Pravastatin pharmaceutical formulations and methods of their use
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.