Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-03-10
2001-06-19
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
Reexamination Certificate
active
06248728
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is broadly concerned with methods and compositions for decreasing the intestinal absorption of cholesterol in humans and animals. More particularly, the inventive methods comprise administering by ingestion a quantity of a substituted ester or ether phosphatidylcholine compound, or a composition including one or more phosphatidylcholine compounds, with the composition having a particular C
18
alkyl group profile.
2 Description of the Prior Art
Cardiovascular disease is a leading cause of death in the United States, with a rather large number of people dying of cardiovascular disease by the age of 50. Atherosclerosis, which contributes to cardiovascular disease and stroke, can begin at a very early age. People with elevated serum cholesterol levels are more likely than their counterparts with normal cholesterol levels to have coronary heart disease.
Cholesterol is used by the body for the synthesis of the steroid hormones by certain endocrine glands and of bile acids by hepatocytes. Cholesterol is only found in animals, and is an essential constituent of cell membranes. Most dietary cholesterol is found in egg yolks and animal fat. Cholesterol that is taken up by the intestine is derived directly from the diet and via the biliary route. Free cholesterol is synthesized in the liver and secreted into the intestine via bile ducts. Cholesterol from the diet and bile are absorbed from the lumen of the small intestine by the intestinal epithelial cells, esterified, and incorporated intracellularly into chylomicrons and, in minor amounts, into very low density lipoproteins (VLDL), both of which are secreted into lymphatics that ultimately join the bloodstream. The chylomicrons and VLDL deliver their triacyglycerols and some of their cholesterol to cells in muscle and adipose tissue. The cholesterol-enriched chylomicron remnants and VLDL remnants (intermediate density lipoprotiens (IDL) and low density lipoproteins (LDL)) then deliver cholesterol back to the hepatocyte. The VLDL from intestinal and liver cells can be converted to LDL by hydrolysis of their triacylglycerols by lipoprotein lipase. LDL contain three-fourths of the total plasma cholesterol.
In hypercholesterolemia, the increase in the blood cholesterol level is associated mainly with a rise in LDL concentrations. However, the specific causes of hypercholesterolemia are complicated and varied. At least one kind of hypercholesterolemia is caused by a mutation in the gene for the LDL receptor that moves cholesterol out of the blood, primarily in the liver. Much more commonly, hypercholesterolemia has been associated with high dietary cholesterol, resulting in high cholesterol uptake from the intestine into the circulating blood. Reduction of hypercholesterolemia results in a delayed onset of atherosclerosis and a decrease in progression of atherosclerosis, thus reducing the risk of coronary heart disease. Specifically, there is evidence that relatively complicated plaques induced by hyperlipidemia will regress, and that further progression of atherosclerosis will cease when hyperlipidemia is removed. Therefore, efforts to prevent atherogenesis, to interrupt progression, and to promote regression of existing lesions by risk factor reduction are warranted.
Some forms of hyperlipidemia, including hypercholesterolemia, are potentially partially reversible with current techniques of preventive management. However, none of the current techniques is completely successful and many involve unwanted side effects and complications. Taking cholesterol-lowering drugs can result in a reduction in serum cholesterol. However, some drugs have serious side effects, including an increase in mortality through liver complications, or less severe side effects, such as constipation (cholestyramine), skin flushes, and muscle dysfunction. Dietary therapy is usually recommended for all patients with hypercholesterolemia but is not always effective.
Accordingly, there is a need for a method and composition which are effective in lowering intestinal absorption of cholesterol and which do not possess significant side effects.
SUMMARY OF THE INVENTION
The present invention overcomes these problems by broadly providing methods and compositions which decrease intestinal absorption of cholesterol. In more detail, the inventive methods comprise simply administering by ingestion a quantity of a compound according to the invention.
In one embodiment, the compound to be ingested is a monoether phosphatidylcholine, a diether phosphatidylcholine (wherein the alkyl group bonded to the second carbon atom of the glycerol moiety is a C
17
or higher alkyl group), or an ester or diester phosphatidylcholine. Preferred such compounds are depicted in Formula I.
wherein:
(1) R
1
is selected from the group consisting of hydrogen, alkyl groups (C
2
-C
24
, and preferably C
12
-C
20
) and the group
where R
3
is selected from the group consisting of hydrogen and alkyl groups (C
1
-C
23
, and preferably C
11
-C
19
);
(2) R
2
is selected from the group consisting of alkyl groups (C
10
or higher, preferably C
16
or higher, and more preferably from C
18
-C
22
) and
where R
4
comprises an alkyl group (C
9
or higher, preferably C
15
or higher, and more preferably from C
17
-C
21
); and
(3) R
1
and R
2
are not both a C
17
or lower alkyl group.
In particularly preferred compounds of Formula I, R
2
comprises a C
18-22
alkyl group or the group
wherein R
4
comprises a C
17
-C
21
alkyl group.
In another embodiment, the inventive compositions include a phosphatidylcholine compound comprising a C
18
or higher alkyl group, preferably bonded to the second carbon atom of the phosphatidylcholine gylcerol moiety. The composition preferably comprises from about 20-70% by weight, preferably from about 35-70% by weight, and more preferably from about 55-70% by weight of the C
18
or higher alkyl group(s), based upon the total weight of the composition taken as 100% by weight. Preferably, essentially all (i.e., at least about 95%, preferably at least about 98%, and more preferably at least about 99%) of the phosphatidylcholine compounds present in the composition are free of unsaturated carbon chains on the first and second carbon atoms of their respective glycerol moieties.
Regardless of the form of the inventive composition, it should be orally ingested (e.g., in a tablet form) within about 60 minutes (either prior to or after), and preferably within about 30 minutes, of the consumption of food or beverages containing cholesterol. Alternately, the composition can be mixed with (or pre-manufactured with) a food or beverage so that the composition is consumed simultaneous to consumption of the food or beverage. Examples of suitable food or beverages for supplementation with the inventive compositions include breads, cookies, cakes, candies, butter, milk, and margarine. In any case, the inventive composition should be consumed in sufficient quantities so that the weight ratio of ingested phosphatidylcholine compound to cholesterol ingested is at least about 2:1, preferably at least about 5:1, and more preferably from about 7:1 to about 30: 1.
Consuming the compositions according to the invention will result in a decrease in intestinal cholesterol absorption of at least about 10%, preferably at least about 20%, and more preferably at least about 50% when compared to the intestinal cholesterol absorption without use of the inventive compositions.
REFERENCES:
O'Connor et al, Chemical Abstracts, vol. 89, abstract No. 21085, 1978.*
Rodgers, J.B. et al., “The Effect of Synthetic Diether Phospholipid on Lipid Absorption in the Rat”,J. Lab. Clin. Med., vol. 89, No. 1, pp. 147-152, Jan. 1977.
Noh, Sang K. et al., “Estradiol Replacement in Ovariectomized Rats Increases the Hepatic Concentration and Biliary Secretion of &agr;-Tocopherol and Polyunsaturated Fatty Acids”,J. Nutr. Biochem., vol. 10, pp. 110-117, Feb. 1999.
Ahn, Joungjwa et al., “Intraduodenal Phosphatidylcholine Infusion Restores the Lymphatic
Hovey Williams Timmons & Collins
Jarvis William R. A.
Kansas State University Research Foundation
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