Novel controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum

Abstract

The present invention provides a controlled release device for sustained or pulsatile delivery of pharmaceutically active substances for a predetermined period of time. This invention further provides such device in which sustained or pulsatile delivery is obtained by the unique blend and intimate mixture of pharmaceutically active substance with a microbial polysaccharide and uncrosslinked linear polymer and optionally a crosslinked polymer and/or lipophillic polymer and/or saturated polyglycolyzed glyceride. The invention also provides a process for the manufacture of such devices and pharmaceutical compositions containing the same.

1 . A controlled release pharmaceutical device which provides sustained or pulsatile delivery of pharmaceutically active substances for a predetermined period of time, the device comprising; 
 about 1 to 60% by weight microbial polysaccaride; and    about 1 to 60% by weight uncrosslinked linear polymer.    
   
   
       2 . The device of  claim 1 , wherein said device additionally comprises about 1 to 80% by weight pharmaceutical active.  
   
   
       3 . The device of  claim 2 , wherein said pharmaceutical active is selected from the group consisting of diltiazem, glipizide, buspirone, tramadol, gabapentin, verapamil, etodolac, naproxen, diclofenac, COX2 inhibitors, budesonide, venlafaxine, metoprolol, carbidopa, levodopa, carbamazepine, ibuprofen, morphine, pseudoephedrine, paracetamol, cisapride, pilocarpine, methylphenidine, nifedipine, nicardipine, felodipine, captopril, terfenadine, pentoxifylline, fenofibrate, aciclovir, zidovudine, moclobemide, potasium chloride, lamotrigine, citalopram, cladribine, loratadine, pancrelipase, lithium carbonate, orphenadrine, ketoprofen, procainamide, ferrous sulfate risperdone, clonazepam, nefazodone, lovastatin, simvastatin, pravachol, ketorolac, hydromorphone, ticlopidine, seligiline, alprazolam, divalproex and phenytoin.  
   
   
       4 . The device of  claim 3 , wherein said device additionally comprises at least of the agents selected from the group consisting of about 1 to 50% by weight crosslinked polymer; about 1 to 50% by weight lipophillic polymer; about 1 to 50% saturated polyglycolyzed glyceride and mixtures thereof.  
   
   
       5 . The device of  claim 4 , wherein said device additionally comprises; 
 about 0.5 to 10% by weight lubricant.    
   
   
       6 . The device of  claim 5 , wherein said lubricant comprises magnesium stearate or talc.  
   
   
       7 . The device of  claim 1 , wherein said microbial polysaccharide is xanthum gum.  
   
   
       8 . The device of  claim 1 , wherein said uncrosslinked linear polymer is a cellulose ether.  
   
   
       9 . The device of  claim 8 , wherein said cellulose ether is hydroxypropylmethyl cellulose.  
   
   
       10 . The device of  claim 4 , wherein said device additionally comprises about 1 to 65% granulating or tabletting aids.  
   
   
       11 . The device of  claim 10 , wherein said granulating or tabletting aids are selected from the group consisting of silicone dioxide, microcrystalline cellulose, calcium phosphate, calcium sulphate, sodium laurel sulphate, silicified microcrystalline cellulose.  
   
   
       12 . The device of  claim 4 , wherein said device is fabricated as a unit dose for pulsatile delivery of the pharmaceutical active or as a uniform matrix tablet for a sustained release of the pharmaceutical active.  
   
   
       13 . The device of  claim 12 , wherein said device is formulated as a tablet having a hardness of about >5 Strong Cobb units and a friability of about <1%.  
   
   
       14 . A pharmaceutical composition comprising; 
 about 1 to 60% by weight microbial polysaccharide;    about 1 to 60% by weight uncrosslinked linear polymer; and    about 1 to 80% by weight pharmaceutical active.    
   
   
       15 . The composition of  claim 14 , wherein said composition additionally comprises at least of the agents selected from the group consisting of about 1 to 50% by weight crosslinked polymer; about 1 to 50% by weight lipophillic polymer; about 1 to 50% saturated polyglycolyzed glyceride and mixtures thereof.  
   
   
       16 . The composition of  claim 15 , wherein said composition additionally comprises about 0.5 to 10% by weight lubricant.  
   
   
       17 . The composition of  claim 16 , wherein said composition additionally comprises about 1 to 65% granulating or tabletting aids.  
   
   
       18 . A method for making a controlled release formulation of pharmaceutically active agents, said method comprising: 
 blending about 1 to 80% by weight pharmaceutical active with about 1 to 60% by weight microbial polysaccharide and about 1 to 60% by weight uncrosslinked linear polymer to form a homogeneous blend; 
 granulating said homogeneous blend and kneading to form wet granules;  
 drying the wet granules to a loss on drying of about <5%;  
   Size reducing the dried granules to provide a granule size of about <1400 microns; 
 blending the dried granules with about 0.5 to 10% lubricant; and  
   compressing the lubricated granules into tablets.    
   
   
       19 . The method of  claim 18 , wherein at least of the agents selected from the group consisting of about 1 to 50% by weight crosslinked polymer; about 1 to 50% by weight lipophillic polymer; about 1 to 50% saturated polyglycolyzed glyceride and mixtures thereof is added to blend with said microbial polysaccharide and uncrosslinked linear polymer.  
   
   
       20 . The device of  claim 4 , wherein said crosslinked polymer is Carbopol 971P.  
   
   
       21 . The device of  claim 4 , wherein said lipophillic polymer is selected from the group consisting of glyceryl palmitostearate, glyceryl stearate and glyceryl behenate.  
   
   
       22 . The device of  claim 4 , wherein said saturated polyglycolyzed glyceride is gelucire 44/14.