Title:
METHOD OF ALLEVIATING WRINKLES ON SKIN
United States Patent 3689668
Abstract:
Cosmetic compositions containing an amine, such as the di-aspartate of arginine para-aminobenzoyl-diethylaminoethanol, and a method for the substantial reduction of folds and wrinkles in the skin are disclosed. The cosmetic compositions are useful in that they have a hydrating effect on the human skin such that the complexion and brightness thereof can be substantially improved, whereas the folds and wrinkles of the skin can be substantially reduced. 13 Claims, No Drawings
Inventors:
Emile Leon, Piette 40 Avenue Moliere
, BE.
, BE.
Application Number:
05/080492
Publication Date:
09/05/1972
Filing Date:
10/13/1970
View Patent Images:
Export Citation:
Primary Class:
Other Classes:
424/583, 424/582
International Classes:
A61K8/44; A61K8/98; A61Q19/00; A61K8/30; A61K8/96; A61K7/00
Field of Search:
424/319
Other References:
Chemical Abstracts, Vol. 63, p. 13415 (b), 1965..
Primary Examiner:
Albert, Meyers T.
Assistant Examiner:
Doris, Funderburk J.
Attorney, Agent or Firm:
Sughrue, Mion, Zinn & Macpeak
Parent Case Data:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of my co-pending application, Ser, No. 736,032, filed June 11, 1968 now abandoned.
Claims:
1. A method of temporarily alleviating wrinkles on human skin, which comprises topically applying to said skin a wrinkle alleviating effective amount of at least one compound of the formula: ##SPC2## in which R represents an alkylene group --(CH2)n wherein n=1 or
2. The method of claim 1 wherein the compound is the di-aspartate of
3. The method of claim 1 wherein the compound is an acid addition salt of
4. The method of claim 1 wherein the compound is the hydrochloride of
5. The method of claim 1 wherein the compound is the di-glutamate of
6. The method of claim 1 wherein the compound is the hydrochloride of
7. The method of claim 1 wherein the compound is the tri-aspartate of
8. The method of claim 1 wherein the compound is an acid addition salt of the tri-aspartate of di-L-arginine para-aminobenzoyl- diethylaminoethanol.
9. The method of claim 1 wherein the compound is the hydrochloride of
10. The method of claim 1 wherein the compound is the tri-glutamate of
11. The method of claim 1 wherein the compound is an acid addition salt of the tri-glutamate of di-L-arginine-para-aminobenzoyl- diethylaminoethanol.
12. The method of claim 1 wherein the ingredient is the hydrochloride of the tri-glutamate of di-L-arginine-para-aminobenzoyl-diethylaminoethanol.
13. The method of claim 1 wherein the compound is contained in a cosmetically acceptable inert carrier at a level of from 0.1% to about 2% by weight of the composition.
2. The method of claim 1 wherein the compound is the di-aspartate of
3. The method of claim 1 wherein the compound is an acid addition salt of
4. The method of claim 1 wherein the compound is the hydrochloride of
5. The method of claim 1 wherein the compound is the di-glutamate of
6. The method of claim 1 wherein the compound is the hydrochloride of
7. The method of claim 1 wherein the compound is the tri-aspartate of
8. The method of claim 1 wherein the compound is an acid addition salt of the tri-aspartate of di-L-arginine para-aminobenzoyl- diethylaminoethanol.
9. The method of claim 1 wherein the compound is the hydrochloride of
10. The method of claim 1 wherein the compound is the tri-glutamate of
11. The method of claim 1 wherein the compound is an acid addition salt of the tri-glutamate of di-L-arginine-para-aminobenzoyl- diethylaminoethanol.
12. The method of claim 1 wherein the ingredient is the hydrochloride of the tri-glutamate of di-L-arginine-para-aminobenzoyl-diethylaminoethanol.
13. The method of claim 1 wherein the compound is contained in a cosmetically acceptable inert carrier at a level of from 0.1% to about 2% by weight of the composition.
Description:
This invention relates to cosmetic compositions having such a hydrating effect on the human skin that the complexion and brightness thereof can be substantially improved, whereas the folds and wrinkles of the skin can be substantially reduced by applying the cosmetic compositions to the human skin.
The appearance of the skin depends from the complexion, brightness, ruggedness (folds and wrinkles) and wear thereof. As is known, the relief of the skin may be influenced by hydrating cosmetic compositions containing, as active ingredients, singly or combined, various products such as extracts (embryo, tissues or placenta), animal serums or plasmas, amniotic fluid, plant extracts, lecithines, amino-alcohols, such as choline and the salts and derivatives thereof, and the like.
This invention relates to cosmetic compositions having a significant hydrating activity when topically applied to human skin, due to the presence in the cosmetic compositions of amine compounds as defined hereafter which have a hydrating activity which was unknown heretofore and which have not been used in cosmetology until now. These amine compounds may also be added to known hydrating cosmetic compositions, in which they increase surprisingly the hydrating activity of the known hydrating ingredients.
