Sustained release compositions of drugs

Abstract

A sustained release pharmaceutical composition has been developed. The composition resists dose dumping when broken, crushed or chewed, which enhances the safety of the dosage form should it be accidentally or intentionally physically compromised. In the preferred embodiment, a drug is modified to increase its lipophilicity. In preferred embodiments the modified drug is homogeneously dispersed within microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments the drug containing microparticles coated with one or more coating layers. The sustained release composition retards the release of drug, even if the physical integrity of the formulation is compromised (for example, by chewing or crushing) and the resulting material is placed in 0.1N HCl. However, when administered as directed, the drug is slowly released from the composition as the composition is broken down or dissolved gradually within the GI tract by a combination of diffusion, surfactant action of bile acids, mechanical erosion, and in some embodiments, enzymatic degradation.

1 . An orally administrable sustained release pharmaceutical composition comprising a therapeutically effective amount of microparticles consisting of
 (a) a lipophilic drug or lipophilic derivative of a drug other than a drug prone to abuse and   (b) one or more carrier materials selected from the group consisting of fats, fatty substances, waxes, wax-like substances and mixtures thereof   wherein the drug is dispersed within the one or more carrier materials, and the release of a portion of incorporated drug is retarded when the physical integrity of the composition is compromised and the compromised composition is exposed to 0.1N HCl.   
     
     
         2 . An orally administrable sustained release pharmaceutical composition comprising a therapeutically effective amount of microparticles consisting of a lipophilic derivative of a drug other than a drug prone to abuse dispersed within one or more carrier materials which are either slowly soluble in water or insoluble in water, wherein the release of a portion of incorporated drug is retarded when the physical integrity of the composition is compromised and the compromised composition is exposed to 0.1N HCl. 
     
     
         3 . The composition of  claim 1  or  2 , wherein the portion of the drug released immediately when the physical integrity of the composition is compromised is less than 80% of the total amount of drug incorporated into formulation. 
     
     
         4 . The composition of  claim 1  or  2 , wherein the lipophilic derivative of a drug is a free base or a free acid of the drug. 
     
     
         5 . The composition of  claim 1  or  2 , wherein the lipophilic derivative of a drug is a salt comprising the ionized drug and a counter-ion. 
     
     
         6 . The composition of  claim 1  or  2 , wherein the lipophilic derivative of a drug is an ester or amide formed between the drug and a fatty acid. 
     
     
         7 . The composition of  claim 5  wherein the counter-ion is selected from the group consisting of stearic acid, palmitic acid, myristic acid, and mixtures thereof. 
     
     
         8 . The composition of  claim 5  wherein the counter-ion is selected from the group consisting of methacrylic acid-methyl methacrylate copolymers, acrylic acid polymers, crosslinked acrylic acid polymers and carboxymethylcellulose. 
     
     
         9 . The composition of  claim 2  wherein the microparticles consist of drug dispersed in a material selected from the group consisting of fats, fatty substances, waxes, wax-like substances and mixtures thereof. 
     
     
         10 . The composition of  claim 1  or  2  comprising one or more carrier materials selected from the group consisting of stearic acid, palmitic acid, and mixtures thereof. 
     
     
         11 . The composition of  claim 1  or  2  comprising one or more carrier materials selected from the group consisting of beeswax, carnauba wax, hydrogenated oil, and mixtures thereof. 
     
     
         12 . The composition of  claim 1  or  2  wherein the carrier materials are selected from the group consisting of myristic acid, palmitic acid, stearic acid, carnauba wax, beeswax and mixtures thereof. 
     
     
         13 . The composition of  claim 2  wherein the microparticles consist of a drug dispersed in a carrier material selected from the group consisting of naturally water insoluble proteins, naturally water insoluble polysaccharides, naturally water insoluble lipids and phospholipids, cross-linked water soluble proteins, cross-linked water soluble polysaccharides and combinations thereof. 
     
     
         14 . The composition of  claim 1  or  2  wherein the individual microparticles are coated with one or more independent layers. 
     
     
         15 . The composition of  claim 14  wherein the coated layer(s) comprise a material selected from the group consisting of naturally water insoluble proteins, naturally water insoluble polysaccharides, naturally water insoluble lipids and phospholipids, cross-linked proteins, cross-linked polysaccharides, mixtures of waxes and fatty substances, and combinations thereof. 
     
     
         16 . The composition of  claim 15  wherein the coated layer(s) comprise a material selected from the group of pH dependent coatings, water insoluble diffusion barrier coatings, water soluble coatings and combinations thereof. 
     
     
         17 . The composition of  claim 1  or  2  wherein the lipophilic derivative is dissolved in the carrier material in a molten state to result in a uniform dispersion within the carrier material. 
     
     
         18 . The composition of  claim 1  or  2  wherein the lipophilic derivative is dissolved in a co-solvent along with a carrier material to result in a uniform dispersion within the carrier material. 
     
     
         19 . The composition of  claim 1  or  2 , wherein the individual microparticles are further formulated into a tablet or capsule for oral administration. 
     
     
         20 . The composition of  claim 19 , wherein the individual microparticles contain one or more drugs. 
     
     
         21 . The composition of  claim 19 , wherein the tablet or capsule further comprises one or more drugs formulated as an immediate release dose, a sustained release dose, a delayed release dose, or a combination thereof.