Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
2001-06-29
2004-03-30
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S059000, C514S023000, C514S024000, C514S025000, C514S026000, C514S033000, C514S182000
Reexamination Certificate
active
06713074
ABSTRACT:
FIELD OF THE INVENTION
This invention provides a composition and method for reducing or preventing wrinkling and damage of skin upon topical application.
BACKGROUND OF THE INVENTION
As women go through menopause and men age, both experience increased skin wrinkling and decreased skin thickness. Until recently, the molecular mechanism responsible for these skin changes was not well understood. In post-menopausal women, the decreasing levels of plasma estrogen obviously plays a role in the process, but estrogen's influence on the molecular pathways that lead to skin wrinkling and skin thinning was not recognized until recently. Ascroft et al. reported that oral estrogen replacement therapy reversed the delay in healing of skin biopsy wounds observed between pre-menopausal women and healthy post-menopausal women. (See G. S. Ascroft et al, “Estrogen Accelerates Cutaneous Wound Healing Associated with an Increase in TGF-&bgr;1,” Nature Medicine 3:1209-1215, 1997; Ascroft et al., “Human Ageing Impairs Injury-induced in Vivo Expression of Tissue Inhibitors of Matrix Metalloproteinases (TIMP-1 and -2 Proteins and mRNA,” J. Pathol. 183:169-176, 1997; Ascroft et al., “Age-Related Changes in the Temporal and Spatial Regulation of Matrix Metalloproteinases (MMP) Protein and mRNA Profiles in Normal Skin and Acute Cutaneous Wounds of Healthy Humans,” Cell tissue Res. 290:581-591, 1997). In addition, they reported that systemic estrogen replacement therapy increased the level of transforming growth factor protein and decreased the levels of matrix metalloproteinases in wound sites. This discovery led Ascroft, et al., to hypothesize that systemic estrogen replacement therapy stimulated production of TGF-&bgr;1, which is known to stimulate synthesis of extracellular matrix proteins including collagen and simultaneously decreases the production of matrix metalloproteinase. The result of these combined effects of estrogen was to promote healing of the full-thickness punch wounds in the skin of post-menopausal women.
In a subsequent paper, Ascroft et al., investigated the effects of topical estrogen treatment in aged humans. (Ascroft et al., “Topical Estrogen Accelerates Cutaneous Wound Healing in Aged Humans Associated with an Altered Inflammatory Response,” Am. J. Pathol. 155:1137-1146, 1999). The skin punch biopsy model was utilized as before, but instead of placing the patients on oral estrogen replacement therapy or not, aged men (average age of 70 years old), and women (average age of 74 years old) were randomized to receive either estrogen (25 micrograms estradiol per 24 hours) delivered topically by a skin patch placed over the wound or placebo. Compared to placebo, topical estrogen treatment increased the extent of wound healing in both males and females with a decrease in wound size at day 7, increased collagen levels at both days 7 and 80, and increased fibronectin levels at day 7.
Taken together, these studies indicate that systemic or topical estrogen may improve healing of full-thickness skin wounds in aged men and women, by increasing the levels of TGF-&bgr;1 which in turn increases synthesis of collagen and simultaneously decreases levels of matrix metalloproteinases.
In U.S. Pat. No. 6,130,254, methods for inhibiting photoaging of skin are disclosed. The method disclosed includes the use of UVA and UVB blockers in combination with an MMP inhibitor, such as a retinoid. In one composition, a composition comprising a retinoid in combination with a flavone or isoflavone compound was disclosed and claimed for application to the skin at least eight hours prior to exposure to the sun.
None of the art identified by the present inventors includes the combination of a MMPI, and an estrogen or phytoestrogen for long-term, daily application to reduce the effects of aging on skin (wrinkling, fine lines, loss of tone, and the like). The present invention provides a solution that meets this need. In addition, in specific compositions according to this invention, combinations of non-retinoid MMP inhibitors, and non-flavone or isoflavone phytoestrogens are used in combination with known UVA and UVB blockers to treat, including to reverse, reduce, prevent or avoid aging photoaging of skin, including fine lines and wrinkles in skin.
SUMMARY OF THE INVENTION
The cosmetic topical formulation of this invention is directed toward diminishing skin wrinkling, improving skin tone, or both. Preferably, the topical formulation contains a matrix metalloproteinase inhibitor, MMPI, and advantageously includes a natural estrogen, e.g., a true estrogen compound, such as 17-beta estradiol, or an estrogen-like steroid, (such as various phytoestrogens found in herbal preparations), as opposed to a synthetic estrogen. Other forms of the cosmetic topical formulation of this invention include combinations of synthetic estrogen and MMP inhibitor. Exemplary synthetic estrogens include, but are not limited to, ethinyl estradiol and clomiphine citrate. The cosmetic topical formulation is safe and effective in diminishing wrinkling, and improving skin tone. In specific formulations, the composition of this invention may furthermore be used to reduce or reverse photoaging or cigarette smoking induced wrinkling or fine lines that occurs in living human skin.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THIS INVENTION
In one exemplary embodiment of the present invention, a combination of a natural or synthetic estrogen with an MMP inhibitor, such as Ilomostat, is provided in a topical formulation for use as a cosmetic anti-wrinkle cream. The combination of the estrogen and the MMP inhibitor synergistically promotes deposition of new extracellular matrix and reduces its turnover, resulting in the reduction in wrinkling and thinning associated with normal skin aging. In addition, the method and composition according to this invention is useful in limiting the degree of skin wrinkling, fine lines and aging associated with cigarette smoking, cigar smoking, second hand smoke exposure, and the like, bum victims, fire-fighters, and others exposed to smoke.
The matrix metalloproteinase inhibitors (MMPIs) for use according to this invention include, but are not limited to, those MMPI compounds disclosed and claimed in U.S. Pat. Nos. 5,892,112; 5,773,438; 5,696,147, all of which are hereby incorporated herein by reference. Ilomostat is one preferred MMPI.
Collagen molecules provide the major tensile strength of the skin. As a person ages, protein components in the extracellular matrix of the dermis, such as collagen molecules, become degraded. As a result, the skin begins to sag, wrinkle, and thin. The second component of the present topical formulation, the MMP inhibitor, addresses this problem. A preferred MMP-inhibitor is Ilomostat, which is a small, modified dipeptide and an extremely potent inhibitor of the major classes of MMPs present in the skin including collagenases, gelatinases, and stromelysins. Ilomostat also has the desirable property of being amphipathic, which means that it has both hydrophobic and hydrophilic properties. Therefore, Ilomostat can diffuse through the hydrophobic keratinized layers of the epidermal layer of the skin, and also interact with the proteases that are present in the water-filled extracellular matrix of the dermis. Although the topical formulation includes Ilomostat, other MMP inhibitors (natural or synthetic or both) may be used in other embodiments of the topical formulation, such as tissue inhibitors of metalloproteinases (TIMP), Galardin, Batimastat, Marimastat or any hydroxamate-based synthetic inhibitors.
As discussed above, the topical formulation is a cosmetic composition, as opposed to a prescription drug. The cosmetic topical formulation of this invention is directed toward diminishing skin wrinkling, skin tone, or both. Preferably, the topical formulation includes an MMPI, and also advantageously includes a natural estrogen, e.g., a true estrogen compound, such as 17-beta estradiol, or an estrogen-like steroid, (such as various phytoestrogens found in herbal preparations
Lerner David S.
Schultz Gregory
Bencen Gerard H.
Hartley Michael G.
Lamm Marina
Quick Med Technologies Inc.
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