Pravastatin pharmaceutical formulations and methods of their use

Abstract

The present invention relates to formulations comprising a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, and methods of their use. The present formulations and methods are designed to release little or no pravastatin in the stomach but release a therapeutic amount of pravastatin in the small intestine, thereby limiting systemic exposure of the body to pravastatin and maximizing hepatic-specific absorption of the drug. The formulations and methods of the present invention are particularly useful for treating and/or preventing conditions that are benefited by decreasing levels of lipids and/or cholesterol in the body.

1 . A method of treating hypercholesterolemia comprising administering, to a subject in need of such treatment, a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, wherein the formulation inhibits release of the pravastatin in the stomach of the subject, and releases a therapeutic amount of pravastatin in the small intestine of the subject over a period of greater than about 2 hours.  
   
   
       2 . The method according to  claim 1 , wherein the formulation releases greater than about 80% of its pravastatin content in the small intestine.  
   
   
       3 . The method according to  claim 2 , wherein the formulation releases greater than 85% of its pravastatin content in the small intestine.  
   
   
       4 . The method according to  claim 2 , wherein the formulation releases greater than 80% of its pravastatin content in the small intestine over a period of from about 3 hours to about 6 hours.  
   
   
       5 . The method according to  claim 4 , wherein the formulation releases greater than 80% of its pravastatin content in the small intestine over a period of from about 4 hours to about 5 hours.  
   
   
       6 . The method according to  claim 1 , wherein the administration achieves a relative systemic bioavailability, as compared to a conventional rapid release formulation, of less than about 90%.  
   
   
       7 . The method according to  claim 6 , wherein the administration achieves a relative systemic bioavailability, as compared to a conventional rapid release formulation, of less than about 80%.  
   
   
       8 . The method according to  claim 1 , wherein the administration achieves a relative Cmax, as compared to a conventional rapid release formulation, of less than about 80%.  
   
   
       9 . The method according to  claim 8 , wherein the administration achieves a relative Cmax, as compared to a conventional rapid release formulation, of less than about 70%.  
   
   
       10 . The method according to  claim 1 , wherein the formulation is administered to the subject to treat one or more cardiovascular diseases that are secondary to the hypercholesterolemia.  
   
   
       11 . The method according to  claim 2 , wherein the administration reduces the low density lipoprotein-cholesterol (LDL-C) levels in a subject following administration of the formulation.  
   
   
       12 . The method according to  claim 2 , wherein the administration increases the high density lipoprotein-cholesterol (HDL-C) levels in a subject following administration of the formulation.  
   
