Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Reexamination Certificate
2000-08-29
2002-08-27
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
C514S718000, C424S439000
Reexamination Certificate
active
06441050
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to oral compositions comprising coenzyme Q (ubiquinone) or ubiquinol (a reduced form of coenzyme Q) in a liquid form which provides enhanced bioavailability and is palatable to patients, especially children.
BACKGROUND OF THE INVENTION
Syrups, elixirs, solutions, and suspensions are traditional dosage forms for oral medication and are particularly useful for certain applications where children represent the main target pool of patients. Liquid formulations, at least with respect to a target pool of children, represents a favorable approach for enhancing patient compliance. However, the sine qua non for enhancing patient compliance via an oral route is a formulation with favorable palatability.
Coenzyme Q (ubiquinone), a dietary supplement, is a vitamin-like substance which is used to treat congestive heart failure and other cardiac problems, including heart ailments and diseases such as congestive heart failure, as well as a number of other conditions including high blood pressure, mitochochondrial disorders, including mitochondrial encephalomyopathy, anoxia, lactic acidosis, strokelike symptoms, neurodegenerative diseases, Kearns-Sayre syndrome and Alper's disease, among others. 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. 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.
An 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.
There are several problems with the administration of Coenzyme Q and its reduced form, ubiquinol. First, Coenzyme Q is essentially insoluble in water and ubiquinol is only slightly better. Second, in general, Coenzyme Q and ubiquinol are poorly absorbed, although their bioavailability may be enhanced in hydrosoluble form. Notwithstanding the increased bioavailability of coenzyme Q and especially, ubiquinol, in hydrosoluble form, the taste of the hydrosoluble form of coenzyme Q and ubiquinol is such that formulation as a pleasant tasting liquid for children as an oral dosage form is simply not possible. This is especially problematic for treating children with coenzyme Q and/or ubiquinol in rare orphan diseases such as mitochondrial cytopathies and other disease states or conditions.
Objects of the Invention
It is therefore an object of the present invention to provide a palatable form of Coenzyme Q (ubiquinone) or ubiquinol which can be administered to children in an oral dosage form as a pleasant-tasting liquid.
It is another object of the invention to provide a method for treating children for mitochondrial cytopathies and other diseases and conditions using an oral dosage form which is palatable to children and promotes high bioavailability of coenzyme Q or ubiquinol.
It is a further object of the invention to provide a method for making an oral dosage form of ubiquinone/ubiquinol more palatable.
These and/or other objects of the invention may be readily gleaned from a description of the invention which follows.
SUMMARY OF THE INVENTION
The present invention relates to a composition in pharmaceutical dosage form of coenzyme Q or ubiquinol which can be administered to children in an oral dosage form as a pleasant-tasting liquid. The dosage form comprises an effective amount of coenzyme Q or ubiquinol ranging from about 0.05% to about 10%, more preferably about 1% to about 7.5% by weight of the composition in combination with a minor amount of a polysorbate surfactant such as a Tween™ surfactant, most preferably, polysorbate 80, a major amount of a vegetable oil or triglyceride, in further combination with an amount of phospholipid such as hydroxylated lecithin effective to substantially enhance the palatability of ubiquinone or ubiquinol in combination with a sweetener solution as well as an amount of water preferably ranging from about 5% to about 45% by weight.
In addition to the above components, compositions according to the present invention may optionally comprise solvents, flavorings and optionally, at least one additional surfactant such as a Span surfactant in relatively minor amounts (i.e., in amounts which do not substantially impact the ability of the other components to work together to form a palatable liquid oral dosage form). In the case of the inclusion of ubiquinol, effective amounts of a lipid soluble reducing agent is preferably included in compositions according to the present invention.
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 the 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 coenzyme Q
10
.
The term “ubiquinol” is used throughout the specification to describe the reduced form of coenzyme Q which is used as an 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
by the reduction of coenzyme Q
10
.
The amount of ubiquinone/ubiquinol which is included in compositions according to the present invention ranges from about 0.1% to about 10% (preferably, no more than about 7.5% by weight and even more preferably no more than about 5% by weight of the final liquid composition). The amount of ubiquinol which is included in compositions according to the present invention 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 term “surfactant” or “emulsifier” is used interchangeably to describe additives to compositions according to the present invention. Surfactants are solubilizers which are used to promote the solubility of the ubiquinone/ubiquinol. These are to be used in combination with a triglyceride or vegetable oil and a phospholipid. Polysorbate surfactants (Tween™) are clearly preferred as primary surfactants, but they may be supplemented in the present compositions with minor amounts of secondary surfactants, for example the Span™ surfactants. The amount of surfactant used in the present invention ranges from about 0.1% to about 35% by weight, more preferably about 1.5% to about 25%, preferably about 2% to about 15% by weight. Surfactants for use in the present invention are pharmaceutically acceptable and include, for example, the polysorbate surfactants as primary surfactants and complex esters or ester-ethers prepared from hexahydric alcohol
Coleman Henry D.
Coleman Sudol Sapone P.C.
Pryor Alton
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