Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1999-05-13
2002-04-02
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C514S824000
Reexamination Certificate
active
06365186
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.
Fibrates are also a known class of compounds which has been used as cholesterol-lowering agents. Fibrates are peroxisome proliferator-activated receptor antagonist that effectively lower plasma triglycerides by increasing VLDL lipolysis and clearance, and by decreasing hepatic VLDL triglyceride output. Fibrate treatment also raises HDL levels by increasing hepatic HDL synthesis. Examples of fibrates include, Clofibrate (ATROMID-S®), Gemfibrozil (LOPID®), Fenofibrate, Benzafibrate and the compounds listed in Table 1.
Another class of compounds which have been used as cholesterol-lowering agents are nicotinic acid, commonly referred to as niacin, and derivatives thereof. Niacin is a potent triglyceride reducing agent with an HDL-elevating effect. Niacin therapy is prescribed to treat patients with moderate to severe hypertriglyceridemia and does not usually produce a significant LDL cholesterol-lowering effect. Niacin acts within the liver to decrease VLDL triglyceride output and in the periphery to increase its clearance. The side effects of niacin are well-known and usually limit usage. For example, high doses cause pruritis and flushing. In addition, an elevation in liver enzymes, abdominal cramps, diarrhea, nausea and vomiting have been observed. Niacin is available, for example, as NICOLAR® tablets. Nicotinic acid derivatives include, Acipimox, Aluminum Nicotinate, Niceritrol, Nicoclonate, Nicomol and Oxiniacic Acid.
Another class of compounds which are useful in cholesterol-lowering therapy are thyroid hormones and analogs such as Etiroxate, Thyropropic Acid and Thyroxine.
In addition, there are many known cholesterol-lowering agents which are not members of a particular class of agents. These other cholesterol-lowering agents include, Acifran, Azacosterol, Benfluorex, &bgr;-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomestrone, Detaxtran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meglutol, Melinamide, Mytatrienediol, Ornithine, &ggr;-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, &agr;-phenybutyramide, Priozadil, Probucol, B-Sitosterol, Sultosilic Acid, Piperazine Salt, Tiadenol, Triparanol and Xenbucin.
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 a cholesterol-lowering agent selected from the group consisting of fibrates, nicotinic acid and derivatives thereof, and other cholesterol-lowering agents such as Acifran, Azacosterol, Benfluorex, &bgr;-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomestrone, Detaxtran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meglutol, Melinamide, Mytatrienediol, Ornithine, &ggr;-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, &agr;-phenybutyramide, Priozadil, Probucol, B-Sitosterol, Sultosilic Acid, Piperazine Salt, Tiadenol, Triparanol and Xenbucin, and combinations thereof. The first and second amounts together comprise a therapeutically effective amount. Further, the combination therapy can also include HMG CoA reductase inhibitors such as those described in U.S. patent application Ser. No. 09/311,402 filed on May 13, 1999 entitled, Combination Therapy for Treating Hypercholesterolemia, by C. Huval, S. Holmes-Farley, J. Petersen and P. Dhal, the entire content of which is 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 a cholesterol-lowering agent selected from the group consisting of fibrates, nicotinic acid and derivatives thereof, and other cholesterol-lowering agents such as Acifran, Azacosterol, Benfluorex, &bgr;-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomestrone, Detaxtran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meglutol, Melinamide, Mytatrienediol, Ornithine, &ggr;-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, &agr;-phenybutyramide, Priozadil, Probucol, B-Sitosterol, Sultosilic Acid, Piperazine Salt, Tiadenol, Triparanol and Xenbucin, and combinations thereof. The first and second amounts together comprise a therapeutically effective amount. Further, the pharmaceutical compositions can also include HMG CoA reductase inhibitors such as those described in U.S. patent application Ser. No. 09/311,402 filed on May 13, 1999 entitled, Combination Therapy for Treating Hypercholesterolemia, by C. Huval, S. Holmes-Farley, J. Petersen and P. Dhal, the entire content of which is incorporated herein by reference. The pharmaceutical compositions of the present invention may optionally contain a pharmaceutically acceptable carrier.
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 crossliked. 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.
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 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
Dhal Pradeep K.
Holmes-Farley Stephen Randall
Huval Chad Cori
Petersen John S.
GelTex Pharmaceuticals Inc.
Hamilton Brook Smith & Reynolds P.C.
Webman Edward J.
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