Patent Application
20140107223
The present invention is directed to stabilized, UBIQUINOL supplement, skin care compositions suitable for reducing oxidative stress, adjunctively restoring “local” UBIQUINOL levels in the skin, revitalizing skin indicating aging and/or exposure to U.V., and responding to inflammatory challenges.
UBIQUINOL is the reduced, active antioxidant form of coenzyme Q10 (CoQ10). Produced naturally within healthy bodies, UBIQUINOL is CoQ10 that has been converted (activated by the addition of two electrons).
UBIQUINOL is considered to be the strongest lipid soluble antioxidant that is biosynthesized, to provide an active defense against oxidative insult to lipids, protein and DNA; while maintaining redox balance. See: THE POWER OF UBIQUINOL, by Dr. Robert Barry, Ph.D. (2010), Health Point Press, Sherman Oaks, Calif. 91303.
UBIQUINOL supplement, such as Kaneka QH™ UBIQUINOL SUPPLEMENT is unstable in the presence of oxygen and light. This instability has limited UBIQUINOL SUPPLEMENT use since its commercial introduction in 2008 to oral administration via gelatin capsules. R&D efforts from 2008 to the present by many companies, research organizations, etc., attempting to stabilize UBIQUINOL supplement for topical administration to the skin have been unsuccessful.
An object of the present invention is to stabilize UBIQUINOL supplement in the presence of oxygen and light.
Another object of the invention is to develop a manufacturing process suitable for producing light- and oxygen-stable UBIQUINOL supplements useful for topical administration.
Yet another object of the invention is to develop topical UBIQUINOL supplement compositions suitable for dispensing as crèmes, balms, lotions, ointments, etc., onto skin for adjunctively supplementing and restoring “local” UBIQUINOL levels.
Another object of the invention is to: reduce oxidative stress, adjunctively restore UBIQUINOL levels, respond to inflammatory challenges, revitalize aged and/or U.V. damaged skin.
The present invention is directed to stable, topical, UBIQUINOL supplement, skin care compositions useful for reducing oxidative stress and adjunctively restoring “local” UBIQUINOL levels.
The UBIQUINOL in stable, UBIQUINOL supplement, skin care compositions of the present invention is represented by the following structural formula:
Stable UBIQUINOL supplements for skin care compositions of the present invention include a stabilizing composition comprising: ascorbyl palmitate in a weight ratio to UBIQUINOL from between about 0.75 and 2.5 and an emulsion of polydimethylsiloxane in a nonionic surfactant.
The stable, UBIQUINOL supplement, skin care composition also includes trans-dermal absorption facilitators compositions.
The present invention is directed to a stable, topical, UBIQUINOL, skin supplement compositions useful in: reducing oxidative stress, restoring “local” UBIQUINOL levels, revitalizing aging and/or U.V. damaged skin and responding to inflammatory challenges, comprising:
Specifically, stable UBIQUINOL supplement compositions of the invention, upon topical administration to the skin, effect passive diffusion through the skin, reducing oxidative stress by restoring UBIQUINOL levels and revitalizing aging skin.
CoQ10 is a fat soluble, essential, quinone molecule, found in every cell, tissue and organ in the body. CoQ10 partners with other enzymes in the body and plays a vital role in cellular and bodily health, including: energy production and free radical production. CoQ10 production in the body decreases with aging. CoQ10 has been shown to have antioxidant potential and to promote ATP production in the mitochondria inner membrane.
Oxidized (ubiquinone) and reduced (ubiquinol) forms have been identified for CoQ10. Ubiquinone is converted by NADPH-dependent CoQ10 reduction, which uses NADPH as an electron donor, into UBIQUINOL. UBIQUINOL is known to exist as the active form of the coenzyme in the body. In a study in which ubiquinone was orally administered to rats, most CoQ10 molecules detected from the lymph were in the form of UBIQUINOL, suggesting that the coenzyme is reduced immediately after being absorbed from the intestinal tract. UBIQUINOL molecules circulating in the body are incorporated into lipoproteins in the liver and are distributed to tissues all over the body via the blood stream.
