Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-01-20
2004-05-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S400000, C424S451000, C424S439000, C424S463000, C424S464000, C424S455000, C514S904000, C514S966000, C514S720000
Reexamination Certificate
active
06740338
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a reduced form of Coenzyme Q also known as Ubiquinol in a gelatin capsule, preferably a soft gelatin capsule, in oral administrable form. Compositons according to the present invention exhibit unexpectedly high bioavailability of the reduced (active) form of Coenzyme Q.
BACKGROUND OF THE INVENTION
The use of dietary supplements has become an increasingly common approach to obtaining and maintaining good health. One of these dietary supplements, Coenzyme Q, is a vitamin-like substance which is used to treat congestive heart failure and other cardiac problems. Coenzyme Q is the best known of a group of lipophilic quinones which have the capacity to transfer reducing equivalents or electrons within a lipid phase of cellular membranes. Other quinones of this general lipophilic type found in cells are of diverse species. A few include, for example, rhodoquinone, menaquinone, plastoquinone, chlorobiumquinone, thermoplasmaquinone and phylloquinone. See, Collins, 1985
, Methods in Micobiol
. 18: 329-360. It is postulated that the diene dione chemical structure of these compounds provides a platform for the transfer of one or two electrons and associated protons within the lipid bilayers of cells or to and from hydrophobic redox centers in proteins.
Reduced benzoquinones in general are effective reductants for oxygen or lipid radicals. Early studies showed that reduced coenzyme Q is an effective antioxidant. See, Mellors and Tappel, 1996
, J. Biol. Chem
., 241: 4353-4356. Reduced coenzyme Q now appears to function as part of a complex chain of antioxidant activity. The most important role of coenzyme Q can be in reduction of radicals of &agr;-tocopherol and ascorbate formed when these antioxidants are oxidized by oxygen or carboxyl radicals. There are no enzymes for direct reduction of tocopheryl radical or external ascorbate radical, but there are enzymes in all membranes which can reduce coenzyme Q and the reduced coenzyme Q can reduce the tocopheryl or ascorbate radicals to restore tocopherol or ascorbate. Without the support of enzymes to reduce coenzyme Q, the reduced coenzyme Q would not be a very effective antioxidant because the semiquinone formed by interaction with lipid or oxygen radicals is readily autooxidized with formation of a superoxide radical.
The enzymes involved in coenzyme Q reduction are the primary dehydrogenases for succinate. NADH or other substrates in mitochondria, the NADH cytochorome b
5
reductase in endo and plasma membranes and DT diaphorase or NADPH dehydrogenase enzymes primarily located in the cytosol. Villalbe, et al.,
Proc. Natl. Acad. Sci
. 92:4887-4891 (1995); Beyer, et al.,
Molec. Aspects Med
,. 18(S): 15-23 (1997); and Kishi, et al.,
Molec. Aspects Med
,. 18(S): 71-77 (1997).
Coenzyme Q in endo membranes or plasma membranes is extensively in the reduced form, most of the coenzyme Q in total rat and human tissue is in the reduced form and most of the coenzyme Q in serum is in the reduced state. See, Takahashi, et al.,
Lipids
, 28: 803-809, (1993); Äberg, et al.,
Arch. Biochem. Biophys
., 295: 230-234 (1992); and Yamamoto and Yamashita,
Molec. Aspects Med
., 18 (S) (1997).
Studies performed to date have not focused on the differential uptake and bioavailability of one form of coenzyme Q versus another form of coenzyme Q. Nor has the art recognized the desirability of using ubiquinol as an active pharmacological agent to enhance the bioavailability of coenzyme Q from oral formulations.
OBJECTS OF THE INVENTION
It is an object of the invention to provide storage stable compositions for administering a reduced form of coenzyme Q.
It is an additional object of the invention to provide a method for enhancing the bioavailability of coenzyme Q to patients by administering effective amounts of coenzyme Q in a reduced form.
