Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
1998-08-10
2002-12-03
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S059000
Reexamination Certificate
active
06488940
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method of treating mammalian skin conditions to stimulate connective tissue synthesis in situations in which such connective tissue synthesis is beneficial. Specifically, the invention relates to novel compositions and methods of using the composition for treatment of aged skin, sun-damaged skin, acne, skin atrophy and for healing of wounds.
BACKGROUND OF THE INVENTION
Estrogens are hormonal compounds that exert wide-ranging biological effects on target tissues. The major organs affected by estrogens are the reproductive tract, genitals, bone, blood vessels and skin.
The most important natural estrogen is 17-&bgr;-estradiol, considered the hormone responsible for most, if not all the normal physiologic processes of this class of compounds. Two other natural estrogens are estrone, a precursor of 17-&bgr;-estradiol and estriol, a metabolic product of 17-&bgr;-estradiol.
Another estrogen, 17-&agr;-estradiol, is the isomer or epimer of 17-&bgr;-estradiol and is biologically much weaker than its &bgr;-isomer when given systemically. In animal studies, 17-&agr;-estradiol is reported to possess only 0.4 to 2% of the potency of 17-&bgr;-estradiol on reproductive function in rodents. When administered to humans subcutaneously, 17-&agr;-estradiol lacked biological activity on a number of markers of reproductive function. For these reasons, 17-&agr;-estradiol is thought to be a physiologically unimportant estrogen and, accordingly, to have minimal therapeutic value or medicinal use.
The skin is known to respond to some estrogens including 17-&bgr;-estradiol. Estrogens stimulate fibroblasts within the dermis and increase the levels of connective tissue matrix molecules. The synthesis of collagen, elastin and non-protein molecules such as hyaluronic acid are elevated when estrogens are administered by systemic or topical routes. Consequently, skin maintains or has an enhanced thickness and integrity. Such skin has a better appearance and is functionally able to resist environmental stresses. Topical treatment of the skin of estrogen-deficient women also showed effacement of wrinkles, increase in water content and improved skin elasticity when treated topically with 17-&bgr;-estradiol. In addition, when wounded, skin would be expected to heal more rapidly in the presence of estrogens because fibroblasts would be in an activated state.
Because 17-&bgr;-estradiol affects multiple organ systems, it is not desirable to use this chemical in treatment solely of topical skin-related conditions. Rather, it would be more desirable to use an estrogen that is more selective in its action on skin. Although 17-&bgr;-estradiol can be administered topically and have local effects on skin, it has the potential to be absorbed into the bloodstream where it can cause undesirable biological responses in non-cutaneous tissues. For example, the delivery of 17-&bgr;-estradiol for estrogen replacement therapy is commonly accomplished through sustained release from a device that is applied topically to skin. This method of delivery demonstrates that 17-&bgr;-estradiol is ideally suited as a compound to cross the skin barrier and accumulate in the bloodstream. Thus by this route, sufficient blood levels of 17-&bgr;-estradiol can be achieved to exert biological activity on all organ systems. Thus, topical administration of 17-&bgr;-estradiol is undesirable, although its effects may be beneficial to the skin.
Surprisingly, we have discovered that a relatively unimportant entity which has low potency in biological systems, 17-&agr;-estradiol, may be used as a topical treatment that is more selective in its effects on skin. Our studies show that topical 17-&agr;-estradiol is just as effective as 17-&bgr;-estradiol at inducing the synthesis of new connective tissue molecules in the dermis of mouse skin, yet, because of its weak activity as a systemically administered estrogen, 17-&agr;-estradiol is expected to exert insignificant biological responses on non-cutaneous tissues such as the reproductive tract if it is absorbed into the bloodstream after topical application. While the use of 17-&agr;-estradiol has been reported in connection with alopecia, hair loss or hair growth, there has been no data showing that it was effective in the treatment of other skin conditions.
Thus it is an object of our invention to provide a method for treatment of skin conditions where stimulated connective tissue synthesis is beneficial.
It is yet another object of this invention to provide a method for treatment of skin conditions including aged, sun-damaged skin, skin atrophy and for healing of wounds, without undue side effects.
It is yet another object of the invention to provide a novel composition containing a pharmaceutically effective agent and a pharmaceutically acceptable carrier for use in treating skin in which synthesis of connective tissue is beneficial.
SUMMARY OF THE INVENTION
We have found, surprisingly, that a composition containing a connective tissue synthesizing-effective amount of 17-&agr;-estradiol and a pharmaceutically acceptable carrier can be used in a method of treating the skin which would benefit from connective tissue synthesis by topical application. Unexpectedly, the compositions of this invention are capable of generating connective tissue synthesis when applied topically, but do not engender other biological or physiological effects systemically. Furthermore, we have also found that an epidermal proliferation enhancing-effective amount of 17-&agr;-estradiol and a pharmaceutically acceptable carrier can be used in a method of treating the skin which would benefit from enhanced epidermal proliferation, such as in the treatment of acne and other such skin conditions.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The compositions and methods of this invention relate to the use of 17-&agr;-estradiol as a topical treatment of skin which requires the stimulation of connective tissue synthesis, such as skin which is aged or sun-damaged and/or enhancement of epidermal proliferation, such as skin which is affected by acne or other conditions.
More particularly, this invention relates to novel compositions and methods of using the composition for treatment of aged, sun-damaged skin, skin atrophy, acne and for healing of wounds and possibly for prevention of scarring due to trauma to the skin, inter alia. The estrogen 17-&agr;-estradiol is a compound of the following structure:
Compositions of the present invention preferably contain 17-&agr;-estradiol in an effective amount to stimulate connective tissue synthesis and/or enhance epidermal proliferation and/or generally affect skin-related growth processes. Preferably, the compositions of this invention contain from about 0.001% to about 5%, more preferably from about 0.01% to about 2% and most preferably from about 0.1% to about 1% by weight of the active ingredient, 17-&agr;-estradiol.
The compounds which are active in the compositions and methods of this invention may be delivered topically by any means known to those of skill in the art. If the delivery parameters of the topically active pharmaceutical or cosmetic agent so require, the topically active composition of this invention may preferably be further composed of a pharmaceutically or cosmetically acceptable vehicle capable of functioning as a delivery system to enable the penetration of the topically active agent into the skin. Thus, the topically active composition of this invention may be formulated in the form of a liquid, gel or cream or any other conventional pharmaceutically or cosmetically acceptable vehicle.
Preferably, the compositions of this invention are applied to the skin over a period of time sufficient to affect skin-related processes, e.g., stimulate connective tissue synthesis or enhance epidermal proliferation. Generally, the effects of the application and use of the compositions of this invention become visible after approximately four to about twenty-four weeks of treatment. It is preferable to apply the compositions of this i
Gendimenico Gerard J.
Mezick James A.
Johnson & Johnson Consumer Companies Inc.
Page Thurman K.
Pulliam Amy
LandOfFree
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