These molecules appear to be converted to oxidized molecules in the blood when exposed to oxidative stress caused by various factors. However, since the ubiquinone molecules are re-reduced in the liver, over 90% of all CoQ10 molecules present in the blood of a healthy person are in the form of UBIQUINOL, suggesting that the molecules are in a strong reduction condition.
It is well established that CoQ10 (ubiquinone) is not well absorbed into the body, as has been published in many peer-reviewed, scientific journals. Since the reduced CoQ10 (ubiquinol) form has two additional hydrogens, it results in the conversion of two ketone groups into hydroxyl groups on the action portion of the molecule. This causes an increase in the polarity of the CoQ10 molecule and may be a significant factor behind the observed enhanced bioavailability of UBIQUINOL. Orally, UBIQUINOL exhibits greater bioavailability than ubiquinone: 150 mg per day of UBIQUINOL in a softgel resulted in peak blood values of 3.84 mcg/ml within 28 days. Reduced CoQ10 is absorbed faster and in a larger amount than oxidized CoQ10. See U.S. Pat. No. 6,184,255 assigned to KANEKA CORP.
Oxidative stress is detectable as changes in plasma CoQ10 concentrations and composition and plays an important role in aging of skin, inflammation, etc. For example, deficiencies of Coenzyme Q10 (CoQ10), both oxidized (ubiquinone) and reduced (ubiquinol), have been implicated in: skin aging, U.V. damage of skin and various skin inflammations. “Local” oxidative stress of the skin is associated with wrinkled skin.
UBIQUINOL is the first lipid soluble antioxidant available for antioxidant defenses of the skin associated with oxidative stress. Stable, UBIQUINOL supplements applied topically to the skin via compositions of the invention, would be the first lipid soluble, antioxidant response to oxidative stress in the skin. In this regard, the plasma redox status of UBIQUINOL in the “local” systemic circulation of the oral cavity provides a measure of “local” systemic oxidative stress.
Adjunctive UBIQUINOL mediated effects on “local” skin inflammatory markers, with the topical, stable, UBIQUINOL supplement, skin care compositions of the invention, are expected to indicate reductions in the secretion of several pro-inflammatory cytokines. Damage to nuclear or mitochondrial DNA, indicated by mitochondrial dysfunction caused by oxidative stress is proposed as a common link among various inflammatory and oxidative stress conditions of the skin.
The role of UBIQUINOL supplement responding to inflammatory challenges is particularly well documented in the adjunctive UBIQUINOL supplement treatment of inflammatory challenges to the oral mucosa. The literature references cited below apply with equal force to responding to oxidative stress and inflammatory challenges associated with the skin, where reducing oxidative stress and restoration of UBIQUINOL levels is achieved via topical administration of stable, UBIQUINOL supplement, skin care products of the invention.
Gingivitis and periodontitis are inflammatory disorders caused by bacteria living in biofilm. It is known that oxidative stress in the bloodstream and gingiva is increased by oral inflammatory disorders, including: gingivitis and periodontitis. The net effect of this oxidative stress . . . UBIQUINOL deficiencies, which are to be relieved with the compositions of the invention. See:
Therapy of gum disease with UBIQUINOL and coenzyme Q10 (CoQ10) is reported by:
It is well established that oral inflammations, including gingivitis an periodontitis, are accompanied by a deficiency of coenzyme Q10 (both oxidized and reduced versions).
Hanioka, et. al. (1994) topically applied CoQ10 once weekly via syringe to periodontal sites, for six weeks. The authors reported:
A June 2011, KANEKA/Nihon University presentation reports that oral administration of UBIQUINOL @ 150 mg capsule/day for two months “is effective in improving oral environment for periodontal disease.”
