Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-01-19
2004-03-16
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S057000, C424S451000, C424S464000
Reexamination Certificate
active
06706695
ABSTRACT:
The invention relates to an antilipemic composition and in particular to a composition for lowering cholesterol.
As outlined in a recent publication [Facts About Cholesterol: The Plague of Plaque, FDA Consumer magazine, January-February 1999], cholesterol, C27H45OH, is a monohydric alcohol, a sterol, widely distributed in animal tissues. It can be synthesized in the liver and is a normal constituent of bile. It is the principal constituent of most gallstones. It is important in metabolism, serving as a precursor of various steroid hormones (e.g., sex hormones, adrenal corticoids). In most individuals, however, an elevated blood level of cholesterol constitutes an increased risk of developing coronary heart disease (CHD). Scientific evidence has established that lowering definitely elevated blood cholesterol (specifically, blood levels of low-density lipoprotein cholesterol) reduces the risk of heart attacks due to CHD.
Cholesterol is needed for some important body functions, but when present in excessive amounts, it can injure blood vessels and cause heart attacks and stroke. The body needs cholesterol for digesting dietary fats, making hormones, building cell walls, and other important processes. The bloodstream carries cholesterol in particles called lipoproteins that are like blood-borne carriers delivering cholesterol to various body tissues to be used, stored or excreted. But too much of this circulating cholesterol can injure arteries, especially the coronary ones that supply the heart. This leads to accumulation of cholesterol-laden “plaque” in vessel linings, a condition called atherosclerosis. If a blood clot completely obstructs a coronary artery affected by atherosclerosis, a heart attack (myocardial infarction) or death can occur.
Lipoproteins are conjugated proteins consisting of simple proteins combined with lipid components: cholesterol, phospholipid, and triglyceride. Most plasma lipids do not circulate in an unbound state but are chemically linked with proteins. Analysis of their concentrations and proportions in the blood can provide important clues as to their role in certain diseases, particularly cardiovascular abnormalities, hypertension, atherosclerosis, and coronary artery disease. Lipoproteins are classified as very low-density (VLDL), low-density (LDL), intermediate-density (IDL) and high-density (HDL). It is thought that individuals with high blood levels of HDL are less predisposed to coronary heart disease than those with high blood levels of VLDL or LDL.
Two types of lipoproteins and their quantity in the blood are main factors in heart disease risk:
Low-density lipoprotein (LDL)—This “bad” cholesterol is the form in which cholesterol is carried into the blood and is the main cause of harmful fatty buildup in arteries. The higher the LDL cholesterol level in the blood, the greater the heart disease risk.
High-density lipoprotein (HDL)—This “good” cholesterol carries blood cholesterol back to the liver, where it can be eliminated. HDL helps prevent a cholesterol buildup in blood vessels. Low HDL levels increase heart disease risk.
One of the primary ways LDL cholesterol levels can become too high in blood is through eating too much of two nutrients: saturated fat, which is found mostly in animal products, and cholesterol, found only in animal products. Saturated fat raises LDL levels more than anything else in the diet. Several other factors such as heredity, weight, exercise, age and gender, and stress also affect blood cholesterol levels.
Cholesterol levels may be decreased by several factors, including diet, avoiding smoking, and avoiding anabolic steroids. Drugs commonly used to control cholesterol include lovastatin, niacin, gemfibrozil, clofibrate, probucol, and bile-acid resins (cholestyramine, colestipol). The decision of which drug to prescribe is based on factors such as degree of cholesterol lowering desired, side effects, and cost.
A number of substances have been applied to reduce cholesterol levels in blood. One of the early therapies involved heparin, a polysaccharide isolated from natural sources. However, the isolation process is costly and heparin therapy is therefore rather expensive at efficient doses. This led to the introduction of sulphated polysaccharides known as heparinoides. The additional sulphatation and the presence of the OSO3H groups brought about a lower efficiency and a higher toxicity compared to heparin.
Another group of polymers applied as antilipemics have been anion exchange resins of varying degree of basicity, exchanging Cl-ions for anions of bile acids. Cholestyramine and colestipol bind bile acids in the intestine and prevent their recycling through the liver. Because the liver needs cholesterol to make bile, it increases its uptake of cholesterol from the blood. These drugs are, in most cases, not resorbed from the gastrointestinal tract, but can adversely affect resorption of other drugs. Due to the rather high daily doses (up to 30 g) they may also cause gastric problems.
Antilipemic properties have also been observed for certain hormones such as gestagens. Their complex hormonal activity precludes, however, their common use in antilipemic therapy.
Nicotinic acid (niacin) lowers total and LDL cholesterol and raises HDL cholesterol. It also can lower triglycerides. Because the dose needed for treatment is about 100 times more than the recommended daily allowance for niacin and thus can potentially be toxic, the drug must be taken under a doctor's care.
Fibric acid derivatives such as gemfibrozil and fenofibrate can also increase HDL levels, but are used mainly to lower triglycerides.
The most prominent cholesterol drugs are in the statin family, an array of powerful treatments that includes lovastatin, fluvastatin, pravastatin, simvastatin), cervastatin, and atorvastatin. Statins work by interfering with the cholesterol-producing mechanisms of the liver and by increasing the capacity of the liver to remove cholesterol from circulating blood. Adverse side effects have also been reported recently for antilipemic drugs based on statins such as fluvastatin.
The invention in particular involves the use of polyanhydroglucuronic acids and salts thereof The term polyanhydroglucuronic acid and salts there of as used herein also includes copolymers thereof, especially with anhydroglucose. This is hereinafter referred to as PAGA.
Co-pending patent application PCT IE98/00004 describes particular polyanhydroglucuronic acids and salts thereof and a method of preparing such compounds. In particular therefore, the term polyanhydroglucuronic acids and salts thereof includes the acids and salts referred to in this co-pending application.
STATEMENTS OF INVENTION
We have now found an important antilipemic effect, comparable with that of statins, in non-sulphated polysaccharides containing glucuronic acid in the polymer chain. Glucuronoglucanes, notably those bound with 1,4 &bgr; glycosidic bonds in the form of PAGA as prepared, particularly, according to PCT IE/98/00004, their salts, complex salts, and intermolecular complexes thereof with cationic polymer counterions such as, notably, gelatine or chitosan, when applied perorally, preferably in the form of tablets, pellets, granules, or microspheres, display a significant cholesterol lowering activity at relatively low daily doses of 15 to 100 mg per kg body weight.
In tests on volunteers it has been observed that the effect of increasing HDL cholesterol level, and reducing both LDL/ VLDL and total cholesterol levels was comparable with a control group of patients treated with fluvastatin with no adverse side effects reported.
It may be hypothesised that the mechanism of this effect is related to the increased supply of glucuronic acid and their oligomers to the organism during absorption and degradative clearance of the orally administered glucuronoglucane.
One advantage of the therapy based on the invention is due to the inherent biocompatibility, lack of toxicity and virtual absence of adverse side effects inherent to PAGA salts and intermolecular complex
Briestensky Jiri
Kiss Frantisek
Santar Ivan
Alpenstock Holdings Limited
Delacroix-Muirheid C.
Jacobson & Holman PLLC
Spivack Phyllis G.
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