   
       13 . A modified-release pravastatin formulation comprising pravastatin, or a pharmaceutically acceptable salt thereof, and a pH-dependent coating, which formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1 N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following: 
 2 hours, in HCl media: less than or equal to about 20%;    2 hours, in pH 6.8: greater than or equal to about 20%;    4 hours, in pH 6.8: greater than or equal to about 40%;    6 hours, in pH 6.8: greater than or equal to about 60%; and    12 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       14 . The modified-release pravastatin formulation according to  claim 13 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1 N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following: 
 2 hours, in HCl media: less than or equal to about 20%;    1 hour, in pH 6.8: 0 to about 50%;    2 hours, in pH 6.8: about 20% to about 80%;    4 hours, in pH 6.8: greater than or equal to about 50%;    6 hours, in pH 6.8: greater than or equal to about 70%; and    12 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       15 . The modified-release pravastatin formulation according to  claim 14 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1 N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following: 
 2 hours, in HCl media: less than or equal to about 10%;    1 hour, in pH 6.8: about 10 to about 40%;    2 hours, in pH 6.8: about 30 to about 70%;    3 hours, in pH 6.8: greater than or equal to about 45%;    4 hours, in pH 6.8: greater than or equal to about 60%;    5 hours, in pH 6.8: greater than or equal to about 75%; and    6 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       16 . The modified-release pravastatin formulation according to  claim 15 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1 N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following: 
 2 hours, in HCl media: less than or equal to about 5%;    1 hour, in pH 6.8: about 10 to about 40%;    2 hours, in pH 6.8: about 30 to about 70%;    3 hours, in pH 6.8: greater than or equal to about 45%;    4 hours, in pH 6.8: greater than or equal to about 60%; and    5 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       17 . A modified-release pravastatin formulation comprising pravastatin, or a pharmaceutically acceptable salt thereof, and a pH-dependent coating, which formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 2 hours, in pH 6.8: greater than or equal to about 20%;    4 hours, in pH 6.8: greater than or equal to about 40%;    6 hours, in pH 6.8: greater than or equal to about 60%; and    12 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       18 . The modified-release formulation according to  claim 17 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 1 hour, in pH 6.8: about 0 to about 50%;    2 hours, in pH 6.8: about 20 to about 80%;    4 hours, in pH 6.8: greater than or equal to about 50%;    6 hours, in pH 6.8: greater than or equal to about 70%; and    12 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       19 . The modified-release formulation according to  claim 18 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 1 hour, in pH 6.8: about 10 to about 40%;    2 hours, in pH 6.8: about 30 to about 70%;    3 hours, in pH 6.8: greater than or equal to about 45%;    4 hours, in pH 6.8: greater than or equal to about 60%;    5 hours, in pH 6.8: greater than or equal to about 75%; and    6 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       20 . The modified-release formulation according to  claim 19 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 1 hour, in pH 6.8: about 10 to about 40%;    2 hours, in pH 6.8: about 30 to about 70%;    3 hours, in pH 6.8: greater than or equal to about 45%;    4 hours, in pH 6.8: greater than or equal to about 60%; and    5 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       21 . A modified-release pravastatin formulation comprising pravastatin, or a pharmaceutically acceptable salt thereof, and a pH-independent coating, which formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 1 hour, in pH 6.8: less than or equal to about 20%;    3 hours, in pH 6.8: greater than or equal to about 20%;    5 hours, in pH 6.8: greater than or equal to about 40%;    7 hours, in pH 6.8: greater than or equal to about 60%; and    12 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       22 . The modified-release formulation according to  claim 21 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 1 hour, in pH 6.8: less than or equal to about 20%;    2 hours, in pH 6.8: about 0 to about 50%;    3 hours, in pH 6.8: about 20 to about 80%;    5 hours, in pH 6.8: greater than or equal to about 50%;    7 hours, in pH 6.8: greater than or equal to about 70%; and    12 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       23 . The modified-release formulation according to  claim 22 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 1 hour, in pH 6.8: less than or equal to about 10%;    2 hours, in pH 6.8: about 10 to about 40%;    3 hours, in pH 6.8: about 30 to about 70%;    4 hours, in pH 6.8: greater than or equal to about 45%;    5 hours, in pH 6.8: greater than or equal to about 60%;    6 hours, in pH 6.8: greater than or equal to about 75%; and    7 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       24 . The modified-release formulation according to  claim 23 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 1 hour, in pH 6.8: less than or equal to about 5%;    2 hours, in pH 6.8: about 10 to about 40%;    3 hours, in pH 6.8: about 30 to about 70%;    4 hours, in pH 6.8: greater than or equal to about 45%;    5 hours, in pH 6.8: greater than or equal to about 60%; and    6 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       25 . A method for treating one or more cardiovascular diseases that are not secondary to hypercholesterolemia comprising administering, to a subject in need of such treatment, a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutically formulation, wherein the formulation inhibits release of the pravastatin in the stomach of the subject, and releases a therapeutic amount of pravastatin in the small intestine of the subject over a period of greater than about 2 hours.  
   
   
       26 . A method for increasing the hepatic availability of pravastatin comprising administering to a subject a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation exhibiting a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1 N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following: 
 2 hours, in HCl media: less than or equal to about 10%    1 hour, in pH 6.8: about 10 to about 40%;    2 hours, in pH 6.8: about 30% to about 70%;    3 hours, in pH 6.8: greater than or equal to about 45%;    4 hours, in pH 6.8: greater than or equal to about 60%;    5 hours, in pH 6.8: greater than or equal to about 75%; and    6 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       27 . The formulation of  claim 26 , wherein the therapeutically effective amount of pravastatin ranges from about 1 to about 200 mg.  
   
   
       28 . The formulation of  claim 27 , wherein the therapeutically effective amount of pravastatin ranges from about 5 to about 80 mg.  
   