Folkers K. (1992) states:
From 1994 to date, extensive, published research by Kaneka Corp. on CoQ10 has established:
Additional relevant references include:
The present invention is directed to relieving “oxidative stress” and restoring UBIQUINOL levels associated with aging and/or U.V. damaged skin, inflammatory challenges of the skin, etc. Adjunctive, UBIQUINOL, skin care supplements, topically applied by the compositions of the present invention to the skin: reduce oxidative stress, restore UBIQUINOL levels and respond to inflammatory challenges, as evidenced by reduced circulating markers of inflammation. See: X. Wang, et. al. Am. J. Clinical. Nutr. 2004, September; 80(3):649-655:
Subsequent “inflammation” studies carried out with ubiquinol by C. Schmelzer, et. al. J. Clin. Biochem. Nutr. 44:62-66, January 2009, indicated:
Topical administration of stable, UBIQUINOL supplement, skin care compositions of the invention is designed to maximize the therapeutic potential of stabilized UBIQUINOL supplement by adjunctively restoring “local” UBIQUINOL deficiencies within circulating lipoproteins at systemic “uptake” rates. Multiple, topical doses of skin care crèmes, balms, ointments, etc., throughout the day; provide an ongoing adjunctive response to “local” UBIQUINOL deficiencies caused by oxidative stress. These multiple, topical doses are projected to be responsive to systemic UBIQUINOL uptake. Such a controlled, adjunctive, dosing response to local UBIQUINOL deficiencies caused by oxidative stress is not available from orally administered UBIQUINOL supplement using one or more capsules of UBIQUINOL SUPPLEMENT daily.
Orally administered, UBIQUINOL supplement's low water solubility (less than 0.1 mg/ml) and high molecular weight of 865, results in:
In contrast, topical, multiple dose administration of stable, UBIQUINOL supplement, skin care compositions of the invention relies on ongoing trans-dermal absorption to directly enter “local” systemic circulation (lymph system, bloodstream, gingiva, etc.). This alternative administration of stable, UBIQUINOL supplement, skin care compositions of the invention avoids the “first-pass drug effect,” which is experienced by orally administered drugs, where the drugs undergo metabolism. This “first pass drug effect” reduces the bioavailability of orally administered, stable UBIQUINOL supplement before it reaches systemic circulation. A therapeutic UBIQUINOL plasma level objective of >3.5 μg/ml is projected to be sufficient to respond to oxidative stress of the skin. The level of systemic oxidative stress associated with the skin can be established via the plasma redox status of UBIQUINOL.
Proposed advantages of multiple topical administrations of stable, UBIQUINOL supplement, skin care compositions of the invention from a crème, applied in repetitive doses throughout the day to oxidatively stressed skin; versus a single oral administration of UBIQUINOL supplement via capsule, include:
UBIQUINOL is considered to be the strongest lipid-soluble antioxidant that is biosynthesized, providing an active defense against oxidative insult to lipids, proteins and DNA.
UBIQUINOL supplement is unstable in the presence of oxygen, which has limited its use since its introduction in 2008 to oral capsules. R&D efforts, from 2008 to the present, by many companies attempting to stabilize UBIQUINOL for topical administration to skin have been unsuccessful.
The present invention represents a major R&D and manufacturing breakthrough in the stabilization and dispensing of Kaneka QH™ UBIQUINOL supplement for Topical applications to the skin, for relief of oxidative stress associated with: reduced UBIQUINOL levels, aging and/or U.V. damaged skin, inflammatory challenges, etc.
The present invention relies on transporting stabilized Kaneka QH™ UBIQUINOL supplement to the skin for diffusion into the “local” circulatory system. Proprietary: formulating, processing and dispensing conditions for this combination: assures that the oxidative properties of Kaneka QH™ UBIQUINOL supplement have not been compromised and that “reduced” Kaneka QH™ UBIQUINOL supplement is delivered topically to the skin.
Up to the present, restoration of UBIQUINOL deficiencies in the skin associated with oxidative stress has been primarily through adjunctive Kaneka QH™ UBIQUINOL supplement capsules administered orally.
The stabilized, Kaneka QH™ UBIQUINOL, skin care supplement, in combination with its dermal absorption facilitator, is rapidly diffused into the skin. The stabilized Kaneka QH™ UBIQUINOL supplement, combined with ULTRAMULSION® and an absorption facilitator, enters the “local” circulatory system via penetration through the skin. This topical, adjunctive administration of stable UBIQUINOL supplement is projected to help: restore “local” UBIQUINOL deficiencies, reduce oxidative stress and provide relief from inflammatory challenge, as discussed in the cited references.
This trans-dermal, stable absorption of Kaneka QH™ UBIQUINOL supplement, in the reduced state, continues until the topical crème is totally worked into the skin.
