Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-05-02
2003-09-16
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C514S844000
Reexamination Certificate
active
06620803
ABSTRACT:
The present invention relates to the use of 7-hydroxylated steroids for the preparation of cosmetic or dermatological compositions for preventing and/or treating the cutaneous effects of aging and of the action of ultraviolet irradiation.
The formation of steroid hormones, their interrelations and their functions have been widely described in the prior art. The functions of pregnenolone (PREG) and of dehydroepiandrosterone (DHEA) as well as of certain of their derivatives are especially mentioned in the PCT patent application published under the number WO 94/08588.
DHEA and its sulfate derivative (S-DHEA) circulate in a significant quantity in adult men, but its level decreases with age (Orentreich et al.,
J. Clin. Endocr. Metab.
59: 551-555, 1984). It was thus proposed, for example in the French patent application published under the number 2 729 854 or the corresponding European patent application published under the number 723 775, to use S-DHEA in a cosmetic composition for topical application which is intended for the treatment of certain signs of aging. Multiple effects of DHEA have been described, but some of them oppose the processes and the pathologies associated with aging (Watson et al.,
Drug
&
Aging
9: 274-291, 1996).
Despite numerous experiments, it has not been possible to prove any of the explanations advanced for the effects of DHEA (Kalimi et al.,
Molec. Cell. Biochem.
131: 99-104, 1994), and the therapeutic use of DHEA has revealed undesirable secondary effects, in particular in women, as a potential precursor of androgenic hormones.
It has now been shown that the 7-hydroxylated derivatives of PREG and of DHEA are formed by an enzymatic system present in numerous tissues and organs, including the skin, where they favor the mechanisms connected with immunity (Morfin & Courchay,
J. Steroid Biochem. Molec. Biol.
50: 91-100, 1994). Like the levels of circulating DHEA, the activity of these hydroxylating enzymes decreases with age (Doostzadeh & Morfin,
Steroids
61: 613-620, 1996).
The Applicant is therefore interested in the effects of 7-hydroxylated steroids and their derivatives on cells which form the human skin and which are affected during aging or after UV irradiation. The research work carried out by the Applicant has allowed it to be demonstrated that the effects of glucocorticoids leading to cell apoptosis are cancelled out by the 7-hydroxylated steroids and that their action on the cutaneous cells is manifested by beneficial and protective effects.
Surprisingly, the results obtained with the compounds of the invention do not correspond to those conventionally expected with steroid hormones. Indeed, the hydroxylation process carried out by the body on PREG or DHEA is irreversible, and therefore the conventional steroid hormones cannot be produced from 7-hydroxylated derivatives.
Consequently, the use of 7-hydroxysteroids for cosmetological purposes for treating or preventing the cutaneous effects of aging has outstanding advantages with respect to the steroids of the cosmetic compositions of the prior art.
The recent work concerning the cutaneous modifications caused by age or UV and their medical treatment specifically envisages retinoic acid, &agr;-hydroxy acids and DHEA, but does not mention 7-hydroxysteroids (Gilchrest,
Brit. J. Dermatol.
135: 867-875, 1996; Watson et al.,
Drugs
&
Aging
9: 274-291, 1996).
The production of 7-hydroxylated derivatives of DHEA has been known for a long time in the tissues of the human fetus (Sulcova et al.,
Endocr. Experiment.
2: 167-172, 1968), and in the amniotic epithelium (Sulcova et al.,
J. Steroid Biochem.
7: 101-104, 1976), the human liver (Starka,
Sond. Zeit. Natur.
17: 1-2, 1965), human testicles and epididymis (Sulcova & Starka,
Experimentia
28: 1361-1362, 1972) and in human preadipocytes (Khalil et al.
J. Steroid Biochem. Molec. Biol.
46: 585-594, 1993). In addition, the circulating levels of 7&agr;-hydroxy-DHEA have been measured in premenopausal women at 200-300 pg/ml (Skinner et al.
