Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-08
2004-12-14
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S220000, C549S403000
Reexamination Certificate
active
06831098
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the field of bioflavanoids, and more specifically to forms of bioflavanoids that increase their bioavailability, and to the use of these compounds for the treatment of disease.
BACKGROUND OF THE INVENTION
Hesperidin and the a glycone of hesperidin, hesperetin, are flavonoids found in lemons, grapefruits, tangerines, and oranges, and have the following structures:
Flavonoids from citrus fruits, known as bioflavonoids exhibit beneficial effects, suppressing oxidative stress, inhibit breast cancer and have anti-inflammatory function.
Hesperidin has been used for the prevention and treatment of cerebral anemia, and pelioma. Recently has been found that hesperidin and hesperetin are effective inhibitors of 3-hydroxy-3-methylglutaryl CoA (U.S. Pat. No. 5,763,414, herein incorporated by reference). Moreover, hesperetin has topical application for sebum control and treatment of acne in mammalian skin and scalp (U.S. Pat. No. 5,587,176, herein incorporated by reference).
The bioavailability of flavonoids is an important problem in physiological effects, statistically; less than 20% of administered flavonoid is absorbed to blood which subsequently is metabolized to glucuronides and sulfates. Only free flavonoids without sugar molecule, the so-called aglycones are able to pass through the gut wall. Hydrolysis of flavonoid glycosides only occurs in the colon by microorganisms, which in the same time degrade released flavonoids.
SUMMARY OF THE INVENTION
A hesperitin pro-form is provided. The invention provides both a hydrophilic and a lipophilic hesperetin pro-form.
A pharmaceutical composition is provided which is suitable for topical or oral administration in an individual, the composition comprising a hydrophilic hesperetin pro-form and a pharmaceutically acceptable carrier. A pharmaceutical composition is also provided which is suitable for topical or oral administration in an individual, the composition including a lipophilic hesperetin pro-form and a pharmaceutically acceptable carrier.
A method is provided for treating a subject having or at risk of having a cell proliferative disorder, including administering to the subject a therapeutically effective amount of a hesperetin pro-form.
A method is also provided for decreasing oxidative stress in a subject having a disorder associated with oxidative stress, including administering to the subject a therapeutically effective amount of a hesperitin pro-form.
A method is further provided for treating a subject having or at risk of having a disorder associated with sebacous gland activity, including administering to the subject a therapeutically effective amount of a hesperetin pro-form.
A method is provided for treating a subject having or at risk of having a cardiovascular disorder, including administering to the subject a therapeutically effective amount of a hesperetin pro-form.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
It must be noted that as used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the disease” includes reference to one or more diseases and equivalents thereof known to those skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. Although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described.
All publications mentioned herein are incorporated herein by reference in full for the purpose of describing and disclosing the compounds, reagents, and methodologies which are described in the publications which might be used in connection with the presently described invention. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.
A “hesperetin pro-form” is hydrophilic or a lipophilic pro-form of hesperetin of the general formula:
A “hydrophilic hesperetin pro-form” is a compound of the formula indicated above wherein:
R is H and R
1
is an organic or an inorganic salt of phosphoric or sulfuric acid residue.
Wherein R
1
is H and R is an organic or an inorganic salt of phosphoric or sulfuric acid residue.
A “lipophilic hesperetin pro-form” is a compound of the formula indicated above, wherein:
One of R and R
1
is a saturated or unsaturated fatty acid moiety.
One of R and R
1
is an acid moiety selected from the group consisting of a straight or branched aliphatic chain, including an alkyl, alkenyl, alkynyl, alkoxyalkyl, alkythioalkyl, aminoalkyl group, including substituted or non-substitued cycloalkyl, and an aromatic group, including aryl, aryalkyl, and substitued derivatives such as where a ring contains one or more nitrogen, sulfer, or oxygens.
Without being bound by theory, a hesperetin pro-form has increased metabolic resistance and improved absorption as compared to hesperetin. “Metabolic resistance” as used herein refers to a decreased ability of an enzyme, normally found in a metabolic pathway, to degrade the compound, as compared to a control compound. “Improved absorption” as used herein refers to an increased ability of an organism to absorb a compound, via any route (e.g. dermal absorption, intestinal absorption) as compared to a control compound. Methods and compositions of the present invention provide increased bioavailability of hesperetin by converting this flavanone into pro-compound. This is preferably accomplished by attaching leaving group, which can be readily hydrolyzed under physiologic conditions to produce the starting flavanone.
In one embodiment, hydroxyl groups at 7 and 3′ positions are converted to carboxylic, phosphoric and sulfuric acid esters. In an in vivo environment, enzymatic or spontaneous hydrolysis of the pro-compounds in gastrointestinal tract or skin, release free hesperetin as a function of time. Kinetics of this process can be controlled by appropriate formulation of the procompounds to decrease metabolic transformation and increase absorption of hesperetin in the target cells.
In other aspect of the invention, the pro-compounds may advantageously be employed therapeutically or prophylactically for variety conditions, provided as a dietary supplement, drug or bioactive component of cosmetics.
The molecule of hesperetin has three hydroxyl groups, which differ from each other with different reactivity to acylating reagent. High reactivity of 7-hydroxyl group made possible direct formation of hesperetin-7-esters using activated carboxylic acids or acyl chlorides at the presence of base. Synthesis of hesperetin-3′-eters, required prior esterification of 3′-OH conversion of 7-OH group to benzylformyl or t-butyldimethylsilyl derivatives.
Pharmaceutical Compositions
The invention also contemplates various pharmaceutical compositions containing a hesperetin pro-form that are effective in treating a variety of disorders. These disorders include “cell proliferative disorders”, “disorders associated with oxidative stress”, “skin disorders”, and “cardiovascular disorders”.
The term “neoplasia” refers to a disease of inappropriate cell proliferation. This derangement is most evident clinically when tumor tissue bulk compromises the function of vital organs. The term “cell proliferative disorder” denotes malignant as well as nonmalignant cell populations which often appear to differ from the surrounding tissue both morphologically and genotypically. Malignant cells (i.e., tumors or cancer) develop as a result of a multistep process. Concepts describing normal tissue growth are applicable
Cray Cary Ware & Freidenrich, LLP
McKane Joseph K.
Wright Sonya
Zielinski Laboratory
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