Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
1999-10-29
2001-05-22
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C514S054000, C514S055000, C514S057000, C514S059000
Reexamination Certificate
active
06235305
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to lipase inhibitors that have been rendered non-absorbable by linking such lipase inhibitors to a non-absorbable support.
BACKGROUND OF THE INVENTION
Lipase inhibitors such as esterastin (see U.S. Pat. No. 4,189,438), tetrahydroesterastin (3,5-hydroxy-2hexadeca-7,10-dienoic 1,3-lactone), 3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone, 3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like, are well-known as lipase inhibitors and as pancreatic cholesterol esterase inhibitors. However, such lipase inhibitors are, inter alia, also substantially orally active as immunosuppressants (see U.S. Pat. No. 4,189,438 and U.S. Pat. No. 4,202,824), which can be a highly undesired side activity in a normal or immunosuppressed person.
A popular lipase inhibiting compound which is substantially non-absorbable is known as Orlistat ((2S,3S,5S)-5-[(S)-2-formamido4-methylvaleryloxy]-2-hexyl-3-hydroxy-hexadecanoic 1,3 acid lactone, see U.S. Pat. No. 5,643,874). Orlistat has been used to inhibit lipases in the body and thereby prevent the absorption of dietary fat. At a 120 mg dose of Orlistat, taken before consuming a fat-containing meal (or up to one hour after eating such a meal), up to one-third of the fat eaten at a given meal will not be absorbed by the average person and utilized as dietary fat calories. The undigested fat passes directly through the digestive system as an oil and is ehininated from the bowel in its oily undigested form.
Certain polysaccharides are non-absorbable and some polysaccharides have the side benefit of reducing lipid absorption by the body. Defatted rice germ polysaccharides and sulfated polysaccharides are also lipase inhibitors. The super fiber Chitosan, which is a deacylated polysaccharide derived from shellfish chitan, has an ability to absorb fat and cholesterol, particularly in combination with vitamin C. Chitosan compositions may actually absorb up to 6 to 8 times its weight in fat and oils. While the polysaccharide from shellfish is similar to crude cellulose plant fiber, it has the ability to significantly bind fat in the digestive system as compared to plant fiber. Further, since polysaccharides, including those which do not preferentially bind oils over water, are not absorbed by the digestive systems of anmals such as humans, non-human primates, dogs and cats, there is no caloric value to such polysaccharides and they pass through the such digestive systems unabsorbed and substantially intact. Examples of non-absorbable polysaccharides are polysaccharides having a molecular weight of greater than 8 kDa such as dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose, argar, chitosan and the like.
There is a need in the art for non-absorbable lipase inhibitors, as well as for improved antiadiposity compositions and methods which do not require an absolute low-fat diet in order to lower the absorption of dietary fat as calories.
SUMMARY OF THE INVENTION
In one aspect the present invention relates to novel derivatives of lipase inhibitors which are non-absorbable. In particular, absorbable lipases such as esterastin are coupled to a non-absorbable biocompatible, pharmaceutically acceptable polymer support, such as a polysaccharide, to render the lipase essentially non-absorbable by the digestive system of an animal such as a dog, cat, non-human primate or humans. Preferred lipase inhibitors are at one lipase inhibitor which is a member selected from the group consisting of esterastin, tetrahydro-esterastin (3,5-hydroxy-2-hexadeca-7,10-dienoic 1,3-lactone), 3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone, 3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like, wherein such lipase inhibitor is coupled to a non-absorbable biocompatible, pharmaceutically acceptable polymer support, such as a polysaccharide, to render the lipase non-absorbable by the digestive system of an animal such as a dog, cat, non-human primate or humans. Particularly preferred polysaccharides have at least one member selected from the group consisting of dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose, argar, chitosan and the like. Particularly preferred bound lipase inhibitors are lipase inhibitors bound via a derivatized group on the lipase such as a derivatized nitrogen, acid or alcohol group to a group on the polymer support such as a derivatized alcohol, acid or amino group. Preferably, a diether bridge is formed between the lipase inhibitor and the support, wherein the bridge is derived from an alcohol group on the lipase and an alcohol group on the support, each reacting with an etherizing bridging group.
In another aspect the present invention relates to pharmaceutical compositions comprising a lipase inhibiting effective amount of at least one lipase inhibitor which is coupled to a digestively non-absorbable support. Preferred are such pharmaceutical compositions comprising an effective amount of a lipases coupled to a non-absorbable biocompatible, pharmaceutically acceptable polymer support, such as a polysaccharide, wherein the lipase is essentially non-absorbable by the digestive system of an animal such as a dog, cat, non-human primate or humans.
In still another aspect, the present invention relates to a method for treating adiposity or obesity by administering to a patient before a fat-contain meal, or up to one hour after such a meal is consumed, an amount of at least one lipase inhibitor which is bound to a non-absorbable polymer support in an amount effective to inhibit the absorption of up to one-third of the dietary fat in such a meal. In particular, a preferred method comprises administering at one lipase inhibitor which is a member selected from the group consisting of esterastin, tetrahydro-esterastin (3,5-hydroxy-2hexadeca-7,10-dienoic 1,3-lactone), 3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone, 3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like, wherein such lipase inhibitor is coupled to a non-absorbable biocompatible, pharmaceutically acceptable polymer support, such as a polysaccharide, to render the lipase non-absorbable by the digestive system of an animal such as a dog, cat, non-human primate or humans. Particularly preferred polysaccharides are at least one member selected from the group consisting of dextrans, molecular microcrystalline cellulose, wheat bran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose, argar, chitosan and the like. Particularly preferred bound lipase inhibitors are lipase inhibitors bound via a derivatized nitrogen, acid or alcohol group to a derivatized alcohol, acid or amino group on the polymer support. A diether bridge between the lipase inhibitor and the support which is derived from an alcohol group on the lipase and an alcohol group on the support, respectively reacting with a bridging group is the preferred coupling of the lipase inhibitor to the support.
The preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term “alkenyl” refers to a trivalent straight chain or branched chain unsaturated aliphatic radical. The term “alkinyl” (or “alkynyl”) refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms.
The term “alkyl” refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. The term “cycloalkyl” as used here
2Pro Chemical
Di Nola-Baron Liliana
Kishore Gollamudi S.
Lev Robert
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