Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-07-25
2004-06-29
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S439000, C514S054000, C514S056000, C514S058000, C514S169000, C514S449000
Reexamination Certificate
active
06756364
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field
The present invention relates to pharmaceutical combinations, compositions and methods for treating obesity.
2. Description
Bile acids are synthesized 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 the hepatic portal vein. 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. Reducing reabsorption of bile acids within the intestinal tract can lower levels of bile acid circulating in the enterohepatic system thereby potentially reducing emulsification in the upper intestinal tract of dietary fat and reducing intestinal absorption of fat soluble drugs. 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.
Orlistat (also known as tetrahydrolipstatin and sold under the brand name XENICAL®) is a potent inhibitor of gastrointestinal lipases, i.e. lipases that are responsible for breaking down ingested fat (gastric lipase, carboxylester lipase, pancreatic lipase). As a consequence of this, unabsorbed fat is excreted in the feces. Pancreatic lipase is the key enzyme for the hydrolysis of dietary triglycerides. Triglycerides that have escaped hydrolysis are not absorbed in the intestine. Pharmacological studies with human patients demonstrate potent inhibition of fat absorption and medically relevant reduction of body weight was achieved using lipase inhibitors. However, in a subgroup of the patients, unpleasant gastrointestinal side effects such as oily spotting, fatty/oily stools, fecal urgency, increased defecation and fecal incontinence are observed. Accordingly, there is a need in the art for lipase inhibiting compositions that minimize or suppress the side effects caused by inhibitors of digestive lipases.
SUMMARY OF THE INVENTION
The subject invention provides a pharmaceutical composition which comprises a lipase inhibitor and a pharmaceutically acceptable bile acid sequestrant.
Preferrably, the composition further comprises one or more pharmaceutically acceptable excipients, the lipase inhibitor is orlistat, and the pharmaceutically acceptable bile acid sequestrant is selected from the group consisting of cholestyramine, colestipol, colesevelam, colestimide, sevelamer, cellulose derivatives, dextran derivatives, starch, starch derivatives, and pharmaceutically acceptable salts thereof. Especially preferred bile acid sequestrants are cellulose derivatives and dextran derivatives, such as DEAE-cellulose, guanidinoethylcellulose, or DEAE-Sephadex. Favorable starches or starch derivatives are &bgr;-cyclodextrin, &ggr;-cyclodextrin, retrograded starch, degraded starch, a combination of retrograded and degraded starch, hydrophobic starch, amylose, starch-diethylaminoethylether, and starch-2-hydroxyethylether.
Useful pharmaceutically acceptable excipients include fillers, surfactants, disintegrants, binders, lubricants, flowability enhancers, sweeteners, and colorants. A desirable composition comprises (a) from about 5 to about 1000 mg of a lipase inhibitor and (b) from about 0.1 to about 20 g of a bile acid sequestrant and favorably contains (a) from about 5 to about 1000 mg of a lipase inhibitor; (b) from about 0.1 to about 20 g bile acid sequestrant; (c) from about 0.1 to about 10 g of a filler; (d) from about 0.05 to about 3.0 g of a surfactant; (e) from about 0.05 to about 2.0 g of a disintegrant; (f) from about 0.02 to about 2.0 g of a binder; (g) from about 0.001 to about 1.0 g of a lubricant; (h) from about 0.1 to about 5.0 g of a flowability enhancer; (i) from about 0.01 to about 4.0 g of a sweetener; and (j) and about 0.001 to about 0.5 g of a colorant.
Preferred amounts of lipase inhibitor include from about 10 to about 500 mg, e.g. 120 mg, and 20 to about 100 mg, e.g. about 60 mg. Preferred amount of bile acid sequestrant are from about 0.5 to about 10 g and from about 1 to about 5 g.
Another aspect of the subject invention is a kit for use in the treatment of obesity, which comprises (a) a first component which is a lipase inhibitor and (b) a second component which is a bile acid sequestrant, present in oral unit dosage form.
A method of treating obesity in an obese patient is also provided. This method comprises administering to a patient in need of such treatment (a) a therapeutically effective amount of a lipase inhibitor and (b) a pharmaceutically acceptable bile acid sequestrant in an amount effective to reduce gastrointestinal side effects associated with the lipase inhibitor. The lipase inhibitor and bile acid sequestrant can be administered simultaneously, separately, and/or sequentially.
Further, the subject invention provides a method of reducing the gastrointestinal side effects associated with the lipase inhibitor treatment. This method comprises administering to a patient being treated with a lipase inhibitor an amount of a bile salt sequestrant effective to reduce the side effects associated with the lipase inhibitor treatment.
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.
The invention relates to a combination or composition comprising a lipase inhibitor, preferably a compound of formula I (orlistat),
a pharmaceutically acceptable bile acid sequestrant and optionally one or more pharmaceutically acceptable excipient(s), e.g. a diluent or carrier. The present invention provides pharmaceutical combinations and compositions which are able to minimize or suppress the above mentioned side effects caused by inhibitors of digestive lipases. These compositions or combinations comprise a lipase inhibitor, preferably orlistat, a pharmaceutically acceptable bile acid sequestrant, optionally in conjunction with a pharmaceutically acceptable excipient, e.g. a diluent or carrier. The invention comprises also a method of treatment of obesity and associated comorbidities and other diseases treatable by lipase inhibitors which comprises administration of a therapeutically effective amount of a lipase inhibitor, preferably orlistat, and a therapeutically effective amount of a bile acid sequestrant.
It has been surprisingly found that pharmaceutically acceptable bile acid sequestrants, when ingested together with a lipase inhibitor, are able to suppress unpleasant gastrointestinal events. The reduction of unpleasant gastrointestinal side effects can improve the quality of life in sensitive patients during treatment with a lipase inhibitor and may further enhance compliance of the patients with drug intake and thus enhance the therapeutic benefit.
In more detail, the present invention relates to a pharmaceutical composition or combination comprising a lipase inhibitor, preferably a compound of formula I (orlistat) and a pharmaceutically acceptable bile acid sequestrant, optionally in conjunction with a pharmaceutically acceptable excipient, e.g. a diluent or carrier. The pharmaceutically acceptable bile acid sequestrant may be selected from the group consisting of cholestyramine, colestipol, diethylaminoethylcellulose (DEAE-cellulose), and starch derivatives like &bgr;-cyclodextrin and &ggr;-cyclodextrin, more preferably from cholestyramine, colestipol, diethylaminoethylcellulose, &bgr;-cyclodextrin, and &ggr;-cyclodextrin, and even more preferably from cholestyramine and colestipol, and most preferably the bile acid sequestrant is cholestyramine. The invention also provides the use of the above combination of compounds in the manufacture of a medicament for the treatment and prevention of obesity. Addi
Barbier Pierre
Hadvary Paul
Lengsfeld Hans
Hoffmann-La Roche Inc.
Johnston George W.
Parise John P.
Peselev Elli
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