Pharmaceutical formulation

Abstract

The instant invention provides a pharmaceutical composition comprised of a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor, one or more anti-oxidants, microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate and lactose. The composition need not contain ascorbic acid in order to obtain desirable stability.

1 - 40 . (canceled)  
     
     
         41 . A pharmaceutical composition comprised of from 1% to 20% by weight of a cholesterol absorption inhibitor; from 1% to 80% by weight of simvastatin; from 0.01% to 2% by weight of at least one antioxidant agent; and citric acid up to a maximum of 10% by weight, provided that the composition is not comprised of ascorbic acid.  
     
     
         42 . The pharmaceutical composition of  claim 41  wherein the antioxidant agent is selected from the group consisting of butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT), propyl gallate, edetate disodium, calcium metabisulphite and combinations thereof.  
     
     
         43 . The pharmaceutical composition of  claim 41  wherein the weight % of citric acid is from 0.1% to 1.25%.  
     
     
         44 . The pharmaceutical composition of  claim 43  wherein the weight % of citric acid is about 0.25%.  
     
     
         45 . The pharmaceutical composition of  claim 41  wherein the antioxidant agent is selected from BHA, propyl gallate and a combination thereof.  
     
     
         46 . The pharmaceutical composition of  claim 45  wherein the antioxidant agent is a combination of BHA and propyl gallate.  
     
     
         47 . The pharmaceutical composition of  claim 46  wherein the weight % of BHA is from 0.01% to 0.05%.  
     
     
         48 . The pharmaceutical composition of  claim 47  comprised of about 0.02% of BHA.  
     
     
         49 . The pharmaceutical composition of  claim 47  comprised of from 0.001% to 0.05% by weight of propyl gallate.  
     
     
         50 . The pharmaceutical composition of  claim 49  comprised of about 0.005% by weight of propyl gallate.  
     
     
         51 . The pharmaceutical composition of  claim 49  further comprised of from 5% to 20% by weight of microcrystalline cellulose; from 1% to 4% by weight of hydroxypropyl methylcellulose; and from 0.5% to 2% by weight of magnesium stearate.  
     
     
         52 . The pharmaceutical composition of  claim 49  comprised of 10% or less of croscarmellose sodium.  
     
     
         53 . The pharmaceutical composition of  claim 52  comprised of from 2% to 4% by weight of croscarmellose sodium.  
     
     
         54 . The pharmaceutical composition of  claim 41  in the form of a tablet which does not have a film coating.  
     
     
         55 . The pharmaceutical composition of  claim 54  that is not comprised of pregelatinized starch.  
     
     
         56 . The pharmaceutical composition of  claim 41 , comprised of from 1% to 80% by weight of simvastatin; from 0.01% to 2% by weight of BHA; and from 0.1% to 1.25% by weight of citric acid.  
     
     
         57 . The pharmaceutical composition of  claim 56  comprised of from 1% to 20% of simvastatin.  
     
     
         58 . The pharmaceutical composition of  claim 57  comprised of from 5% to 10% of simvastatin.  
     
     
         59 . The pharmaceutical composition of  claim 56  comprised of 0.01% to 0.05% of BHA.  
     
     
         60 . The pharmaceutical composition of  claim 59  comprised of about 0.02% of BHA.  
     
     
         61 . The pharmaceutical composition of  claim 56  further comprised of 0.2% or less by weight of propyl gallate.  
     
     
         62 . The pharmaceutical composition of  claim 61  comprised of from 0.001% to 0.05% by weight of propyl gallate.  
     
     
         63 . The pharmaceutical composition of  claim 62  comprised of about 0.005% by weight of propyl gallate.  
     
     
         64 . The pharmaceutical composition of  claim 56  further comprised of from 5% to 20% by weight of microcrystalline cellulose; from 1% to 4% by weight of hydroxypropyl methylcellulose; and from 0.5% to 2% by weight of magnesium stearate.  
     
     
         65 . The pharmaceutical composition of  claim 56  further comprised of 10% or less by weight of croscarmellose sodium.  
     
     
         66 . The pharmaceutical composition of  claim 65  comprised of from 2% to 4% by weight of croscarmellose sodium.  
     
     
         67 . The pharmaceutical composition of  claim 56  wherein the composition is a tablet and provided that the tablet does not have a film coating.  
     
     
         68 . The pharmaceutical composition of  claim 67  provided that it is not comprised of pregelatinized starch.  
     
     
         69 . A pharmaceutical composition comprised of a mixture of ezetimibe granules and simvastatin granules, wherein the ezetimibe granules and the simvastatin granules are each comprised of lactose, microcrystalline cellulose, croscarmellose sodium, povidone, BHA, ascorbic acid, and citric acid.  
     
     
         70 . The pharmaceutical composition of  claim 69 , wherein the mixture is in tablet form.  
     
     
         71 . The pharmaceutical composition of  claim 70 , comprised of magnesium stearate as lubricant/binder for the granules.  
     
     
         72 . The pharmaceutical composition of  claim 71 , 
 wherein the tablets are comprised of 0.75 mg/tablet magnesium stearate,    wherein the ezetimibe granules are comprised of: 
 10.0 mg/tablet ezetimibe;  
 53.74 mg/tablet lactose;  
 20.0 mg/tablet microcrystalline cellulose;  
 8.0 mg/tablet croscarmellose sodium;  
 4.0 mg/tablet povidone;  
 0.01 mg/tablet BHA;  
 2.5 mg/tablet ascorbic acid; and  
 1.25 mg/tablet citric acid;  
   wherein the simvastatin granules are comprised of: 
 10.0 mg/tablet simvastatin (0.025% BHA);  
 21.87 mg/tablet lactose;  
 10.0 mg/tablet microcrystalline cellulose;  
 4.0 mg/tablet croscarmellose sodium;  
 2.0 mg/tablet povidone;  
 0.005 mg/tablet BHA;  
 1.25 mg/tablet ascorbic acid; and  
 0.625 mg/tablet citric acid.  
   
     
     
         73 . A composition according to  claim 41  for use in treating a condition selected from hyperlipidemia, hypercholesterolemia and atherosclerotic disease.  
     
     
         74 . A composition according to  claim 41  for use in preventing atherosclerotic disease or myocardial infarction.  
     
     
         75 . A composition according to  claim 69  for use in treating a condition selected from hyperlipidemia, hypercholesterolemia and atherosclerotic disease.  
     
     
         76 . A composition according to according to  claim 69  for use in preventing atherosclerotic disease or myocardial infarction.