Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-08
2001-02-20
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S866000
Reexamination Certificate
active
06191162
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of reducing serum glucose levels. More particularly, the invention relates to the administration of controlled release formulations of lipoic acid to reduce a human patients' glucose levels.
BACKGROUND OF THE INVENTION
The compound &agr;-lipoic acid was first isolated by Reed and coworkers as an acetate replacing factor. It is assumed to be substantially insoluble in water, but soluble in organic solvents. &agr;-lipoic acid is a chiral molecule and is known by a variety of names, including thioctic acid; 1,2-diethylene-3 pentanoic acid; 1,2-diethylene-3 valeric acid; and 6,8-thioctic acid. See Gerreke Biewenga et a.,
An Overview of Lipoate Chemistry
, Lipoic Acid in Health and Disease 1 (1997) (Marcel Dekker). This document, and all other documents cited to herein, is incorporated by reference as if reproduced fully herein.
After being isolated &agr;-lipoic acid was tentatively classified as a vitamin, but it was later found to be synthesized by animals and humans. The complete enzyme pathway that is responsible for the de novo synthesis has not yet been definitively elucidated. Several studies indicate that octanoate serves as the immediate precursor for the 8-carbon fatty acid chain, and cysteine appears to be the source of sulfur. As a lipoamide, it functions as a cofactor in the multienzyme complexes that catalyze the oxidative decarboxylation of &agr;-keto acids such as pyruvate, &agr;-keto glutarate, and branched chain &agr;-keto acids.
More recently, a great deal of attention has been given to possible antioxidant functions for &agr;-lipoic acid, and its reduced form, dihydrolipoic acid (DHLA). Lipoate, or its reduced form, DHLA, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, DHLA may exert prooxidant actions to reduction of iron.
The administration of &agr;-lipoic acid has been shown to be beneficial in a number of oxidative stress models such as ischemia-repercussion injury, diabetes (both &agr;-lipoic acid and DHLA exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin, and NF-&kgr;B transcription factor.
Lipoate may also have other activities. For example, DHLA has been found in vitro to be an anti-inflammatory agent which at the same time interferes with nitric oxide release from inflammatory macrophages and protects target cells from oxygen radical attack. V. Burkhart,
Dihydrolipoic Acid Protects Pancreatic Islet Cells from Inflammatory Attack
, Agents Actions 38:60 (1993).
Lipoic acid is a coenzyme for several enzymes. Lipoic acid is a coenzyme for both &agr;-keto acid dehydrogenase complex enzymes (i.e. pyruvate dehydrogenase complex and &agr;-keto glutarate dehydrogenase complex), branched chain &agr;-keto acid dehydrogenase complex, and the glycine cleavage system. In the enzyme system, the body forms a multi-enzyme complex involving lipoic acid, that breaks down molecules of pyruvate produced in earlier metabolism, to form slightly smaller high energy molecules called acetyl-coenzyme A. This results in molecules that can enter into a series of reactions called the citric acid cycle, or Krebs cycle, which finishes the conversion of food into energy. Essentially, lipoic acid stimulates basal glucose transport and has a positive effect on insulin stimulated glucose uptake.
SUMMARY OF THE INVENTION
A method of reducing a patient's serum glucose level via the oral administration of an active ingredient is disclosed. The active ingredient is lipoic acid, or a pharmaceutically acceptable salt, amide, ester or metabolite thereof. The active ingredient is formulated so that (1) it is not degraded in the stomach and (2) is released in the intestines at a controlled rate so that it enters the circulatory system gradually and continuously over time thereby maintaining a constant effect on suppressing serum glucose levels.
An aspect of the invention is a method of treating human patients by the oral administration of lipoic acid.
An advantage of the invention is that undesirable effects of elevated glucose levels can be suppressed.
A feature of the invention is that lipoic acid is formulated with excipient materials which result in a useful oral dosage form.
An object of the invention is to reduce a patient's glucose level over time and thereby treat insulin resistance.
An aspect of the method of the invention is that relatively low blood serum levels of lipoic acid are maintained over long periods (e.g. 6 hours or more, preferably 12 hours or more per day) each day for months or years to suppress blood serum glucose levels over those periods.
A feature of the invention is that lower blood serum levels of lipoic acid (over longer periods) are obtained as compared to single dose injectables and unformulated oral formulations of lipoic acid.
These and other objects, aspects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the methodology as more fully described below.
DETAILED DESCRIPTION OF THE INVENTION
Before the present, methods of treatment, formulations and components used therein are disclosed and described, it is to be understood that this invention is not limited to particular methods, formulations or components as such may, of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
The publications discussed herein 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 present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided are subject to change if it is found that the actual date of publication is different from that provided here.
Definitions
The term “lipoic acid” is intended to mean &agr;-lipoic acid which is a chiral molecule also known as thioctic acid; 1,2-diethylene-3 pentanoic acid; 1,2-diethylene-3 valeric acid; and 6,8-thioctic acid. Unless specified the term covers the racemic mixture as well as any other (non-50/50) mixture of the enantiomers including substantially pure forms of either the R-(+) or the S-(−) enantiomer. Further, unless specified otherwise the term covers pharmaceutically acceptable salts (e.g. Na and K salts) and amides, esters and metabolites of the acid. The molecule formula is C
8
H
14
O
2
S
2
the molecular weight is 206.32 and it has a pKa of 4.7. In referring to pharmaceutically acceptable salts the term is intended to encompass a conventional term of pharmaceutically acceptable acid addition salts which refer to salts which retain the biological effectiveness and properties of the free-base form of the acid and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosp
Byrd Edward A.
Janjikhel Rajiv
Bozicevic Karl
Bozicevic Field & Francis LLP
Criares Theodore J.
Kim Jennifer
Medical Research Institute
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