| PATENT ASSIGNEE'S COUNTRY | France |
| UPDATE | 10.99 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 26.10.99 |
| PATENT TITLE |
Products extracted from a plant of the genus Commiphora, particularly the Commiphora mukul plant, extracts containing same and applications thereof, for example in cosmetics |
| PATENT ABSTRACT |
Extracts of the plant Commiphora mukul are used as pigmenting agents and melanocyte culture agents, and for the manufacture of cosmetic and pharmaceutical compositions. Particularly preferred are extracts of the formula IIa, designated Commipherol, and abstracts of the formula IIb designated Commipherin. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 20.05.98 |
| PATENT CT FILE DATE | 13.09.96 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | 20.03.97 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. Product of formula (I): ##STR6## in which R is: a) a CH.sub.2 OH group or b) a COOH group, and salts and esters thereof. 2. Product according to claim 1 of formula (II): ##STR7## in which R is: a) a CH.sub.2 OH group, the product being denoted by formula II.sub.a. b) a COOH group, the product being denoted by formula II.sub.b, c) a group ##STR8## in which R.sub.1 is a linear or branched alkyl group having from 1 to 6 carbon atoms, d) a group COOM, where M denotes an alkali metal, e) a group COOM'.sub.0.5, where M' denotes an alkaline earth metal, or f) a group COOR.sub.2 where R.sub.2 denotes a linear or branched alkyl group having from 1 to 6 carbon atoms. 3. Product according to claim 2, having a formula (II).sub.a : ##STR9## 4. Product according to claim 2, having a formula (II.sub.b): 5. Process for the preparation of a product as defined in claim 1, comprising the steps of treating resin of Commiphora mukul by extraction with an organic solvent to prepare an extract designated extract G, subjecting said extract G to at least one fractionation step in order to isolate a fraction consisting essentially of at least one product selected from the group consisting of the product of formula II.sub.a the product of formula II.sub.b ##STR10## and mixtures thereof, and, optionally forming a salt from or esterifying the product II.sub.b. 6. The process according to claim 5, wherein the solvent used to perform the extraction has a solubility parameter p' which is less than 5.5. 7. The process according to claim 6, wherein the solvent used to perform the extraction is selected from the group consisting of n-pentane, n-hexane, petroleum ether, cyclohexane, n-decane, dichloromethane, isopropanol, n-propanol, chloroform, ethanol, ethyl acetate, acetone and methanol. 8. A method for modifying the surface of the skin by reducing the depth of large and small wrinkles to give the skin a smoother appearance, comprising application to an area of the skin to be treated of a cosmetic composition containing an effective amount of at least one product of formula (I): ##STR11## in which R is: a) a CH.sub.2 OH group or b) a COOH group, and salts and esters thereof. 9. The method according to claim 8, wherein said cosmetic composition contains at least one product of formula (II): ##STR12## in which R is: a) a CH.sub.2 OH group, the product being denoted by formula II.sub.a. b) a COOH group, the product being denoted by formula II.sub.b, c) a group ##STR13## in which R.sub.1 is a linear or branched alkyl group containing from 1 to 6 carbon atoms, d) a group COOM, where M denotes an alkali metal, e) a group COOM'.sub.0.51, where M' denotes an alkaline earth metal, or f) a group COOR.sub.2, where R.sub.2 denotes a linear or branched alkyl group containing from 1 to 6 carbon atoms. 10. The method according to claim 8, wherein said cosmetic composition comprises a product of formula (II.sub.a): ##STR14## 11. The method according to claim 8, wherein said cosmetic composition comprises a product of formula (II.sub.b): 12. The method according to claim 8, wherein said cosmetic composition contains from 0.001 to 1% by weight of said product of formula (I). 13. The method according to claim 8, wherein said cosmetic composition further contains a product for improving fibronectin synthesis. 14. The method according to claim 8, wherein said cosmetic composition further contains a product for improving collagen synthesis. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION The invention relates to the use in cosmetics of extracts of a plant of the genus Commiphora, particularly the plant Commiphora mukul, especially as an agent with antiwrinkle activity. It further relates, by way of novel industrial products, to two particularly active products isolated from these extracts, and to derivatives of these novel products. It is known that the plant Commiphora mukul belongs to the family of the Burseraceae. Commiphora mukul is a plant of Indian origin which is very widely used in traditional Indian medicine and in ayurvedic medicine. A resin produced by Commiphora mukul, which is also called guggul, is used in particular in these applications. This ayurvedic treatment was known to comprise the treatment of obesity and lipidic disorders, as well as rheumatic diseases. It should be noted that the term "guggul" denotes both the plant and the resin it produces. Also, this