Pharmaceutical compositions of dispersions of drug 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.

What is claimed is: 
     
         1 . A solid amorphous dispersion pharmaceutical composition comprising:
 (i) a drug having a solubility in aqueous solution of up to about 1 to 2 mg/ml at any pH from 1 to 8, wherein the drug has been determined to be acid sensitive by determining whether, when the drug was administered to an acidic aqueous solution having a pH from 1-4, the concentration of the drug decreases by at least 1 wt % within 24 hours after administration;   (ii) a neutral concentration-enhancing dispersion polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate (HPMCA); and   (iii) an excipient selected from the group consisting of a base and a basic buffer, wherein the pharmaceutical composition is a homogeneous solid amorphous dispersion that provides improved chemical stability relative to a first control composition comprised of either an equivalent quantity of a dispersion of the drug and an acidic polymer or of an equivalent quantity of a dispersion of the drug and the neutral polymer but free from the base and the buffer.   
     
     
         2 . The composition of  claim 1  wherein the drug has a degree of degradation of at least 0.01% when the drug is stored in the control acidic dispersion for a period of six months at 40° C. and 75% relative humidity. 
     
     
         3 . The composition of  claim 2  wherein the drug has a degree of degradation of at least 0.1% when in the control acidic dispersion. 
     
     
         4 . The composition of  claim 1  wherein the drug has a relative degree of improvement in chemical stability of at least 1.25. 
     
     
         5 . The composition of  claim 1  wherein the drug has a relative degree of improvement in chemical stability at least 3. 
     
     
         6 . The composition of  claim 1  wherein the drug in the pharmaceutical 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. 
     
     
         7 . The composition of  claim 1  wherein the drug has a dose-to-aqueous solubility ratio of at least 10 mL. 
     
     
         8 . The composition of  claim 1  wherein the dispersion polymer is present in an amount such that the dispersion polymer provides a relative bioavailability that is at least 1.25 relative to a second control composition comprising an equivalent quantity of the acid sensitive drug and is free from the dispersion polymer. 
     
     
         9 . The composition of  claim 1  wherein the dispersion polymer is present in an amount such that the dispersion polymer provides a relative bioavailability that is at least 2 relative to a second control composition comprising an equivalent quantity of the acid sensitive drug and is free from the dispersion polymer. 
     
     
         10 . The composition of  claim 1  wherein the basic buffer is selected from the group consisting of sodium acetate, ammonium acetate, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, trisodium phosphate, and mixtures thereof. 
     
     
         11 . The composition of  claim 1  wherein the basic buffer comprises at least 10 wt % of the dispersion. 
     
     
         12 . A solid amorphous dispersion pharmaceutical composition comprising:
 (a) a drug that has been determined to be acid-sensitive such that degradation occurs when dispersed in a pharmaceutical composition;   (b) a neutral concentration-enhancing dispersion polymer selected from the group consisting of HPMC and HPMCA   (c) an excipient selected from the group consisting of a base and a buffer;   (d) wherein the acid-sensitive drug has a minimum solubility in aqueous solution of less than 1 mg/ml at a pH of from about 1 to about 8 when in the absence of the concentration-enhancing dispersion polymer; and   (e) wherein the solid amorphous dispersion pharmaceutical composition provides improved chemical stability relative to a control composition comprised of either an equivalent quantity of a dispersion of the acid-sensitive drug and an acidic polymer or of an equivalent quantity of a dispersion of the drug and the neutral concentration-enhancing dispersion polymer but free from the base and the buffer.   
     
     
         13 . The composition of  claim 12  wherein the drug is determined to be acid-sensitive by administering a first portion of the drug to an acidic aqueous solution having a pH from 1-4, and determining the drug is acid sensitive when the concentration of the drug decreases by at least 1 wt % within 24 hours after administration.