Drug delivery system for enhanced bioavailability of hydrophobic active ingredients

Abstract

The present invention provides a drug delivery system for the oral administration of a hydrophobic active ingredient. The active ingredient's post-ingestion dissolution rate and its corresponding bioavailability can be optimized by intimately mixing a micronized hydrophobic drug with suitably sized inert particles to a dispersion that will facilitate desired bioavailability. In a particular embodiment, the hydrophobic active ingredient is fenofibrate. Suitably sized inert particles include microcrystalline cellulose and lactose. Dispersion may be monitored by microscopic visualization.

We claim:  
     
         1 . A drug delivery system comprising a micronized hydrophobic drug and an inert substrate of suitable particle size.  
     
     
         2 . The drug delivery system of  claim 1 , wherein said inert substrate particle is either microcrystalline cellulose or lactose.  
     
     
         3 . The drug delivery system of  claim 1 , wherein said inert substrate particle has a mean particle size range of between about 1 micron and about 500 microns.  
     
     
         4 . The drug delivery system of  claim 3 , wherein said inert substrate particle has a mean particle size of less than about 50 microns.  
     
     
         5 . The drug delivery system of  claim 1 , wherein said micronized hydrophobic drug is fenofibrate or a pharmaceutically acceptable salt thereof.  
     
     
         6 . The drug delivery system of  claim 5 , wherein said inert substrate particle is microcrystalline cellulose or lactose.  
     
     
         7 . The drug delivery system of  claim 1 , wherein the ratio of said inert substrate particle to said hydrophobic drug is from about 0.1 to about 10.0.  
     
     
         8 . The drug delivery system of  claim 7 , wherein the ratio of said inert substrate particle to said hydrophobic drug is from about 0.1 to about 4.0.  
     
     
         9 . The drug delivery system of  claim 8 , wherein the ratio of said inert substrate particle to said hydrophobic drug is from about 0.3 to about 2.0.  
     
     
         10 . The drug delivery system of  claim 7 , wherein said inert substrate particle is microcrystalline cellulose or lactose.  
     
     
         11 . The drug delivery system of  claim 6 , wherein said system is in solid form.  
     
     
         12 . The drug delivery system of  claim 11 , wherein said system is in a liquid form.  
     
     
         13 . The drug delivery system of  claim 11 , wherein said solid drug delivery form is a capsule.  
     
     
         14 . The drug delivery system of  claim 11 , wherein said solid drug delivery form is a tablet.  
     
     
         15 . The drug delivery system of  claim 11 , wherein said solid drug delivery form is a powder.  
     
     
         16 . A method of improving the bioavailability of a hydrophobic drug, comprising the steps of micronizing said hydrophobic drug and intimately mixing it with a suitably sized inert substrate particle until said drug and said particle are adequately dispersed to achieve improved bioavailability.  
     
     
         17 . The method of  claim 16 , wherein said inert substrate is microcrystalline cellulose or lactose.  
     
     
         18 . A method for treating high cholesterol by administering to a patient in need thereof a pharmaceutical composition comprising fenofibrate and microcrystalline cellulose.  
     
     
         19 . A method of preparing a pharmaceutical composition with increased bioavailability from a hydrophobic active ingredient, comprising the steps of: 
 (a) mixing intimately said active ingredient with a suitably sized inert substrate particle;    (b) wet-granulating the mixture in the presence of solution;    (c) drying the wet granules;    (d) milling the dried granules to desirable granule size;    (e) blending the milled granules with a lubricant; and    (f) filling the milled granules into a capsule of suitable size.    
     
     
         20 . The method of  claim 19 , wherein said active ingredient and said particle are mixed until a desired dispersion is achieved.  
     
     
         21 . The method of  claim 19 , further comprising the step of adding a disintegrant.  
     
     
         22 . The method of  claim 19 , further comprising the step of adding a surfactant.  
     
     
         23 . The method of  claim 19 , further comprising the step of adding a binder.  
     
     
         24 . The method of  claim 19  in which said particle is microcrystalline cellulose or lactose.  
     
     
         25 . The method of  claim 20  wherein said desired dispersion yields a drug delivery system in which at least about 36% of fenofibrate dissolves in the first five minutes after being placed in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia 23 at 37° C. in aqueous solution containing a surfactant at 75 rpm.  
     
     
         26 . The drug delivery system of  claim 6 , which after oral administration of a single 67 mg dose of said drug delivery system in adults produces blood plasma levels of fenofibric acid ranging between the minimum and maximum level as seen for Formulation P, 67 mg, over a twenty-four hour period as shown in FIG. 6.  
     
     
         27 . The drug delivery system of  claim 6  which after oral administration of a single 67 mg dose of said drug delivery system in adults maintains post ingestion blood plasma levels of fenofibric acid of: 
 at least about 100 ng/ml at one hour;  
 at least about 350 ng/ml at two hours;  
 at least about 750 ng/ml at four hours;  
 at least about 850 ng/ml at five hours; and  
 at least about 650 ng/ml at twenty-four hours.  
 
     
     
         28 . The drug delivery system of  claim 6  which after oral administration of a single 67 mg dose of said drug delivery system in adults maintains post ingestion blood plasma levels of fenofibric acid of: 
 at least about 200 ng/ml at one hour;  
 at least about 600 ng/ml at two hours;  
 at least about 1000 ng/ml at four hours;  
 at least about 1200 ng/ml at five hours; and  
 at least about 800 ng/ml at twenty-four hours.  
 
     
     
         29 . The drug delivery system of  claim 5 , wherein said fenofibrate exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia 23 at 37° C. in aqueous solution containing a surfactant at 75 rpm: 
 a) from about 40% to 50% of the total fenofibrate is released after five minutes of measurement in said apparatus;  
 b) from about 60% to 75% of the total fenofibrate is released after ten minutes of measurement in said apparatus; and  
 c) no less than about 75% of the total fenofibrate is released after twenty minutes of measurement in said apparatus.  
 
     
     
         30 . The drug delivery system of  claim 5 , wherein at least about 36% of fenofibrate dissolves in the first five minutes after being placed in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia 23 at 37° C. in aqueous solution containing a surfactant at 75 rpm.  
     
     
         31 . The drug delivery system of  claim 5 , wherein said system contains 67 mg fenofibrate.  
     
     
         32 . The drug delivery system of  claim 31 , wherein said fenofibrate exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia 23 at 37° C. in aqueous solution containing a surfactant at 75 rpm: 
 a) from about 40% to 50% of the total fenofibrate is released after five minutes of measurement in said apparatus;  
 b) from about 64% to 75% of the total fenofibrate is released after ten minutes of measurement in said apparatus; and  
 c) no less than about 80% of the total fenofibrate is released after twenty minutes of measurement in said apparatus.  
 
     
     
         33 . The drug delivery system of  claim 5 , wherein said system contains 200 mg fenofibrate.  
     
     
         34 . The drug delivery system of  claim 33 , wherein said fenofibrate exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia 23 at 370° C. in aqueous solution containing a surfactant at 75 rpm: 
 a) from about 20% to 50% of the total fenofibrate is released after five minutes of measurement in said apparatus;  
 b) from about 50% to 64% of the total fenofibrate is released after ten minutes of measurement in said apparatus; and  
 c) no less than about 64% of the total fenofibrate is released after twenty minutes of measurement in said apparatus.