Oral Tablet Formulation Consisting Of Fixed Combination Of Rosuvastatin And Ezetimibe For Treatment Of Hyperlipidemia And Cardiovascular Diseases

Abstract

The present invention is an orally consumed fixed combination formulation of both rosuvastatin and ezetimibe in one tablet that is expected to have the same Area Under Curve as two active ingredients taken together individually orally, and pharmaceutically acceptable additives suitable for the preparation. In preferred embodiments of this invention, the rosuvastatin is in the form of rosuvastatin calcium and the pharmaceutically acceptable additives are selected from diluents, disintegrants, glidants, lubricants, colorants and combinations thereof.

What is claimed is: 
     
         1 . A solid dosage form of rosuvastatin and ezetimibe combined in one bilayer tablet in weight ratio of 0.5:1, 1:1 or 2:1, wherein the tablet when orally administered to healthy individuals is bioequivalent to corresponding dosages of rosuvastatin and ezetimibe taken together individually orally; and
 the tablet is a stable composition of rosuvastatin and ezetimibe comprising less than 0.5% of ezetimibe related impurities after 6 weeks of storage at 40° C. and 75% relative humidity, less than 0.5% of rosuvastatin related lactone impurities and less than 0.5% of rosuvastatin related keto impurities after 6 weeks of storage at 40° C. and 75% relative humidity, and wherein   a top layer of the tablet comprises rosuvastatin, pharmaceutically acceptable excipients 1-15% of the weight of the top layer, dicalcium phosphate 0.5-10% of the weight of the top layer, microcrystalline cellulose 20-90% of the weight of the top layer, 2-30% crospovidone of the weight of the top layer, and pharmaceutically acceptable lubricants 0.1-2% of the weight of the top layer; and   a bottom layer of the tablet comprises ezetimibe, pharmaceutically acceptable excipients 2-20% of the weight of the bottom layer, lactose 20-90% of the weight of the bottom layer, binders 0.5-10% of the bottom layer, and magnesium stearate 0.2-5% of the bottom layer.   
     
     
         2 . The solid dosage form of  claim 1 , wherein the rosuvastatin dosage ranges from 2.5 mg to 40 mg, and ezetimibe dosage ranges from 5 mg to 20 mg. 
     
     
         3 . The solid dosage form of  claim 1 , comprising no ezetimibe related impurities after 6 weeks at 40° C. and 75% relative humidity, less than 0.2% of rosuvastatin related lactone impurities and less than 0.2% of rosuvastatin related keto impurities after 6 weeks of storage at 40° C. and 75% relative humidity. 
     
     
         4 . The solid dosage form of  claim 1 , wherein the rosuvastatin comprising top layer additionally contains butylated hydroxy anisole as an antioxidant in an amount of 0.05-2% of the weight of the top layer and fumed silica as a dispersion agent in an amount of 1-10% of the weight of the top layer. 
     
     
         5 . A method of making a solid oral dosage form of  claim 1 , the method comprising the steps of:
 a) blending rosuvastatin calcium with pre-gelatinized starch, calcium hydrogen phosphate dihydrate, microcrystalline cellulose an crospovidone to provide a blend, and passing the blend through sieve and lubricating the blend with lubricant to create a rosuvastatin layer blend;   b) mixing ezetimibe with a wetting agent and a disperse material in isopropyl alcohol and dichlormethane mixture;   c) absorbing the dispersion of step b) on lactose, and mixing thoroughly,   d) air drying the dispersion of step c) passing through a sieve, mixing with croscarmellose sodium, and blending;   e) granulating the mix of step d) with polyvinylpyrrolidone solution and drying to obtain the ezetimibe granules; and   
       creating bilayer tablet by compressing the blend of step a) and the granules of step e) in a bilayer compression machine, followed by film coating. 
     
     
         6 . The method of  claim 5 , wherein the lubricant in step a) is sodium stearyl fumarate and the wetting agent in step b) is sodium lauryl sulphate. 
     
     
         7 . A method of treating hyperlipidemia, cardiovascular diseases, congestive heart failure, myocardial infarction, or atherosclerosis said method comprising administering orally the solid dosage form of  claim 1  to a patient in need of such treatment.