Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-01-05
2003-06-03
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S451000, C424S452000, C424S457000, C424S463000, C424S464000, C424S465000, C424S474000, C424S475000, C424S489000, C424S490000, C424S400000
Reexamination Certificate
active
06572888
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to a controlled release oral formulation of pharmaceutically active compounds. More particularly the invention relates to controlled release lipoic acid oral formulations.
BACKGROUND OF THE INVENTION
A compound known as &agr;-lipoic acid was first isolated by Reed and coworkers as an acetate replacing factor. It is slightly soluble in water, and 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. &agr;-lipoic acid was tentatively classified as a vitamin after its isolation, 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. &agr;-lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia-reperfussion injury (IRI), 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). This document, and all other documents cited to herein, is incorporated by reference as if reproduced fully herein.
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
An oral formulation of lipoic acid is disclosed which formulation is comprised of lipoic acid and one or excipient materials. A wide range of different controlled release formulations will be apparent to those skilled in the art upon reading this disclosure. The formulation of lipoic acid and excipient material is designed to obtain a desires result, e.g. reduce serum glucose levels and/or reduce the amount of medication such as insulin or metformin hydrochloride the patient requires to control symptoms of diabetes mellitus. The desired results are obtained by increasing the period of time that a therapeutic level of lipoic acid is continuously maintained in the patient. The therapeutic level as well as the period of time over which that level must be maintained can vary between patient based on a range of factors such as the condition of the patient and the patient's reactivity to lipoic acid. However, the period of time will be greater than that obtained with a conventional quick release lipoic acid formulation.
The ratio of lipoic acid to excipient material and the particular excipients used result in a formulation which allows the lipoic acid to be released in a controlled manner for absorption into the circulatory system. By maintaining a desired serum level of lipoic acid in blood serum the oral formulation of the invention achieves physiological effects which are superior to those which might be obtained when higher serum levels are obtained for a short term with a quick release oral dosage formulation or a single dose injectable formulation.
By providing for controlled release of lipoic acid the physiological effects are continually provided over a period of time resulting in reduced glucose levels and Alc levels and thereby obtaining a range of associated health benefits. The controlled release formulation of the invention shows that highly desirable therapeutic effects can be obtained by maintaining a therapeutic lipoic acid blood serum level over a period of time which is meaningfully longer than that obtained with a quick release formulation and results are improved by maintaining such day after day. A formulation of the invention will preferably maintain therapeutic levels of lipoic acid over a period which is 10% or more, more preferably 50% or more and still more preferably 100% or more than a quick release formulation. To obtain a particularly preferred result the oral formulation of the invention will quickly release a sufficient amount of lipoic acid so as to quickly obtain a therapeutic level and thereafter release lipoic acid at a rate which substantially matches the rate at which the lipoic acid is being metabolized. Accordingly, the formulation is designed to maintain a therapeutic level over a maximum amount of time based on the amount of lipoic acid in the formulation and to not significantly exceed the therapeutic level.
An aspect of the invention is an oral formulation of lipoic acid, and excipient compounds which provide for controlled release.
A more specific aspect of the invention is that the formulation protects lipoic acid from degradation and allow it to be slowly released over time.
An advantage of the invention is that by maintaining relatively low serum levels of lipoic acid over long periods of time serum glucose levels are suppressed over long periods thereby inhibiting adverse effects which result from abnormally high serum glucose levels.
Another advantage of the invention is that by administering the formulation over long periods the patient is provided with a reduced risk of developing insulin resistance and/or diabetes mellitus.
Another aspect of the invention is that the formulation provides a method of treating type 2 diabetes, i.e. non-insulin-dependent diabetes mellitus (NIDDM).
Yet another aspect of the invention is that the lipoic acid may be present as a racemic mixture or with the R-(+) enantiomer present in amounts greater than 50% and constituting up to 100% of lipoic acid in the formulation.
An advantage of the invention is that a convenient oral delivery dosage form is used to obtain the results which are superior to a single dose injectable.
Another advantage of the invention is that glucose levels can be reduced and be maintained at levels substantially below levels without treatment via the present invention.
A feature of the invention is that the oral formulation may be a tablet, capsule, caplet, etc. containing any desired amount
Bozicevic Karl
Bozicevic Field & Francis LLP
Evans Charesse
Medical Research Institute
Page Thurman K.
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