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Growth factor mediated cosmeceuticals and use thereof to enhance skin quality

Growth factor mediated cosmeceuticals and use thereof to enhance skin quality description/claims

The present application claims priority to U.S. Provisional Application No. 60/895,942, filed Mar. 20, 2007.

The present invention is a cosmeceutical formulation containing VEGF, and methods of use thereof to improve skin quality, for example skin quality decreased by diabetes or aging.

Current popular methods to treat facial signs of aging are many and very limited. The popular BOTOX® Cosmetic-with 3.3 million people receiving treatment last year-works by using a low dose of a potent toxin to temporarily paralyze the muscles surrounding the wrinkles, thus smoothing their appearance. However it is limited. Popular ingredients such as alpha-hydroxy acids and retinols can cause the skin to dry and tighten, which could worsen the appearance of wrinkles. Collagen injections can trigger allergic reactions or yield uneven results.

Vascular endothelial growth factor (VEGF), is known by most medical professionals as a sign for poor survival in cancer patients because a tumor will express higher levels of VEGF when it is metastasizing. VEGF serves an important function of facilitating new blood vessel formation. Therefore, a lot of medical attention has been paid to “anti-VEGF” components to try to inhibit the growth and spread of tumors. VEGF's ability to promote blood vessel formation is making it increasingly popular as an ingredient in various cosmeceutical products that claim to fight the appearance of aging skin. One of the biggest problems in treating wrinkles and other signs of aging is getting active ingredients past the natural protective barriers of the skin's surface. However, studies have shown that VEGF may serve to increase permeability in surfaces such as the skin, making its anti-aging effects even more potent.

One successful cosmetic application including VEGF is in Nouricel-MD®, manufactured by Advanced Tissue Sciences. U.S. Pat. No. 6,372,494 describes a method of obtaining growth factors in which cosmetic pursuits are stated as a possible use for the harvested growth factors. Nouricel-MD is used in a concentration of 93% by SkinMedica, a dermatological corporation, in their non-prescription product Tissue Nutrient Solution (TNS) Recovery Complex, which claims to “enhance skin texture, reduce the appearance of age spots and blotchiness, and improve skin elasticity”. Its only claim specific to VEGF is that it is “believed to” stimulate blood vessel formation. The SkinMedica supports its claims by referencing one study, “Reversal of Photodamage with Topical Growth Factors: a Pilot Study” (Fitzpatrick, Rostan, 1995 Cosmetic Laser Associates).

The so-called “Transformation” line manufactured by Jan Marini Skin Research, Inc. contains a moisturizer, serum, and eye cream that all contain a mixture of growth factors, including VEGF. U.S. Pat. No. 6,821,524 details the use of VEGF as “it has been reported that VEGF increases the permeability of blood vessels” and uses a 1995 study by Palade and Roberts to support this claim. The Palade and Roberts study she cites, however, was not conducted on human skin, yet she claims in the parent “the compositions of the invention find use in improving the appearance of fine lines and wrinkles, i.e. in sun damaged skin, etc.”

U.S. patent Application Nos. 20040265268 and 20030068297 both claim that a cosmetic product containing a blend of biological growth factors, including VEGF, would be effective to fight the appearance of aging skin, promote hair growth, as well as have wound-healing properties, based on its use as “a protein that stimulates the growth of new blood vessels”. The applications claim that the products will “repair and rejuvenate mammalian skin” and “reduce the appearance of fine facial lines and wrinkles.

Aging skin is a common concern, and there is a large demand in the market for products to combat the appearance of aging skin, characterized by fine lines, wrinkles, age spots, and loss of elasticity. The latest for treatment of this aesthetic problem is the use of pharmaceutical components, like growth factors and retenoid in topical application. Such products are known unofficially as cosmeceuticals. These contain mixtures of many different things.

From a biological standpoint, an effective plan for rejuvenating and repairing skin must address the rejuvenation of skin cells at both the epidermal and the dermal layers, protection of the rejuvenated cells and cellular activity, stimulation of the production of skin matrix elements, and the sustainability of the rejuvenated conditions over the long term.

It is therefore an object to provide a purely biologic formulation that stimulates the dermis and epidermis and is dose responsive.

It is another object to provide compositions that enhance migration of keratinocytes and collagen deposition to reduce wrinkles, enhance skin quality, and increase skin thickness to normal levels in individuals where skin has thinned due to age or disorders such as diabetes, and which is useful as a cosmeceutical.

It is a further object of the present invention to provide a cosmeceutical containing controlled amounts of specific growth factors, which have defined dosage ranges and proven efficacy.

It has been discovered that vascular endothelial growth factor (“VEGF”) promotes migration of activated (but not differentiating) keratinocytes to skin. This growth factor specifically increases migration of keratinocytes of the “wounded skin” phenotype but does not have significant effects upon differentiated keratinocytes. It also increases collagen deposition and reduces wrinkles, enhances skin quality, and increases skin thickness to normal levels in individuals where skin has thinned due to age or disorder such as diabetes. It is particularly well suited for use as cosmeceuticals when applied in purified form and in known amounts. The data presented in the examples demonstrate efficacy and specificity of VEGF in enhancing migration of normal human keratinocytes as well as formation of new granulation tissue including collagen formation. VEGF induces keratinocyte and fibroblast migration, formation of new tissue, and not only induces deposition of collagen but improves alignment of the collagen fibers. Accordingly, this growth factor is highly suitable for use as a cosmeceutical, especially for skin resurfacing and reduction in wrinkles.

Formulations and methods of use thereof are described. A preferred formulation is a sustained release formulation, most preferably in an easy to administer topical formulation which enhances prolonged delivery and uptake of the growth factor to the skin, or a gene therapy vector. In a preferred embodiment, the carrier includes a pH buffering or neutralizing agent. The formulations may be applied topically to the skin, or adjacent to the site where increased keratinocyte and collagen deposition is desired, or injected or implanted within a sponge or other materials for use as a bulking agent which forms tissue in place of the implant. The formulation provides an effective amount of the growth factor over the necessary time to improve the skin quality, form new tissue, or enhance healing. It has been discovered that there is no additional beneficial effect with using a mixture of growth factors and such a combination may be detrimental. The effects of VEGF are not dependent on angiogenesis.

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