Pharmaceutical Compositions of Dispersions of Drugs and Neutral Polymers

Abstract

In one aspect, pharmaceutical compositions comprising dispersions of an acid-sensitive drug and a neutral dispersion polymer are disclosed. The acid-sensitive drug has improved chemical stability relative to dispersions of the drug and acidic polymers. In another aspect, pharmaceutical compositions of low-solubility drugs and amphiphilic, hydroxy-functional vinyl copolymers are disclosed.

1 - 76 . (canceled)  
     
     
         77 . A pharmaceutical composition comprising a solid amorphous dispersion comprising 
 (i) an acid-sensitive drug;    (ii) a neutral concentration-enhancing dispersion polymer: and    (iii) optionally, an excipient selected from the group consisting of a base and a buffer;    wherein 
 (a) said dispersion is substantially homogeneous and is formed by spray-drying;  
 (b) said drug in the absence of said polymer has a minimum solubility in aqueous solution of less than 1 mg/ml at any pH of from about 1 to 8; and  
 (c) said polymer is cellulosic and is selected from the group consisting of HPMC and HPMCA;  
   wherein said composition provides improved chemical stability relative to a control composition comprised of either an equivalent quantity of a dispersion of said drug and an acidic polymer or of an equivalent quantity of a dispersion of said drug and said neutral polymer but free from said base and said buffer.    
     
     
         78 . The composition of  claim 77  wherein said acid-sensitive drug has one or more functional groups selected from the group consisting of sulfonyl ureas, hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxy ureas, esters, and amides.  
     
     
         79 . The composition of  claim 77  wherein said acid-sensitive drug when present in said control acidic dispersion and stored for a period of six months at 40° C. and 75% relative humidity has a degree of degradation of at least 0.01%.  
     
     
         80 . The composition of  claim 79  wherein said acid-sensitive drug in said control acidic dispersion has a degree of degradation of at least 0.1%.  
     
     
         81 . The composition of  claim 77  wherein said drug in said composition has a relative degree of improvement in chemical stability of at least 1.25.  
     
     
         82 . The composition of  claim 81  wherein said relative degree of improvement is at least 3.  
     
     
         83 . The composition of  claim 77  wherein said drug in said composition has a relative degree of improvement in chemical stability of at least 1.25 when stored at 40° C. and 75% relative humidity for a period of six months.  
     
     
         84 . The composition of  claim 77  wherein said drug has a dose-to-aqueous-solubility ratio of at least 10 mL.  
     
     
         85 . The composition of  claim 77  wherein said dispersion polymer is present in a sufficient amount so that said dispersion provides a relative bioavailability that is at least 1.25 relative to a second control composition comprising an equivalent quantity of said acid-sensitive drug and free from said polymer.  
     
     
         86 . The composition of  claim 77  wherein said relative bioavailability is at least 2 relative to said second control composition.  
     
     
         87 . The composition of  claim 77  wherein said drug is also base-sensitive.  
     
     
         88 . The composition of  claim 77  wherein said dispersion further comprises said buffer.  
     
     
         89 . The composition of  claim 88  wherein said buffer is selected from the group consisting of sodium acetate, ammonium acetate, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, trisodium phosphate, and mixtures thereof.  
     
     
         90 . The composition of  claim 77  wherein said buffer comprises at least 10 wt % of said dispersion.  
     
     
         91 . The composition of  claim 90  wherein said dispersion has a pH from about 6 to about 10.  
     
     
         92 . The composition of  claim 77  further comprising said base and wherein said dispersion has a pH of from about 6 to about 10.  
     
     
         93 . The composition of  claim 77  wherein said composition further comprises a second polymer, said dispersion is free from at least a portion of said second polymer, and said second polymer is concentration-enhancing.  
     
     
         94 . The composition of  claim 93  wherein said second polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate.  
     
     
         95 . The composition of  claim 77  wherein said solid amorphous dispersion has a glass transition temperature intermediate between that of pure amorphous drug and pure polymer.  
     
     
         96 . The composition of  claim 77  wherein said solid amorphous dispersion is a solid solution of said amorphous drug and said polymer.