In a preferred embodiment of the invention, stable, UBIQUINOL supplement compositions are included in a topical skin care treatment of the invention, where UBIQUINOL supplement adjunctively administered: reduces oxidative stress by increasing “local” UBIQUINOL levels, and restores aging and U.V. damaged skin.
The present invention includes methods:
For purposes of the present invention, suitable emulsions include ULTRAMULSIONS® that are comprised of polydimethylsiloxane in a nonionic surfactant, as described in the following U.S. Pat. Nos. 5,032,387; 5,098,711; 5,538,667 and 5,651,959; all of which are hereby incorporated by reference.
Preferred nonionic surfactants suitable for the invention are selected from the group consisting of: poloxamer 237, poloxamer 338, poloxamer 407 and combinations thereof.
For the purposes of the present invention, trans-dermal absorption facilitators are selected from the group consisting of: dexpanthenol, d-Limonene, poloxamer, PEG, benzyl alcohol, carbopol, chitosan, N-trimethylchitosan, menthol and combinations thereof.
Preferred emulsions for use as carriers of for stabilized UBIQUINOL supplement in the compositions of the present invention include emulsions of polydimethylsiloxane (PDMS) at viscosities ranging from between about 1000 cs and about 2.5 million cs. Particularly preferred, aqueous-free emulsions include as the discontinuous phase PDMS at viscosities between 10,500 cs and 2.5 million cs with those nonionic surfactants described in detail in U.S. Pat. No. 5,651,959, as the continuous phase.
Preferred emulsions for purposes of the present invention include those emulsions disclosed in U.S. Pat. Nos. 5,009,881; 5,032,387; 5,057,306; 5,057,307; 5,057,309; 5,538,667 and 5,651,959; all of which are included herein by reference.
Preferred polydimethylsiloxanes are selected from the group consisting of polydimethylsiloxane: at 1500 cs, at 12,500 cs, at 100,000 cs, at 250,000 cs, at 500,000 cs, at 750,000 cs, at 1.5 million cs, at 2.2 million cs, at 2.5 million cs and combinations thereof.
Preferred application means for the UBIQUINOL skin care supplement compositions of the present invention include: crèmes, ointments, balms, lotions, etc.
The present invention is further described by additional enclosed samples of stable UBIQUINOL supplement, skin care compositions of the invention.
Tank A: 2 L stainless steel vessel was fitted with an overhead stirrer and an aluminum foil cover with constant purging with nitrogen. Deaerated water, 868.8 gm, was added and heated to 70 degrees C. with moderate stirring. The additional ingredients for this vessel were added: glycerin, 24 gm; sodium chloride, 12 gm; and oat kernel flour, 24 gm, were added and heated to 70 degrees C.
A 250 mL stainless steel beaker (Tank B) with overhead stirring and a nitrogen flush was heated to 70 degrees C. The following ingredients were added: cetyl alcohol, 30 gm; benzyl alcohol, 7.3 gm; methyl paraben, 2.4 mg; propyl paraben, 0.6 gm; isopropyl palmitate, 24 gm; petrolatum, 36 gm; and distearyldimonium chloride, 45 gm. After 10 minutes, the homogeneous contents were added to a 2 L stainless steel vessel (Tank C) fitted with overhead stifling and a nitrogen flush with heating to 70 degrees C.
A 100 mL stainless steel beaker (Tank D) was fitted with a nitrogen purge. An aqueous-free emulsion [poloxamer 338/polydimethylsiloxane (1000 cs)] (80:20), 84 gm, was added and heated to 70 degrees C. with overhead stifling. Propylene glycol, 24 gm, UBIQUINOL, 9 gm, and ascorbyl palmitate, 9 gm, were added to the beaker under a nitrogen blanket with stifling. When homogeneous, the contents of Tank D were added to Tank C under nitrogen with stirring and cooling to 30 degrees C. The white colored UBIQUINOL skin lotion was packaged under nitrogen in laminate tubes. Application of UBIQUINOL skin lotion to the forearm gave a silky smooth, moisturizing effect.
EXAMPLES 2 through 4 were prepared following the procedure detailed in Example 1:
Spilanthes extract
