelatinized polysaccharide in said suspension with a functionalizing agent under alkaline conditions, to obtain said functionalized polysaccharide, wherein said functionalized polysaccharide has a degree of substitution of from about 0.1 to about 0.3; 
 d) complexation of said functionalized polysaccharide with a divalent cation chosen from calcium, magnesium, zinc, aluminum, copper, or combinations thereof; 
 e) separation of said functionalized polysaccharide from said alkaline solvent mixture of water and alcohol to obtain a low functionalization polysaccharide; 
 wherein said polyol is ethylene glycol, propylene glycol, glycerol, sorbitol or combinations thereof; 
   an anionic polysaccharide complexed with a divalent cation,   a disintegrating agent; and   said active pharmaceutical ingredient.   
     
     
         2 . The monolithic solid dosage form of  claim 1 , wherein said disintegrating agent is cross-linked povidone, cross-linked carmelose, starch glycolate, or combinations thereof. 
     
     
         3 . The monolithic solid dosage form of  claim 1 , further comprising a sustained release agent. 
     
     
         4 . The monolithic solid dosage form of  claim 3 , wherein said sustained release agent is a combination of arginine and/or lysine. 
     
     
         5 . The monolithic solid dosage form of  claim 1 , wherein said anionic polysaccharide complexed with a divalent cation has a degree of substitution of from about 0.5 to about 1.5. 
     
     
         6 . The monolithic solid dosage form of  claim 1 , wherein said divalent cation is chosen from calcium, magnesium, zinc, aluminum, copper, or combinations thereof. 
     
     
         7 . The monolithic dosage form of  claim 1 , wherein said polysaccharide is chosen from a starch, a cellulose, a chitosan, a guar gum, a gellan gum, a xanthan gum, an agar, an agarose, an arabic gum, a pullulan, a dextran, a dextrin, a maltodextrin, a cyclodextrin and/or chosen from modified polysaccharides selected from the group consisting of hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methyl starch, hydroxypropyl methyl cellulose, ethyl-cellulose, methyl-cellulose, succinyl starch, octenyl starch and combinations thereof. 
     
     
         8 . The monolithic dosage form of  claim 1 , wherein said alkaline solvent mixture of water and alcohol is a binary solvent mixture of water and alcohol or ternary solvent mixture of water, alcohol and polyol. 
     
     
         9 . The monolithic dosage form of  claim 8 , wherein said binary solvent mixture of water and alcohol comprises water and at least one of ethanol, methanol, isopropanol, or combinations thereof, and said ternary solvent mixture of water and alcohol comprises water, ethanol or methanol and propylene glycol or glycerol or propanol or combination thereof. 
     
     
         10 . The monolithic dosage form of  claim 8 , wherein said water or said alcohol is from about 5% to about 50% v/v of said binary or ternary solvent mixture. 
     
     
         11 . The monolithic dosage form of  claim 8 , wherein said polyol is from about 50% to about 95% v/v of said binary or ternary solvent mixture. 
     
     
         12 . The monolithic dosage form of  claim 1 , wherein said functionalizing agent is sodium chloroacetate, succinic anhydride, n-Octenyl succinic anhydride, acrylic acid, and combinations thereof. 
     
     
         13 . The monolithic dosage form of  claim 1 , wherein e) comprises filtration of said functionalized polysaccharide and resuspension in alcohol, to obtain a resuspended functionalized polysaccharide. 
     
     
         14 . The monolithic dosage form of  claim 13 , further comprising neutralization of said resuspended functionalized polysaccharide, to obtain a neutralized functionalized polysaccharide. 
     
     
         15 . The monolithic dosage form of  claim 14 , further comprising washing of said neutralized functionalized polysaccharide, to obtain a precipitated functionalized polysaccharide. 
     
     
         16 . The monolithic dosage form of  claim 15 , further comprising drying of said precipitated functionalized polysaccharide, to obtain said low functionalization polysaccharide. 
     
     
         17 . The monolithic dosage form of  claim 1 , wherein said functionalization is carboxymethylation.