Insoluble drug particle compositions with improved fasted-fed effects

#The present invention relates to novel pharmaceutical compositions containing small particles of phospholipid-stabilized fenofibrate that provide reduced in vivo variability in the bioavailability of the drug active species among fed and fasted patients when administered orally. In a preferred aspect, the present invention relates to an orally administered pharmaceutical composition comprising microparticles of solid fenofibrate that are prepared in the presence of and stabilized by a phospholipid surface active substance, wherein a therapeutically effective amount of the composition provides a quantity of fenofibrate active species to a fasted human patient in need of treatment by fenofibrate that is greater than 80% of the quantity of fenofibrate active species provided by the same amount to the same patient when the patient is fed at least 1000 calories 50% of which are from fat.

#The present invention also relates to a method of treatment of dislipidemia and dislipoproteinemia in a mammal which comprises administering to the mammal a therapeutically effective oral dosage form comprising microparticles of a solid poorly water soluble fibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides into the blood of the mammal in a fasted state a therapeutically effective amount of the fibrate active species that is at least 90% of the AUC amount of the fibrate active species provided by the dosage form into the blood of the patient in a fed state.

#In a preferred aspect, the present invention relates to a method of treatment of dislipidemia and dislipoproteinemia in a human patient which comprises administering to the patient a therapeutically effective oral dosage form comprising microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides into the blood of the mammal in a fasted state a therapeutically effective amount of the fenofibrate active species that is at least 90% of the AUC amount of the fenofibrate active species provided by the dosage form into the blood of the patient in a fed state.

#FIG. 1 is an optical microscopic comparison of microfluidized fenofibrate with micronized fenofibrate and fenofibrate compositions prepared in the presence of starch.

#FIG. 2 is a comparison of the oral bioavailability of microparticles of fenofibrate prepared by microfluidization in the presence of a phospholipid stabilizing agent versus the oral bioavailability of micronized fenofibrate under fasting, low fat fed, and high fat fed conditions.

#FIG. 3A is a graph of fenofibric acid mean plasma concentration (in ng/ml) versus time (in hours) found after oral administration of a 160 mg fenofibrate-containing tablet prepared according to this invention compared to that of a commercially available 200 mg Tricor® capsule each taken proximal to ingestion of a low fat meal (n=24).

#The present invention provides a method of treating dislipidemia and dislipoproteinemia in a mammal which method comprises administering to said mammal a therapeutically effective oral dosage form comprising microparticles of a solid fibrate that are stabilized by a phospholipid surface active substance wherein said dosage form provides into the blood of said patient in a fasted state a therapeutically effective amount of said fibrate that is at least 90% of the AUC amount of said fibrate provided by said dosage form into the blood of said patient in a fed state. AUC refers to area under the curve.

#In a preferred aspect, the present invention provides a method of treating dislipidemia and dislipoproteinemia in a human patient which method comprises administering to said patient a therapeutically effective oral dosage form comprising microparticles of a solid fenofibrate that are stabilized by a phospholipid surface active substance wherein said dosage form provides into the blood of said patient in a fasted state a therapeutically effective amount of fenofibrate active species that is at least 90% of the AUC amount of said fenofibrate active species provided by said dosage form into the blood of said patient in a fed state.

#In another aspect the present invention also provides an orally administered pharmaceutical composition comprising microparticles of solid fibrate that are stabilized by a phospholipid surface active substance, wherein said microparticles are prepared in the presence of said phospholipid surface active substance, and wherein a therapeutically effective amount of said composition provides a quantity of fibrate active species to a fasted human patient in need of treatment by said fibrate that is greater than 90% of the quantity of said fibrate active species provided by said amount to said patient when fed a high fat meal.