Patent ID: 9622967
Date: 2017-04-18
CPC Classifications: A61K,A61P

Claim:
1. A composition comprising an orally active nucleotide analogue phosphonate prodrug which is amorphous, which is orally bioavailable, and a pharmaceutically acceptable and inactive polymer that stabilizes the orally active nucleotide analogue phosphonate prodrug against degradation, wherein the nucleotide analogue phosphonate prodrug degrades to provide a composition containing no more than (a) 0.8% by weight of a less bioavailable impurity, relative to the original amount of the orally active nucleotide analogue phosphonate prodrug, when the composition is maintained at a temperature of 25° C. and at a relative humidity (RH) of 60% for a period of 1 month; (b) 1.2% by weight of a less bioavailable impurity, relative to the original amount of the orally active nucleotide analogue phosphonate prodrug, when the composition is maintained at a temperature of 25° C. and at 60% RH for a period of 12 months; (c) 1.5% by weight of a less bioavailable impurity, relative to the original amount of the orally active nucleotide analogue phosphonate prodrug, when the composition is maintained at a temperature of 25° C. and at 60% RH for a period of 24 months; (d) 2.0% by weight of a less bioavailable impurity, relative to the original amount of the orally active nucleotide analogue phosphonate prodrug, when the composition is maintained at a temperature of 40° C. and at 75% RH for a period of 3 months; (e) 1.75% by weight of a less bioavailable impurity, relative to the original amount of the orally active nucleotide analogue phosphonate prodrug, when the composition is maintained at a temperature of 40° C. and at 75% RH for a period of 2 months; (f) 1.5% by weight of a less bioavailable impurity, relative to the original amount of the orally active nucleotide analogue phosphonate prodrug, when the composition is maintained at a temperature of 40° C. and at 75% RH for a period of 1 month; and/or (g) 2.5% by weight of a less bioavailable impurity, relative to the original amount of the orally active nucleotide analogue prodrug, when the composition is maintained at a temperature of 60° C. and at 75% RH for a period of 5 days; wherein said less bioavailable impurity has at least 10% less oral bioavailability than the orally active nucleotide analogue phosphonate prodrug; wherein the nucleotide analogue phosphonate prodrug is 9-[2-[bis[(pivaloyloxy)-methoxy]phosphinyl]methoxy]ethyl]adenine (or bis(POM)PMEA diester of adefovir) or 9-[(R)-2-[bis[(isopropoxycarbonyl)oxymethoxy]-phosphinyl]methoxy]propyl]adenine (or bis(POC)PMPA diester of tenofovir); wherein the less orally bioavailable impurity is 9-[2-(pivaloyloxy)-methoxyphosphinyl]methoxy]ethyl]adenine, 9-[(R)-2-[(isopropoxycarbonyl)oxy]methoxyphosphinyl]methoxy]propyl]adenine, adefovir, tenofovir, or any combination thereof; and wherein the composition is an amorphous solid solution of the nucleotide analogue phosphonate prodrug and the pharmaceutically acceptable inactive polymer wherein the amorphous solid solution of the orally active nucleotide analogue phosphonate prodrug and the pharmaceutically acceptable inactive polymer is produced by dissolving the orally active nucleotide analogue phosphonate prodrug and the pharmaceutically acceptable inactive polymer in a liquid organic solvent and evaporating the organic solvent.