plant is a small tree or a shrub of 1.2 to 1.8 m in height, which grows essentially in India, and the gum resin can be harvested in the ordinary way by making an incision in the plant. U.S. Pat. Nos. 4,847,071, 4,847,069, 4,946,671 and 4,954,332 have recently described topical compositions, containing free radical absorbers and an anti-inflammatory agent, for protecting against UV radiation. Guggal or guggul extract is among the numerous anti-inflammatory agents mentioned. Furthermore, document EP-A-513 671 has also disclosed compositions containing, as the active ingredient, a total lipophilic extract of the plant Commiphora mukul, which is obtained in particular from the resin of the bark of Commiphora mukul. This extract contains a high proportion of guggulsterones. This composition is described as having an anti-inflammatory, immunomodulating or antiandrogenic activity for the treatment of acne and benign hypertrophy of the prostate. SUMMARY OF THE INVENTION It has now been discovered, surprisingly and unexpectedly, that extracts of a plant of the genus Commiphora, particularly the plant Commiphora mukul, have an antiwrinkle activity and can thus be used as cosmetic agents for improving the surface appearance of the skin and particularly for reducing the depth of large wrinkles and eliminating small wrinkles. On the basis of this discovery, the Applicant carried out complementary systematic studies aimed at identifying particularly active fractions responsible for this activity. It found in particular that these fractions contained two novel products which were particularly active as regards the activity in question. These products could be isolated and totally identified from extracts of the plant Commiphora mukul. They therefore constitute novel industrial products which have a remarkable activity as cosmetic agents for combating wrinkles. DETAILED DESCRIPTION OF THE INVENTION The invention further relates to derivatives of the two novel products isolated according to the invention. Thus, according to a first aspect, the invention relates to the products of formula (I): ##STR1## in which R is: a) a CH.sub.2 OH group or b) a COOH group, and their salts or esters. The invention relates very particularly, by way of novel industrial products, to the products of formula (II): ##STR2## in which R is: a) a CH.sub.2 OH group, the product being denoted by formula II.sub.a, b) a COOH group, the product being denoted by formula II.sub.b, c) a group ##STR3## in which R.sub.1 is a linear or branched alkyl group containing from 1 to 6 carbon atoms, particularly the methyl group, d) a group COOM, where M denotes an alkali metal, preferably sodium or potassium, or a quaternary ammonium or amine group, e) a group COOM'.sub.0.5, where M' denotes an alkaline earth metal, preferably calcium, or f) a group COOR.sub.2, where R.sub.2 denotes a linear or branched alkyl group containing from 1 to 6 carbon atoms. The invention relates very particularly to the two novel industrial products denoted respectively by II.sub.a and II.sub.b and having the following formulae: ##STR4## The two products could be isolated from the plant Commiphora mukul and were completely identified by different analytical techniques, as will become apparent from the following description. The product of formula II.sub.a, the empirical formula of which is C.sub.30 H.sub.50 O.sub.3, will be referred to as "commipherol". Its nomenclature is as follows: (5R,10S,8R,9R)-3-oxopolypoda-13E,17E,21E-triene-8,30-diol. The acid derivative of formula II.sub.b, the empirical formula of which is C.sub.30 H.sub.48 O.sub.4, Will be referred to as "commipherin". This is (5R,10S,8R,9R)-8-hydroxy-3-oxopolypoda-13E,17E,21E-trien-30-oic acid. The nomenclature used to denote the products of formulae II.sub.a and II.sub.b above is based on the name of the corresponding hydrocarbon; this is the triterpene .alpha.-polypodatetraene, which is well known in the literature, for example in the publication by Yoko Arai et al., Tetrahedron Letters, (1992) 33 (10) 1325-8, relating to the plant Polypodiodes formosane. The carbon atoms are numbered as indicated below: ##STR5## It should be noted that various triterpene derivatives possessing the polypodane carbon skeleton have been identified in other plants, particularly in ferns of the families of the Polypodiaceae, such as Polypodium vulgare, P. fauriei and P. virginianum (Y. Arai et al., Phytochemistry, (1991) 30 (10) 3369 -3377; K. Shiojima et al., Tetrahedron Lett., (1983) 24, 5733), the Aspidiaceae (M. Nishizawa et al., J. Chem. Soc., Chem. Commun. (1984) no. 7, 467-8) and the Cheiropleuriaceae (R. Karnaya et al., Chem. Pharm. Bull. (1990) 38 (8) 2130-2). According to a second aspect, the invention further relates to processes for the preparation of the two products II.sub.a and II.sub.b from the plant Commiphora mukul, as well as the acylation derivatives of the product II.sub.a, particularly the acetylation product, and the salts and esters of the product II.sub.b. Different processes can be used to isolate the products of formulae II.sub.a and II.sub.b from the plant Commiphora mukul. In these processes, it is advantageous to start from the resin of Commiphora mukul, which is