Steroids
30: 315-330, 1977), and 3&bgr;,7&agr;-dihydroxy-5&agr;-androstan-17-one (7&agr;-dihydroxyisoandrosterone) has been characterized in human urine (Jacolot et al.
J. Steroid Biochem.
14: 663-669, 1981). More recently, the phenomenon of 7-hydroxylation has been extended to other steroids which have, in common with DHEA, a 3&bgr;-hydroxylated structure. These are PREG (Akwa et al.
Biochem J.
288: 959-964, 1992; Morfin & Courchay
J. Steroid Biochem. Molec. Biol.
50: 91-100, 1994), 5&agr;-androstane-3&bgr;, 17&bgr;-diol (Morfin et al.
Biochimie.
59: 637-644, 1977; Morfin et al.
J. Steroid Biochem.
12: 629-632, 1980), 3&bgr;-hydroxy-5&agr;-androstan-17-one (Akwa et al.
Biochem. J.
288: 959-964, 1992) and 3&bgr;-hydroxy-5&agr;-pregnan-20-one (Stromstedt et al.
Molec. Pharmacol.
44: 1077-1083, 1993).
Some work on 7-hydroxylated steroids proved that they were without characteristic hormonal effects of both androgenic and estrogenic type or on the secretion of pituitary hormones (Celotti et al.
J. Steroid Biochem.
18: 397-401, 1983; Sunde et al.
J. Steroid Biochem.
16: 483-488, 1982). All of these results therefore lead to the 7-hydroxylation of steroids being considered as a terminal process of hormonal inactivation leading to the urinary and biliary excretion of the 7-hydroxylated steroids produced (Ofner et al.
J. Steroid Biochem.
11: 1367-1379, 1979; Strömstedt et al.
Molec. Pharmacol.
44: 1077-1083, 1993; Khalil et al.
J. Steroid Biochem. Molec. Biol.
48: 545-552, 1994). It is only very recently that it has been possible in part to explain the multiple effects noted with DHEA (Watson et al.
Drug
&
Aging
9: 274-291, 1996) by the immunostimulatory properties of its 7-hydroxylated derivatives (Morfin & Courchay
J. Steroid Biochem. Molec. Biol.
50: 91-100, 1994; Padgett & Loria
J. Immunol.
153: 1544-1552, 1994; Loria et al.
J. Endocrinol.
150: S209-S220, 1996). The antiglucocorticoid properties shown by 7&agr;- and 7&bgr;-hydroxy-DHEA have been proved and extended to other 7-hydroxylated steroids like those described in the PCT patent applications published under the numbers WO 93/20687 and WO 94/08588 for their role in the triggering of immune processes.
It therefore appears that DHEA and the production of its 7-hydroxylated derivatives decrease with age although that of the glucocorticoids does not vary. In the course of aging, the contribution of hormonal steroids to the cutaneous level is therefore found to be modified with a predominance of glucocorticoids whose promoter effects on cutaneous aging are known.
Consequently, a localized contribution of 7-hydroxylated steroids endowed with a particular but natural antiglucocorticoid effect allows the treated skin to be restored to its youthful steroid context.
However, these properties have never been described or suggested in the prior art. Thus, the PCT patent application published under the number WO 94/08588 does not describe or teach any cosmetic or dermatological application of steroid hormone derivatives. In addition, this patent application is directed at steroidal derivatives in which the substitutions in positions 3 and 7 indicated in the formula (I) below are either hydroxyls or ester functions of 1 to 10 carbon atoms.
The European patent application published under the number 415 766 describes the use of retinoid agents for combating cutaneous atrophy by an antiglucocorticoid mechanism. However, no structural relationship exists between the retinoids (vitamin A and its derivatives) and the steroids.
The European patent application published under the number 189 738 describes the use of dehydroepiandrosterone (DHEA) and of its ester derivatives for treating drying out of the skin, but these compounds are different from the steroids which are the subject of the present invention.
The European patent application published under the number 723 775 envisages the use of the sulfate of DHEA in cosmetic and dermatological compositions and suggests the addition to these compositions of steroid hormones other than
Badio Barbara P.
Vitasterol SARL
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