Fibrate-statin combinations with reduced fed-fasted effects

Details Fibrate-statin combinations with reduced fed-fasted effects Fibrate-statin combinations with reduced fed-fasted effects

2001-04-20

2003-03-18

Webman, Edward J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S469000, C424S489000, C424S439000, C424S455000, C424S484000, C424S502000, C424S824000, C424S464000, C514S543000, C514S460000, C514S687000, C514S721000

Reexamination Certificate

active

06534088

ABSTRACT:

This invention relates to therapeutically effective compositions and methods for treatment of patients with dyslipidemia, hyperlipidemia, hypercholesterolemia and related conditions comprising a combination in one dosage form of a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor or statin and a fibrate formulated together to provide simultaneously a therapeutically effective amount of the hydroxymethylglutaryl coenzyme A reductase inhibitor and a therapeutically effective amount of the fibrate taken into the blood of a patient in need of treatment where the amount of the fibrate taken into the blood is not substantially affected by the presence or absence of food or levels of fat in food taken by the patient proximal to the administration of the dosage form. The compositions of this invention are also useful for the prevention of type III hyperlipoproteinemia in patients prone to that condition.
In particular, this invention relates to an oral dosage form of a pharmaceutical composition comprising a combination or a statin, a carbohydrate bulking agent, and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 80% and especially at least 85% of the quantity of fenofibrate active species, particularly the AUC quantity of fenofibrate active species, provided by said amount to said patient when fed a meal containing fat, especially when fed at least 1000 calories 50% of which are from fat.
BACKGROUND
In humans, cholesterol and triglycerides (TG) are part of lipoprotein complexes in the bloodstream, and can be separated via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein, (LDL) and very-low-density lipoprotein (VLDL) fractions. Cholesterol and triglycerides are synthesized in the liver, incorporated into VLDL, and released into the plasma. High levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (apo-B, a membrane complex for LDL-C) promote human atherosclerosis, and decreased levels of HDL-C and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Cardiovascular morbidity and mortality in humans can vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.
Orally administered statins are hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are used in patients to lower low density lipoprotein (LDL) cholesterol. Complimentary to this are orally administered fibrates which are used in patients to decrease lipoproteins rich in triglycerides, to increase high density lipoprotein (HDL), and to decrease atherogenic-dense LDL. Patients who take statins or fibrates are frequently on diets with low and variable fat content.
Uptake of a fibrate such as fenofibrate by a patient is sensitive to a positive food effect, hereinafter referred to simply as a food effect. A positive food effect (or food effect) exits when the amount of an active drug taken into the blood from a given oral dosage form by a fasting patient is less than the amount of the active drug taken into the blood from the same dosage form by the same patient who has eaten a fat-containing meal proximal to the time of administration of the dosage form. A negative food effect exits when the amount of an active drug taken into the blood from a given oral dosage form by a fasting patient is more than the amount of the active drug taken into the blood from the same dosage form by the same patient who has eaten a fat-containing meal proximal to the time of administration of the dosage form. The compositions of this invention generally exhibit a positive food effect.
Patients with severe primary hypercholesterolemia often present with blood levels of low density lipoprotein (LDL) cholesterol greater than 190 mg/dl (4.9 mmol/L) and triglyceride levels up to 350 mg/dl (3.9 mmol/L). The use of diet and single-drug therapy does not always decrease LDL cholesterol and triglycerides adequately enough to reach targeted values in patients with primary severe hypercholesterolemia with or without a concomitant increase in triglycerides. In these patients a combination of complementary fibrate therapy and statin therapy can be desirable.
HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A) is the microsomal enzyme that catalyzes the rate limiting reaction in cholesterol biosynthesis (Mevalonate). A statin compound is an HMG-CoA reductase inhibitor that inhibits HMG-CoA reductase, and therefore inhibits or interferes with the synthesis of cholesterol. Inhibition of cholesterol synthesis can lead to a reduction in blood cholesterol levels.
A large number of naturally or synthetically obtained or synthetically modified compounds have been found to inhibit HMG-CoA reductase. These compounds form a category of agents useful for practicing the present invention. Traditionally these agents have been used to treat individuals with hypercholesterolemia. Examples include statins, which are commercially available, such as lovastatin and mevinolin disclosed in U.S Pat. No. 4,231,938, pravastatin and pravastatin sodium disclosed in U.S. Pat. No. 4,346,227, fluvastatin and fluvastatin sodium and XU 62-320 disclosed in EP 0 114 027 and U.S. Pat. No. 4,739,073, atorvastatin disclosed in U.S. Pat. No. 5,273,995, itavastatin also known as NK-104 disclosed in EP304063, mevastatin disclosed in U.S. Pat. No. 3,983,140, rosuvastatin, velostatin and synvinolin and simvastatin disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, cerivastatin and numerous others described in U.S. Pat. Nos. 5,622,985, 5,135,935, 5,356,896, 4,920,109, 5,286,895, 5,262,435, 5,260,332, 5,317,031, 5,283,256, 5,256,689, 5,182,298, 5,369,125, 5,302,604, 5,166,171, 5,202,327, 5,276,021, 5,196,440, 5,091,386, 5,091,378, 4,904,646, 5,385,932, 5,250,435, 5,132,312, 5,130,306, 5,116,870, 5,112,857, 5,102,911, 5,098,931, 5,081,136, 5,025,000, 5,021,453, 5,017,716, 5,001,144, 5,001,128, 4,997,837, 4,996,234, 4,994,494, 4,992,429, 4,970,231, 4,968,693, 4,963,538, 4,957,940, 4,950,675, 4,946,864, 4,946,860, 4,940,800, 4,940,727, 4,939,143, 4,929,620, 4,923,861, 4,906,657, 4,906,624, RE36,520, and U.S. Pat. No. 4,897,402, the disclosures of which patents are incorporated herein by reference.
Lovastatin, an inactive lactone, is a white, nonhygroscopic crystalline powder isolated from a strain of
Aspergillus terreus
that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile. Lovastatin is hydrolyzed after oral ingestion to the corresponding (beta)-hydroxyacid. This metabolite is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. When formulated for oral administration as Mevacor, tablets can contain 10 to 40 mg of lovastatin together with pharmaceutically acceptable excipients such as cellulose, lactose, magnesium stearate, starch, and butylated hydroxyanisole as a preservative. When taken separately, lovastatin can treat related hyperlipidemia such as reduce plasma total-C, LDL-C, total-C/HDL-C ratio and LDL-C/HDL-C ratio as well as increase HDL-C, and modestly decrease VLDL-C and plasma triglycerides TG. Mevacor can lower total-C and LDL-C to target levels, and reduce elevated total-C and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb). Single daily doses given in the evening can be more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night. A recommended starting dose of Mevacor is preferably given with a meal. 20 mg once a day can be given with the evening meal. Storage between 5-30° C. (41-86° F.) is preferred.
Fluvastatin (also known as fluvastatin sodium), a synthetic HMG-CoA reductase inhibitor, is a white to pale yellow, hygroscopic powder soluble in water, ethanol a

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