subjected to different successive extraction and fractionation steps. Thus, particularly advantageously, the resin of Commiphora mukul is subjected to a first so-called extraction step with a solvent or a mixture of solvents, after which the extract is subjected to different separation steps for isolating a particularly active fraction containing at least one of the products of the invention. The first extraction step can be carried out using a wide range of solvents of very different polarities. The following may be mentioned, in order of increasing polarity, as examples of solvents which can be used to carry out this step: petroleum ether, with which 16% by weight of the crude resin can be extracted, dichloromethane, with which 26% by weight of the crude resin can be extracted, ethyl acetate, with which 30.5% by weight of the crude resin can be extracted, ethanol, with which 26.5% by weight of the crude resin can be extracted. FIG. 1 schematically represents different protocols for preparing the products of formulae II.sub.a and II.sub.b from an extract of the resin of Commiphora mukul according to the invention. According to the scheme of FIG. 1, a first extract according to the invention, called extract G, is prepared from the resin of Commiphora mukul. This extract G is obtained by extraction of the resin with 96% ethanol at 45.degree. C. after grinding of the aggregates. In a first step, the extract G is subjected to a series of fractionations by high performance liquid chromatography. Each fraction is tested for its lipogenic activity on fibroblasts in culture using the method explained below. These different fractionations ultimately yield an active fraction, FIIB, whose characteristic peaks are identified on the chromatogram. More precisely, in this first step, the extract G will be subjected initially to a protocol B for isolating the most active fractions, whereby high performance liquid chromatography makes it possible to separate the extract G into three fractions: F representing 92.5% of the extract G, FIII representing 4.5% of this extract, and FIV representing 3%. The fraction FIII could be identified as consisting essentially of sterols, and fraction FIV is composed essentially of the products resulting from the rinsing of the chromatography column with dichloromethane. The fraction F is then subjected to protocol C for separation by liquid chromatography, which yields two fractions called FI and FII respectively. The fraction FI, which is substantially inactive, is discarded. It represents 21.5% of F and consists essentially of sterones (Z- and E-guggulsterone). The fraction FII, which has a lipogenic activity, is in turn subjected to a fractionation by liquid chromatography, whereby it can be separated into three fractions: FIIA representing 19.5% of the extract G, FIIB representing 20% of the extract G, and FIIC representing 31.5% of the extract G. The fraction FIIB is the most active of these three fractions. The positions of the corresponding peaks are identified on the chromatogram. It is then possible, in a second step, to obtain an active fraction called FIIB1, corresponding to the peaks of the fraction FIIB, directly from the extract G by fractionation according to protocol E. The two products of formulae II.sub.a and II.sub.b can then be separated from the extract FIIB1 by preparative high performance liquid chromatography. The two products II.sub.a and II.sub.b, whose activities were found to be substantially equivalent, were perfectly purified and could be isolated by liquid chromatography under the following conditions: Column: RP 18 Lichrospher 5 .mu.m 125.times.4 mm Mixtures: Water+0.1% CF.sub.3 COOH Acetonitrile UV detection: .lambda.=210 nm The product of formula II.sub.a can then be subjected to a conventional acylation step, particularly acetylation step, in order to prepare the corresponding acylated derivatives, particularly the acetylated derivative. The product II.sub.b can easily be converted to one of its salts, described above, by neutralization of the acid function at the end of the chain with a corresponding base. Likewise, the esterification products of the product II.sub.b may easily be obtained by reacting it in conventional manner with a low molecular alcohol. These reactions for acylating the product II.sub.a or esterifying or salifying the product II.sub.b can also be carried out directly on a mixture containing both the active products II.sub.a and II.sub.b, particularly on the mixture FIIB1 described above. For example, the acetylation of II.sub.a with acetic anhydride can be effected by treating the extract FIIB1 in the following manner: FIIB1 is dissolved in dichloromethane (1 volume), 1 volume of pyridine is added, followed by 1.2 equivalents of acetic anhydride per equivalent of FIIB1, and the reaction is allowed to proceed at room temperature overnight. The Applicant found, totally surprisingly, that the extracts of the plant Commiphora mukul, especially the extracts particularly rich in products of formula II.sub.a or II.sub.b, had a stimulating activity on lipogenesis inside the fibroblasts. This results in an increase in the cellular volume of the fibroblasts, leading to better contact with the extracellular