   
       29 . A method for increasing the hepatic availability of pravastatin comprising administering to a subject a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation exhibiting a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 1 hour, in pH 6.8: less than or equal to about 10%;    2 hours, in pH 6.8: about 10 to about 40%;    3 hours, in pH 6.8: about 30 to about 70%;    4 hours, in pH 6.8: greater than or equal to about 45%;    5 hours, in pH 6.8: greater than or equal to about 60%;    6 hours, in pH 6.8: greater than or equal to about 75%; and    7 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       30 . The formulation of  claim 29 , wherein the therapeutically effective amount of pravastatin ranges from about 1 to about 200 mg.  
   
   
       31 . The formulation of  claim 30 , wherein the therapeutically effective amount of pravastatin ranges from about 5 to about 80 mg.  
   
   
       32 . A method of reducing one or more side effects associated with the administration of pravastatin, comprising administering a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation to a subject in need of such reduction in side effects, wherein the formulation inhibits release of the pravastatin in the stomach of the subject, and releases a therapeutic amount of pravastatin in the small intestine of the subject over a period of greater than about 2 hours, and wherein one or more side-effects are reduced relative to those resulting from the administration of an equivalent amount of a conventional formulation of pravastatin.  
   
   
       33 . The method according to  claim 32 , wherein the formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1 N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following: 
 2 hours, in HCl media: less than or equal to about 10%    1 hour, in pH 6.8: about 10 to about 40%;    2 hours, in pH 6.8: about 30% to about 70%;    3 hours, in pH 6.8: greater than or equal to about 45%;    4 hours, in pH 6.8: greater than or equal to about 60%;    5 hours, in pH 6.8: greater than or equal to about 75%; and    6 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       34 . The method according to  claim 32 , wherein the formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following: 
 1 hour, in pH 6.8: less than or equal to about 10%;    2 hours, in pH 6.8: about 10 to about 40%;    3 hours, in pH 6.8: about 30 to about 70%;    4 hours, in pH 6.8: greater than or equal to about 45%;    5 hours, in pH 6.8: greater than or equal to about 60%;    6 hours, in pH 6.8: greater than or equal to about 75%; and    7 hours, in pH 6.8: greater than or equal to about 80%.    
   
   
       35 . A method of reducing one or more drug interactions associated with administration of conventional rapid release pravastatin formulations comprising administering a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, to a subject in need of such a reduction, wherein one or more drug interactions are reduced relative to those resulting from the administration of an equivalent amount of pravastatin from a conventional rapid release formulation.  
   
   
       36 . A method of reducing one or more side effects associated with the administration of pravastatin, or associated with the co-administration of pravastatin with other lipid lowering drugs, comprising: 
 administering a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation to a subject in need of such reduction in side effects, in combination with a different lipid-lowering drug chosen from HMG-CoA reductase inhibitors, fibrates, modifiers of cholesterol absorption, and bile acid-binding resins,    wherein the formulation inhibits release of the pravastatin in the stomach of the subject, and releases a therapeutic amount of pravastatin in the small intestine of the subject over a period of greater than about 2 hours, and    wherein one or more side-effects are reduced relative to those resulting from co-administration of an equivalent amount of a conventional rapid release formulation of pravastatin and said lipid-lowering drug.    
   
   
       37 . The method of  claim 1 , wherein the therapeutically effective amount of pravastatin ranges from about 1 to about 200 mg.  
   
   
       38 . The method of  claim 37 , wherein the therapeutically effective amount of pravastatin ranges from about 5 to about 80 mg.  
   
   
       39 . The formulation of  claim 13 , wherein the formulation comprises an amount of pravastatin ranging from about 1 to about 200 mg.  
   
   
       40 . The formulation of  claim 39 , wherein the formulation comprises an amount of pravastatin ranging from about 5 to about 80 mg.  
   
   
       41 . The formulation of  claim 17 , wherein the formulation comprises an amount of pravastatin ranging from about 1 to about 200 mg.  
   
   
       42 . The formulation of  claim 41 , wherein the formulation comprises an amount of pravastatin ranging from about 5 to about 80 mg.  
   
   
       43 . The formulation of  claim 21 , wherein the formulation comprises an amount of pravastatin ranging from about 1 to about 200 mg.  
   
   
       44 . The formulation of  claim 43 , wherein the formulation comprises an amount of pravastatin ranging from about 5 to about 80 mg.  
   
   
       45 . The method of  claim 32 , wherein the therapeutically effective amount of pravastatin ranges from about 1 to about 200 mg.  
   
   
       46 . The method of  claim 45 , wherein the therapeutically effective amount of pravastatin ranges from about 5 to about 80 mg.