It is also an object of the present invention to provide an economical means for making ubiquinol-containing compositions from the more readily available and economical coenzyme Q
10
(Ubiquionone).
These and/or other objects of the present invention may be readily gleaned from the detailed description of the invention which follows.
SUMMARY OF THE INVENTION
The present invention relates to novel storage stable compositions in oral dosage form comprising effective amounts of ubiquinol, a reduced form of coenzyme Q, in combination with an amount of a lipid soluble reducing agent effective to maintain ubiquinol in its reduced state when preferably formulated in a soft gel capsule. Compositions according to tifpresent invention may be used for treatment of heart ailments and diseases such as congestive heart failure, mitochochondrial disorders, including mitochondrial encephalomyopathy, lactic acidosis, and strokelike symptoms, Keams-Sayre syndrome and Alper's disease. In addition, the use of ubiquinol to aid in the prevention of reperfusion injury of the heart is another potential use of the present invention.
It is an unexpected result that formulations comprising ubiquinol in soft gel capsules, when administered to patients, exhibit a bioavailability of ubiquinol which is substantially greater than when ubiquinone is administered in oral dosage form, preferably soft gel capsule form. Thus, the present compositions also represent a method for substantially enhancing the bioavailability of Coenzyme Q
10
in the patient's blood stream of an orally administrable form of ubiquinol.
DETAILED DESCRIPTION OF THE INVENTION
The term “coenzyme Q” or “ubiquinone” is used throughout the present specification to describe a group of lipid soluble benzoquinones involved in electron transport in mitochondrial preparations, i.e., in the oxidation of succinate or reduced nicotine adenine dinucleotide (NADH) via the cytochrome system. According to the existing dual system of nomenclature, the compounds can be described as: coenzyme Q
n
where n is 1-12 or ubiquinone (x) in which x designates the total number of carbon atoms in rthe side chain and can be any multiple of 5. Differences in properties are due to to the difference in the chain length. The preferred ubiquinone for use in the present invention is the reduced form of coenzyme Q
10
or ubiquinol.
The term “ubiquinol” is used throughout the specification to describe the reduced form of coenzyme Q which is used as the active ubiquinone in compositions according to the present invention. In ubiquinol, the quinone ring of coenzyme Q is reduced such that the structure of the compound appears as set forth below. In ubiquinol, n is preferably 10 and is derived from coenzyme Q
10
. The amount of ubiquinol which is included in compositions according to the present invention ranges from about 0.1% to about 50% by weight of the final composition which is encapsulated in a soft gelatin capsule, more preferably about 0.5% to about 10% by weight, even more preferably about 1% to about 5% by weight. The amount of ubiquinol which is included in compositions to be encapsulated ranges from about 0.1 to about 10.0 times, more preferably about 1 to about 3 times the amount (in weight percent) of the lipid soluble reducing agent which is included in compositions according to the present invention.
The terms “reducing agent” and “lipid soluble reducing agent” are used throughout the specification to describe pharmaceutically acceptable reducing agents which are added to the compositions according to the present invention in effective amounts to convert ubiquinone to ubiquinol during manufacturing and in preferred embodiments, to substantially reduce oxidation of ubiquinol to ubiquinone (Coenzyme Q) during manufacturing and/or storage of the oral dosage form of compositions according to the present invention. Preferred lipid soluble reducing agents include any reducing agent which is lipid or fat soluble and is capable of providing the requisite reducing activity to stabilize ubiquinol for storage, preferred lipid soluble reducing agents include, for example, &agr;-tocopherol (vitamin E), tocopherol esters, ascorbate esters such as ascorbyl palmi
Coleman Henry D.
Page Thurman K.
Sapone William J.
Sheikh Humera N.
Sudol R. Neil
LandOfFree
Reduced form of Cenzyme Q in high bioavailability stable... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Reduced form of Cenzyme Q in high bioavailability stable..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Reduced form of Cenzyme Q in high bioavailability stable... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3216809