protein network. This tones the dermis, making it possible to reduce the depth of the large and small wrinkles and, consequently, to make them less obvious. This activity therefore enabled the Applicant to propose a particularly novel solution for improving the surface appearance of the skin. Thus, according to a third aspect, the invention relates to the use of at least one extract of a plant of the genus Commiphora, particularly the plant Commiphora mukul, as a cosmetic agent for modifying the surface of the skin by reducing the depth of the large and small wrinkles to give the skin a smoother appearance. Different extracts of the plant Commiphora mukul, particularly extracts rich in compounds of formula I, II, II.sub.a or II.sub.b, in a mixture thereof or in derivatives of these products, as defined above, may be used in this application. In a first variant, the gum resin called guggul may be used as the extract of the plant Commiphora mukul. In another variant, an extract obtained after grinding of the aggregates of the resin, followed by extraction with a solvent, is used as the extract of the plant Commiphora mukul. As seen above, a wide range of solvents may be used for this purpose. However, referring to the classification of solvents by polarity, as published in particular by Veronika R. Meyer in Practical High-performance Liquid Chromatography (1988), John Wiley & Sons, pp. 120-121, solvents which will preferably be chosen are those whose polarity parameter p' is less than 5.5 and preferably between 0.1 and 4.5. The above extract is advantageously obtained by extraction with an organic solvent or a mixture of organic solvents selected from the group consisting of n-pentane, n-hexane, petroleum ether, cyclohexane, n-decane, dichloromethane, isopropanol, n-propanol, chloroform, ethanol, ethyl acetate, acetone and methanol. In other variants of the invention, the extract may be made up of different products which share the characteristic of being enriched in at least one of the products of formula I or II, particularly of formula II.sub.a or II.sub.b, obtained from the extract described above. As clearly illustrated in the examples given with reference to the scheme of FIG. 1, the products enriched in product(s) of the invention can be obtained for example from the extract G by subjecting this extract to different successive separation steps, especially involving high performance liquid chromatography or supercritical carbon dioxide extraction. In one particularly advantageous variant of the invention, at least one of the products of formula I or II, particularly of formula II.sub.a or II.sub.b, will be used as the cosmetic agent for modifying the surface of the skin as indicated above. According to a fourth aspect, the invention further relates to a composition, in particular for cosmetic use, characterized in that it contains at least one of the products of formula I or II, particularly II.sub.a or II.sub.b, or plant extracts containing at least one of these products, particularly extracts of a plant of the genus Commiphora and very particularly extracts of the plant Commiphora mukul, preferably in combination with an acceptable, in particular cosmetically acceptable, excipient or carrier. Advantageously this composition contains from 0.001 to 1% by weight of at least one of the products of formula (I) or (II), particularly (II.sub.a) or (II.sub.b), preferably from 0.01 to 0.1%. Alternatively this composition very advantageously contains from 0.005 to 5% by weight, preferably from 0.05 to 1% by weight, of an extract of Commiphora mukul containing at least one of the above-mentioned products, particularly an extract of the resin of this plant. The cosmetic compositions of the invention can be in different forms, in particular in the form of solutions, milks, gels or creams. In one variant of the invention, the cosmetic composition also contains a cosmetically effective amount of a product acting on fibronectin synthesis and/or collagen synthesis. Examples which may be mentioned of products acting on fibronectin synthesis are galactolipids and particularly galactosylglycerides, the use of which is described in the French patent application filed on Feb. 15, 1995 under the number 95.01714, which has not yet been published. Vitamin C may be mentioned as an example of a product acting on collagen synthesis. The invention further relates to a method of cosmetic treatment for modifying the surface of the skin by reducing the depth of the large and small wrinkles to give the skin a smoother appearance, characterized in that an effective amount of a product or a plant extract containing said product is applied to the areas of skin to be treated, particularly to the face, in order to obtain said surface modification, said product or said extract preferably being incorporated in a cosmetically acceptable excipient. In one variant of this method of cosmetic treatment, the above-mentioned plant extract is an extract of the plant Commiphora mukul. Other characteristics and advantages of the invention will become apparent from the following Examples, which are given purely in order to illustrate the invention. |
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