Composition comprising an organic liquid diluent and a specific hydroxyalkyl methylcellulose

Abstract

A liquid composition which comprises an organic liquid diluent and a hydroxyalkyl methylcellulose which has a certain distribution of substituted hydroxyalkoxyl groups and unsubstituted hydroxyalkoxyl groups is stable over an extended time period. In the hydroxyalkyl methylcellulose hydroxyalkoxyl groups are classified into a fraction (A) and a fraction (B), wherein fraction (A) represents the sum of all molar fractions of substituted hydroxyalkoxyl groups having hydroxyl groups substituted further with methoxyl groups and fraction (B) represents the sum of all molar fractions of unsubstituted hydroxyalkoxyl groups having hydroxyl groups not substituted further with methoxyl groups and wherein the ratio fraction (A)/fraction (B) is at least 0.30. The liquid composition is useful for preparing a solid dispersion comprising at least one active ingredient in at least one hydroxypropyl methylcellulose by spray-drying.

1 . A solid dispersion comprising at least one active ingredient in at least one hydroxyalkyl methylcellulose wherein hydroxyalkoxyl groups are classified into a fraction (A) and a fraction (B), wherein fraction (A) represents the sum of all molar fractions of substituted hydroxyalkoxyl groups having hydroxyl groups substituted further with methoxyl groups and fraction (B) represents the sum of all molar fractions of unsubstituted hydroxyalkoxyl groups having hydroxyl groups not substituted further with methoxyl groups and wherein the ratio fraction (A)/fraction (B) is at least 0.30. 
     
     
         2 . The solid dispersion of  claim 1  wherein the ratio fraction (A)/fraction (B) in the at least one hydroxyalkyl methylcellulose is from 0.35 to 0.90. 
     
     
         3 . The solid dispersion of  claim 1  wherein the ratio fraction (A)/fraction (B) in the at least one hydroxyalkyl methylcellulose is from 0.40 to 0.80. 
     
     
         4 . The solid dispersion of  claim 1  wherein the ratio fraction (A)/fraction (B) in the at least one hydroxyalkyl methylcellulose is from 0.50 to 0.70. 
     
     
         5 . The solid dispersion of  claim 1  wherein the ratio fraction (A)/fraction (B) in the at least one hydroxyalkyl methylcellulose is from 0.50 to 0.65. 
     
     
         6 . The solid dispersion of  claim 1  wherein the at least one hydroxyalkyl methylcellulose has a DS of from 1.6 to 2.4 and an MS of from 0.08 to 0.90, wherein DS is the average number of hydroxyl groups substituted by methoxyl groups per anhydroglucose unit and MS is the average number of moles of hydroxyalkoxyl groups per anhydroglucose unit. 
     
     
         7 . The solid dispersion of  claim 1  wherein the at least one hydroxyalkyl methylcellulose has a DS of from 1.7 to 2.2 and an MS of from 0.12 to 0.60, wherein DS is the average number of hydroxyl groups substituted by methoxyl groups per anhydroglucose unit and MS is the average number of moles of hydroxyalkoxyl groups per anhydroglucose unit. 
     
     
         8 . The solid dispersion of  claim 1  wherein the at least one hydroxyalkyl methylcellulose has a viscosity of from 1.20 to 100 mPa·s, measured as a 2 wt.-% solution in water at 20° C. 
     
     
         9 . The solid dispersion of  claim 1  wherein the at least one hydroxyalkyl methylcellulose has a viscosity of from 1.20 to 50 mPa·s, measured as a 2 wt.-% solution in water at 20° C. 
     
     
         10 . The solid dispersion of  claim 1  wherein the at least one hydroxyalkyl methylcellulose has a viscosity of from 1.8 to 10 mPa·s, measured as a 2 wt.-% solution in water at 20° C. 
     
     
         11 . The solid dispersion of  claim 1  wherein the ratio fraction (A)/fraction (B) in the at least one hydroxyalkyl methylcellulose is from 0.40 to 0.80, the at least one hydroxyalkyl methylcellulose has a DS of from 1.6 to 2.4 and an MS of from 0.08 to 0.90, and the at least one hydroxyalkyl methylcellulose has a viscosity of from 1.20 to 50 mPa·s, measured as a 2 wt.-% solution in water at 20° C., and wherein DS is the average number of hydroxyl groups substituted by methoxyl groups per anhydroglucose unit and MS is the average number of moles of hydroxyalkoxyl groups per anhydroglucose unit. 
     
     
         12 . The solid dispersion of  claim 11  wherein the at least one hydroxyalkyl methylcellulose has a viscosity of from 1.8 to 10 mPa·s, measured as a 2 wt.-% solution in water at 20° C. 
     
     
         13 . The solid dispersion of  claim 12  wherein the at least one hydroxyalkyl methylcellulose is a hydroxypropyl methylcellulose. 
     
     
         14 . The solid dispersion of  claim 13  wherein the at least one hydroxyalkyl methylcellulose has a DS of from 1.7 to 2.2 and an MS of from 0.12 to 0.60. 
     
     
         15 . The solid dispersion of  claim 1  wherein the at least one hydroxyalkyl methylcellulose is a hydroxypropyl methylcellulose. 
     
     
         16 . The solid dispersion of  claim 1  wherein the solid dispersion has been formulated into pellets, granules, pills, tablets, caplets, capsules, microparticles, fillings of capsules or into a powder, paste, cream, suspension or slurry. 
     
     
         17 . A process for producing the solid dispersion of  claim 1  comprising the steps of:
 (a) providing a liquid composition comprising a liquid diluent, at least one active ingredient and at least one hydroxyalkyl methylcellulose wherein hydroxyalkoxyl groups are classified into a fraction (A) and a fraction (B), wherein fraction (A) represents the sum of all molar fractions of substituted hydroxyalkoxyl groups having hydroxyl groups substituted further with methoxyl groups and fraction (B) represents the sum of all molar fractions of unsubstituted hydroxyalkoxyl groups having hydroxyl groups not substituted further with methoxyl groups and wherein the ratio fraction (A)/fraction (B) is at least 0.30; and 
 (b) removing the liquid diluent from the liquid composition to produce the solid dispersion of  claim 1 . 
 
     
     
         18 . The process of  claim 17  wherein the viscosity of the liquid composition, measured after 18 hours storage at 25° C., is not more than the 10-fold viscosity of the liquid composition at 25° C. that is measured 60 minutes after the liquid composition has been prepared, when the liquid composition comprises 10 weight percent of the at least one hydroxyalkyl methylcellulose, based on the total weight of the liquid composition. 
     
     
         19 . The process of  claim 17  wherein the liquid diluent consists of (i) an organic diluent or (ii) a blend of more than 50 weight percent of an organic diluent and less than 50 weight percent of water, based on the total weight of the organic diluent and the water, and wherein the organic diluent is an alcohol, ether, ketone, acetate or halogenated hydrocarbon. 
     
     
         20 . The process of  claim 19  wherein the organic diluent is an alcohol, ether or ketone. 
     
     
         21 . The process of  claim 20  wherein the organic diluent is an alcohol or ketone. 
     
     
         22 . The process of  claim 17  wherein the liquid diluent is removed from the liquid composition by spray-drying, by casting the liquid composition into a film or a capsule or by applying the liquid composition onto a solid carrier.