Combination therapy for treating hypercholestrolemia

Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Polymer from ethylenic monomers only

Reexamination Certificate

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C514S824000

Reexamination Certificate

active

06264938

ABSTRACT:

BACKGROUND OF THE INVENTION
Reabsorption of bile acids from the intestine conserves lipoprotein cholesterol in the bloodstream. Conversely, blood cholesterol levels can be diminished by reducing reabsorption of bile acids.
One method of reducing the amount of bile acids that are reabsorbed and, thus, reducing serum cholesterol is the oral administration of compounds that sequester the bile acids and cannot themselves be absorbed. The sequestered bile acids are excreted.
Compounds which have been suggested for bile acid sequestration include various ion exchange polymers. One such polymer is cholestyramine, a copolymer of divinylbenzene and trimethylammoniummethyl styrene. It has been long recognized that this polymer is unpalatable, gritty, and constipating. More recently, various polymers have been suggested which are characterized by hydrophobic substituents and quaternary ammonium radicals substituted upon an amine polymer backbone (Ahlers, et al. U.S. Pat. Nos. 5,428,112 and 5,430,110 and McTaggart, et al., U.S. Pat. No. 5,462,730, which are incorporated herein by reference). In some cases, these polymers have had disappointing efficacy and require complex processes for their manufacture.
Another class of compounds which has been used as cholesterol-lowering agents are HMG Co-A Reductase Inhibitors. This class of compounds inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase. This enzyme catalyzes the conversion of HMG Co-A to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Known HMG Co-A reductase inhibitors include, for example, mevastatin (disclosed in U.S. Pat. No. 3,883140), lovastatin, also referred to as mevinolin (disclosed in U.S. Pat. No. 4,231,938), pravastatin (disclosed in U.S. Pat. No. 4,346,227), simvastatin also referred to as synvinolin (disclosed in U.S. Pat. Nos. 4,444,784 and 4,450,171), fluvastatin (disclosed in U.S. Pat. No. 4,739,073) and atorvastatin (disclosed in U.S. Pat. No. 5,273,995) and compounds listed in Table 1.
The present invention furthers efforts for treating hypercholesterolemia and atherosclerosis, as well reducing serum cholesterol, by providing a combination therapy approach and a novel pharmaceutical composition useful therefor.
SUMMARY OF THE INVENTION
The invention relates to methods for treating hypercholesterolemia and atherosclerosis, and reducing serum cholesterol in a mammal. The methods of the invention comprise administering to a mammal a first amount of a bile acid sequestrant compound which is an unsubstituted polydiallylamine polymer and a second amount of an HMG Co-A reductase inhibitor compound. The first and second amounts together comprise a therapeutically effective amount. Further, the combination therapy can include other active agents for the treatment of hypercholesterolemia, atherosclerosis for reducing serum cholesterol, such as those described in U.S. patent application Ser. No. 09/311/103, entitled Combination Therapy for Treating Hypercholesterolemia, by C. Huval, S. Holmes-Farley, J. Petersen and P. Dhal, the entire contents of which are incorporated herein by reference.
The invention further relates to pharmaceutical compositions useful for the treatment of hypercholesterolemia and atherosclerosis, and for reducing serum cholesterol. The pharmaceutical compositions comprise a combination of a first amount of an unsubstituted polydiallylamine polymer compound and a second amount of an HMG Co-A reductase inhibitor compound. The first and second amounts comprise a therapeutically effective amount. The pharmaceutical compositions of the present invention may optionally contain a pharmaceutically acceptable carrier. Further, the pharmaceutical composition can contain other active agents for the treatment of hypercholesterolemia and atherosclerosis and for reducing serum cholesterol, such as those described in U.S. patent application Ser. No. 09/311,103, entitled Combination Therapy for Treating Hypercholesterolemia, by C. Huval, S. Holmes-Farley, J. Petersen and P. Dhal, the entire contents of which are incorporated herein by reference.
The unsubstituted polydiallylamine polymers are characterized by one or more monomeric units of the formulae:
or a combination thereof and salts thereof. The polymer can be characterized by the substantial absence of one or more alkylated amine monomers and/or the substantial absence of one or more trialkylammonium alkyl groups. The polymers are non-absorbable and optionally crosslinked. In preferred embodiments, the polymer is crosslinked by means of a multifunctional crosslinking agent. The polymer can also be characterized as being linear or branched.
The HMG Co-A Reductase Inhibitors useful in the present invention are listed in Table 1.
Each compound is present in the pharmaceutical composition in an amount which in combination with the other provides a therapeutically effective amount. The pharmaceutical composition can include one or more of each class of compound.
Other features and advantages will be apparent from the following description of the preferred embodiments thereof and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
The features and other details of the invention will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principal features of the invention can be employed in various embodiments without departing from the scope of the present invention.
The invention provides methods for treating hypercholesterolemia and atherosclerosis, and reducing serum cholesterol in a mammal. The methods of the invention comprise administering to a mammal a first amount of a bile acid sequestrant compound which is an unsubstituted polydiallylamine polymer and a second amount of an HMG Co-A reductase inhibitor compound. The first and second amounts of said compounds together comprise a therapeutically effective amount.
As used herein, the term “therapeutically effective amount” is intended to qualify the combined amount of the first and second compounds in the combination therapy. The combined amount will achieve the desired biological response. In the present invention, the desired biological response can be the treatment of hypercholesterolemia, the treatment of atherosclerosis and/or a reduction of serum cholesterol. The mammal can be a human.
The unsubstituted polydiallylamine polymers are characterized by one or more monomeric units of the formulae:
or a combination thereof and salts thereof. The polymer can be characterized by the substantial absence of one or more alkylated amine monomers and/or the substantial absence of one or more trialkylammonium alkyl groups. The polymers are non-absorbable and optionally crosslinked. In preferred embodiments, the polymer is crosslinked by means of a multifunctional crosslinking agent. The polymer can also be characterized as being linear or branched.
As described above, the polymers employed in the method and pharmaceutical composition described herein comprise non-absorbable, optionally cross-linked polydiallylamines characterized by the formula above. Importantly, the polymers can be characterized by the substantial absence of substituted or unsubstituted alkyl substituents on the amino group of the monomer, such as obtained in the alkylation of an amine polymer. That is, the polymer can be characterized in that the polymer is substantially free of alkylated amine monomers.
The polymer can be a homopolymer or a copolymer. Where copolymers are manufactured with a diallylamine monomer, the comonomers are preferably inert, non-toxic and/or possess bile acid sequestration properties. Suitable examples of additional comonomers include substituted and unsubstituted acrylate, substituted and unsubstituted acrylamide, substituted and unsubstituted methacrylate, substituted and unsubstituted methacrylamide, allylamine, triallylamine, allyl alcohol, substituted and unsubstituted vinyl amine and substituted and

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