Pharmaceutical composition containing fenofibrate and method for the preparation thereof

Abstract

A pharmaceutical composition containing fenofibrate, a surfactant and a binding cellulose derivative, as solubilizing adjuvant, preferably hydroxypropylmethylcellulose reduces food effect. The cellulose derivative represents less than 20 wt. % of the composition. The association of fenofibrate with a binding cellulose derivative, as solubilizing adjuvant and a surfactant enhances the bioavailability of fenofibrate. Also provided is a method for preparing said composition without organic solvent.

1 . A pharmaceutical composition in the form of granules comprising:
 (a) a neutral core;   (b) an active layer surrounding the neutral core; and   (c) a hydrosoluble layer surrounding the active layer;   
       wherein said active layer comprises fenofibrate, a surfactant and a binding cellulose derivative; and wherein the fenofibrate has a mean particle size of less than about 15 microns. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the mean particle size of the fenofibrate is from 6.2 microns to 7.6 microns. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the dose of fenofibrate is from about 50 mg to about 300 mg. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the dose of fenofibrate is from about 130 mg to about 200 mg. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the dose of fenofibrate is 130 mg. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the binding cellulose derivative is hydroxypropylmethyl cellulose. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein said hydroxypropylmethyl cellulose is present in an amount from about 2% by weight to about 20% by weight based on the combined weight of the neutral core and the active layer. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein said hydroxypropylmethyl cellulose has an apparent viscosity of between about 2.4 cP and about 18 cP. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, polyoxyethylene 20 sorbitan monooleate, sorbitan monolaurate, polyoxyethylene sorbitan monolaurate, and sucrose stearate. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said surfactant is present in an amount from about 1% by weight to about 10% by weight relative to the weight of fenofibrate. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein said outer hydrosoluble layer comprises a hydrosoluble binder selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, and mixtures thereof. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein said outer hydrosoluble layer is present in an amount from about 1% by weight to about 15% by weight based on the total weight of the composition. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein said outer hydrosoluble layer is present in an amount from about 2% by weight to about 4% by weight based on the total weight of the composition. 
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein the hydrosoluble binder is hydroxypropylmethyl cellulose. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein said hydroxypropylmethyl cellulose in said outer hydrosoluble layer has an apparent viscosity of between about 3 cP and about 15 cP. 
     
     
         16 . The pharmaceutical composition of  claim 11 , wherein said outer hydrosoluble layer further comprises at least one excipient. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein said excipient is a lubricant. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein said excipient is selected from the group consisting of lactose, α-(trimethylsilyl)-ω-methylpoly[oxy(dimethylsilylene)], a mixture of α-(trimethylsilyl)-ω-methylpoly[oxy(dimethylsilylene)] with silicon dioxide, colloidal silicon dioxide, and talc. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein said lubricant is talc present in an amount from about 1% by weight to about 10% by weight based on the total weight of the composition. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein the mass ratio of said hydrosoluble binder to talc is from about 1/1 to about 5/1. 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the neutral core comprises sugar, the binding cellulose derivative and the hydrosoluble layer comprise hydroxypropylmethyl cellulose, the surfactant is sodium lauryl sulfate, and the formulation further comprises dimethicone, simethicone and talc. 
     
     
         22 . The pharmaceutical composition as in  claim 1 , wherein said composition is contained in a capsule. 
     
     
         23 . The pharmaceutical composition as in  claim 1 , wherein the granules are in tablet form. 
     
     
         24 . The pharmaceutical composition of  claim 1 , wherein the fenofibric acid C max  achieved when administered to a fed human patient is no more than about 100% greater than the fenofibric acid C max  achieved when administered to a fasted human patient. 
     
     
         25 . The pharmaceutical composition of  claim 1 , wherein the fenofibric acid C max  achieved when administered to a fed human patient is no more than about 75% greater than the fenofibric acid C max  achieved when administered to a fasted human patient. 
     
     
         26 . A pharmaceutical composition in unit dose form comprising granules of:
 (a) a neutral core;   (b) an active layer surrounding the neutral core; and   (c) a hydrosoluble layer surrounding the active layer;   
       wherein said active layer comprises: fenofibrate of mean particle size less than about 15 microns, a surfactant, and a binding cellulose derivative; and about 50 mg to about 300 mg of said fenofibrate per unit dose. 
     
     
         27 . The pharmaceutical composition of  claim 24 , wherein the unit dose of fenofibrate is about 100 mg to about 200 mg.Propo 
     
     
         28 . The pharmaceutical composition of  claim 24 , wherein the unit dose of fenofibrate is about 120 mg to about 150 mg. 
     
     
         29 . The pharmaceutical composition of  claim 24 , compounded in unit dosage form in a gelatin capsule, and wherein the neutral core comprises sugar, the binding cellulose derivative and hydrosoluble layer comprise hydroxypropylmethyl cellulose, the surfactant is sodium lauryl sulfate, and the formulation further comprises dimethicone, simethicone and talc. 
     
     
         30 . A pharmaceutical composition in the form of granules comprising:
 (a) a neutral core;   (b) an active layer surrounding the neutral core; and   (c) a hydrosoluble layer surrounding the active layer;   
       wherein said active layer comprises micronized fenofibrate, a surfactant and a binding cellulose derivative; and wherein the binding cellulose derivative is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, methylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the fenofibric acid AUC inf  achieved when administered to a fed human patient is no more than about 25% greater than the fenofibric acid AUC inf  achieved when administered to a fasted human patient. 
     
     
         32 . The pharmaceutical composition of  claim 1 , wherein the fenofibric acid T max  achieved when administered to a fed human patient is about 5 hours, or less, and wherein the fenofibric acid T max  achieved when administered to a fasted human patient is about 5 hours, or less. 
     
     
         33 . A pharmaceutical composition in the form of granules comprising:
 an active layer and hydrosoluble layer surrounding said active layer, wherein said active layer comprises micronized fenofibrate, a surfactant and a binding cellulose derivative; and wherein the binding cellulose derivative is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, methylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.   
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the fenofibric acid C max  and AUC inf  achieved when administered to a fed human patient are no more than about 100% greater and about 25% greater than the fenofibric acid C max  and AUC inf  achieved when administered to a fasted human patient, respectively, and wherein the fenofibric acid T max  achieved when administered to a fed or fasted human patient is from about 4 hours to about 5 hours.