Method Of Manufacturing Fine Particles Suitable For Orally Disintegrating Pharmaceutical Dosage Forms

Abstract

Disclosed are methods of making oral pharmaceutical compositions that contain substantially crush-resistant drug-containing microparticles. The microparticles may contain an active pharmaceutical agent, a polymer and a plasticizer. The microparticles may be uncoated (so as to impart an immediate release profile) or coated so as to impart an extended-release (ER), delayed release (DR) or delayed-extended release (DER) profile. One or more of the populations of microparticles may be coated with a taste-masking composition. The methods may produce oral compositions such as orally disintegrating tablets that contain one or more these types of microparticles in order to further customize the release profile. Also disclosed are the oral compositions, per se, and methods of using same for their intended purposes.

1 . An oral pharmaceutical composition comprising immediate release microparticles comprising a therapeutically effective amount of an active pharmaceutical agent, a first plasticizer, and a first cationic pH-dependent polymer,
 wherein the first plasticizer is present in an amount that is sufficient to make the immediate release microparticles substantially crush resistant.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the first cationic pH-dependent polymer is present in an amount of between about 10% w/w and about 99% w/w, based on the total weight of the immediate release particles. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the first plasticizer is present in an amount of between 1% w/w and about 40% w/w, based on the total weight of the first cationic pH-dependent polymer. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the immediate release microparticles further comprise a taste-masking coating comprising a second cationic pH-dependent polymer and a second plasticizer. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the immediate release microparticles further comprise an extended release coating to provide extended release microparticles,
 wherein the extended release coating comprises an extended release polymer and a third plasticizer,   wherein the extended release polymer comprises a polyvinyl acetate/polyvinyl pyrolidone mixture; cellulose acetate; cellulose acetate butyrate; ethyl cellulose; or a copolymer of ethyl acrylate, methyl methacrylate, and a low content of methacrylic acid ester with a quaternary ammonium group, and   wherein the third plasticizer is present in an amount that is sufficient to make the extended release coating substantially crush resistant.   
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the extended release polymer is present in the extended release coating in an amount of between about 5% w/w and about 60% w/w, based on the coating weight gain. 
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein the extended release coating contains the third plasticizer in an amount of between about 5% w/w and about 15% w/w, based on the weight of the extended release polymer. 
     
     
         8 . The pharmaceutical composition of  claim 5 , wherein the extended release microparticles further comprise a taste-masking coating comprising a third cationic pH-dependent polymer and a fourth plasticizer. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the immediate release microparticles further comprise a delayed release coating to provide delayed release microparticles,
 wherein the delayed release coating comprises a delayed release polymer and a fifth plasticizer,   wherein the delayed release polymer comprises hydroxypropyl methyl cellulose phthalate; hypromellose acetate succinate; cellulose acetate phthalate; polyvinyl acetate phthalate; a copolymer of ethyl acrylate and methacrylic acid; or a copolymer of methyl methacrylate and methacrylic acid, and   wherein the fifth plasticizer is present in an amount that is sufficient to make the delayed release coating substantially crush resistant.   
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the delayed release polymer is present in the delayed release coating in an amount of between about 10% w/w and about 60% w/w, based on the coating weight gain. 
     
     
         11 . The pharmaceutical composition of  claim 9 , wherein the fifth plasticizer is present in an amount of between 2% w/w and 30% w/w, based on the weight of the polymer in the delayed release coating composition. 
     
     
         12 . The pharmaceutical composition of  claim 5 , wherein the extended release microparticles further comprise a delayed release coating to provide delayed release/extended release microparticles,
 wherein the delayed release coating comprises a delayed release polymer and a sixth plasticizer, and   wherein the delayed release polymer comprises hydroxypropyl methyl cellulose phthalate; hypromellose acetate succinate; cellulose acetate phthalate; polyvinyl acetate phthalate; a copolymer of ethyl acrylate and methacrylic acid; or a copolymer of methyl methacrylate and methacrylic acid.