Method of treating high plasma cholesterol levels

Details Method of treating high plasma cholesterol levels Method of treating high plasma cholesterol levels

2001-07-25

2003-05-13

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

C514S740000, C514S742000, C514S824000

Reexamination Certificate

active

06562329

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The present invention relates to a new method for the prevention and treatment of diseases associated with high plasma cholesterol levels (hypercholesterolemia).
2. Description
Bile acid sequestrants have been proposed for use in lowering circulating blood cholesterol levels. Biologically, cholesterol is eliminated from the body by conversion to bile acids and excretion as neutral steroids. Bile acids are synthesized from cholesterol in the liver and enter the bile as glycine and taurine conjugates. They are released in salt form in bile during digestion and act as detergents to solubilize and consequently aid in digestion of dietary fats. Following digestion, bile acid salts are mostly reabsorbed in the ileum, complexed with proteins, and returned to the liver through hepatic portal veins. The small amount of bile acid salts which are not reabsorbed by active transport are excreted via the distal ileum and large intestine as a portion of fecal material. Bile acids are synthesized from cholesterol transported in lipoproteins in the liver. Therefore, reabsorption of bile acids, which can be present as the corresponding salts or conjugates, from the intestine conserves lipoprotein cholesterol in the bloodstream. As such, reducing reabsorption of bile acids within the intestinal tract can lower levels of bile acid circulating in the enterohepatic system thereby promoting replacement of bile acids through synthesis from cholesterol, in the liver. The result is a lowering of circulating blood cholesterol levels. One method of reducing the amount of bile acids that are reabsorbed, is oral administration of compounds that sequester the bile acids within the intestinal tract and cannot themselves be absorbed. The sequestered bile acids consequently are excreted.
Orlistat (also known as tetrahydrolipstatin and sold under the trademark XENICAL®) is a potent inhibitor of gastrointestinal lipases, i.e. lipases that break down ingested fat (gastric lipase, carboxylester lipase, pancreatic lipase). Orilistat has the formula:
As a consequence of gastrointestinal lipase inhibition, unabsorbed fat is egested in the faeces. Pancreatic lipase is the key enzyme for the hydrolysis of dietary triglycerides. Triglycerides, which have escaped hydrolysis are not absorbed in the intestine. Orlistat has been shown in animal models to inhibit fat absorption and to reduce body weight. In pharmacological studies with humans potent inhibition of fat absorption was demonstrated.
Hypercholesterolemia is a great problem in modern society. Accordingly, methods for treating hypercholesterolemia are highly sought.
SUMMARY OF THE INVENTION
The subject invention provides a method of reducing plasma cholesterol levels in a hypercholesterolemic patient. This method comprises administering to the patient a therapeutically effective amount of a lipase inhibitor and a therapeutically effective amount of a bile acid sequestrant. A favored lipase inhibitor is orlistat and preferred bile acid sequestrants include cholestyramine, colestipol, colesevelam, colestimide, sevelamer, cellulose derivatives, dextran derivatives, starch, starch derivatives, and pharmaceutically acceptable salts of such bile acid sequestrants. A key advantage of the subject invention is the mitigations of the side effects associated with both orlistat (oily stool) and bile acid sequestrants (constipation).
The bile acid sequestrant can be a cellulose derivative or a dextran derivative, for example DEAE-cellulose, guanidinoethylcellulose, or DEAE-Sephadex. Favored starch derivatives include &bgr;-cyclodextrin, &ggr;-cyclodextrin, retrograded starch, degraded starch, a mixture of retrograded and degraded starch, hydrophobic starch, amylose, starch-diethylaminoethylether, and starch-2-hydroxyethylether, &bgr;-cyclodextrin or &ggr;-cyclodextrin are preferred.
The bile acid sequestrant is favorably cholestyramine, colestipol, colesevelam, colestimide, sevelamer, cellulose, DEAE-cellulose, guanidinoethylcellulose, DEAE-Sephadex, starch, &bgr;-cyclodextrin, and &ggr;-cyclodextrin. More favored are cholestyramine, colestipol, colesevelam, colestimide, sevelamer, DEAE-cellulose, &bgr;-cyclodextrin, and &ggr;-cyclodextrin, and in particular, cholestyramine, colestipol, sevelamer, DEAE-cellulose, &bgr;-cyclodextrin, and &ggr;-cyclodextrin. Presently it is preferred that the bile acid sequestrant is cholestyramine or colestipol or sevelamer.
It is favored when the therapeutically effective amount of a lipase inhibitor and a therapeutically effective amount of a bile acid sequestrant are administered as a medicament that comprises about 5 mg to about 1000 mg lipase inhibitor, about 0.1 g to about 20 g bile acid sequestrant, and one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients are typically fillers, sugars, sugar alcohols, a mixture of one or more sugars and sugar alcohols, surfactants, disintegrants, binders, lubricants, flowability enhancers, sweeteners, and colorants.
Another favored variation is where the medicament comprises: about 5 mg to about 1000 mg lipase inhibitor; about 0.1 g to about 20 g bile acid sequestrant; and a pharmaceutically acceptable excipients selected from the group consisting of about 0.1 to about 10 g fillers, sugars, sugar alcohols and mixtures thereof, about 0.05 g to about 3.0 g surfactants, about 0.05 g to about 2.0 g disintegrants, about 0.02 g to about 2.0 g binder, about 0.001 g to about 1.0 g lubricants, about 0.1 g to about 5.0 g flowability enhancers, about 0.01 g to about 4.0 g sweeteners, and about 0.001 g to about 0.5 g colorants. Such medicaments typically contain about 10 mg to about 500 mg lipase inhibitor, with the range about 20 mg to about 100 mg lipase inhibitor being favored.
Favored is where the medicament comprises about 10 mg to about 360 mg orlistat, 30 mg to about 120 mg orlistat being favored and about 40 mg to about 80 mg orlistat being most favored.
The medicament generally comprises about 0.5 g to about 10 g bile acid sequestrant, although about 1 g to about 5 g bile acid sequestrant is favored. Especially favored is where the bile salt sequestrant is cholestyramine.
Administration of the lipase inhibitor and bile acid sequestrant can be simultaneous, sequential, and/or separate.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
Obesity is often associated with cardiovascular risk factors, especially with elevated levels of plasma cholesterol. A clinically established principle to treat elevated cholesterol levels is the administration of bile acid sequestrants. One side effect of bile acid sequestrants is constipation. The present invention provides improved methods for the prevention and treatment of diseases associated with overweight and high plasma cholesterol levels.
The present invention provides the combined use of a lipase inhibitor and a pharmaceutically acceptable bile acid sequestrant for the manufacture of medicaments for the prevention and treatment of diseases associated with high plasma cholesterol levels. Surprisingly, the combination results in both improved cholesterol lowering and attenuation of the side effects seen with either administration of lipase inhibitors or bile acid sequestrants individually.
In more detail, the present invention relates to the use of a lipase inhibitor, e.g. orlistat, and a pharmaceutically acceptable bile acid sequestrant for the manufacture of a medicament for the prevention and treatment of diseases associated with high plasma cholesterol levels, i.e. for the treatment of hypercholesterolemia. Preferably, the pharmaceutically acceptable bile acid sequestrant is selected from the group consisting of cholestyramine, colestipol, colesevelam, colestimide, sevelamer, cellulose and dextran derivatives, starch and starch derivatives and pharmaceutically acceptable salts thereof.
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