SUMMARY OF THE INVENTION
The invention concerns a method for substantially reducing the folds and wrinkles in skin by topically applying hydrating cosmetic compositions containing, as active ingredient, at least one amine compound, which may be represented by the following general formula: ##SPC1## In which R represents an alkylene group --(CH 2 ) n where n = 1 or 2, and m represents 1 or 2.
DETAILED DESCRIPTION OF THE INVENTION
When each R in the above described formula represents a methylene group (--CH 2 --) and m is 1, the compound of the general formula I is the diaspartate of arginine para-aminobenzoyl-diethylaminoethanol.
When each R represents an ethylene group --(CH 2 ) 2 -- and m is 1, the compound of the general formula I is the di-glutamate of arginine para-aminobenzoyl-diethylaminoethanol.
When each R represents a methylene group (--CH 2 --) and m is 2, the compound of the general formula I is the tri-aspartate of di-L-arginine para-aminobenzoyl-diethylaminoethanol.
When each R represents an ethylene group --(CH 2 ) 2 -- and m is 2, the compound of the general formula I is the tri-glutatmate of di-L-arginine para-aminobenzoyl-diethylaminoethanole
The compounds of the general formula I are crystallizable and have similar physico-chemical and biological properties. They can be used in their dextrogyre (D), levogyre (L) or racemic (DL) forms and also as acid addition salts, such as the hydrochlorides.
The compounds of the general formula I may be prepared by reaction of one or two moles of arginine glutamate or aspartate with one mole of para-aminobenzoyl-diethylamino-ethanol in a solvent, such as distilled water, at the reflux boiling temperature of the reaction medium. After evaporation under reduced pressure, the product is crystallized at a temperature of less than 0° C or is dried in a drying closet. Crystalline pure products, which are clearly distinguished from mere mixtures of the starting reactants, are thus obtained with a yield of 98 to 99%.
The preparation of the compounds of formula I is described with more details in the following examples.
EXAMPLE 1
To 46.82 grams of dry (1-) arginine di-(1+) glutamate dissolved in 500 millilitres of fresh distilled water, heated at 80° C, 23.63 grams of para-aminobenzoyl-diethylaminoethanol are added, while stirring.
The mixture is maintained at the boiling temperature (40°-50° C) under reduced pressure and is then concentrated, by distillation of the aqueous solvent, until an opalescent product is obtained. The product is then crystallized at a temperature of less than 0° C and dried during 24 hours at 45° C in a drying closet. Yield: 98 to 99%. About 69 grams of crystalline di-(1+) glutamate of (1-) arginine para-aminobenzoyl-diethylaminoethanol are thus obtained. Melting Point: 172°-173° C.
EXAMPLE 2
To a solution of 50.45 grams of the monohydrochloride of (1-) arginine di-(1+) glutamate dissolved in 450 millilitres of fresh distilled water, heated at 80° C, 23.63 grams of para-aminobenzoyl- diethylaminoethanol are added, while stirring the reaction medium. By treating this medium as described in Example 1. 72.5 grams of crystalline di-(1+) glutamate of (1-) arginine para-aminobenzoyl-diethylaminoethanol are obtained. This compound starts melting at 159° C with decomposition and melts until 170°-172° C.
EXAMPLE 3
100 millilitres of a 1N solution of hydrochloric acid are added to 46.82 grams of (1-) arginine di-(1+) glutamate. The obtained mixture is heated at boiling temperature and 350 millilitres of fresh distilled water are added thereto. The temperature is maintained at 80° C and 23.63 grams of para-aminobenzoyl-diethylaminoethanol are added, while stirring the reaction medium. This medium is then treated as described in Example 1. 72.5 grams of the crystalline monohydrochloride of di-(1+) glutamate of (1-) arginine para-aminobenzoyl-diethylaminoethanol are obtained as in Example 2.
EXAMPLE 4
To a boiling solution of 44 grams of dry (1-) arginine di-(1-) aspartate in 500 millilitres of fresh distilled water, 23.63 grams of para-aminobenzoyl-diethylaminoethanol are added while stirring. The reaction mixture is then treated as described in Example 1. About 66 grams of crystalline di-(1-) aspartate of (1-) arginine para-aminobenzoyl-diethylaminoethanol are obtained. Melting point: 144°-148° C.
EXAMPLE 5
To a boiling solution of 47.65 grams of the monohydrochloride of (1-) arginine de (1-)aspartate in 500 milliliters of fresh distilled water, 23.63 grams of para-aminobenzoyl-diethylaminoethanol are added while stirring. The reaction mixture is then treated as described in Example 1. About 70 grams of the crystalline monohydrochloride of di(1-) aspartate of (1-)arginine paraaminobenzoyl-diethylaminoethanol are obtained. This compound starts melting at 152° C (with decomposition).
EXAMPLE 6
100 milliliters of a 1N solution of hydrochloric acid are added to 44 grams of (1-) arginine di (1-) aspartate. The obtained solution is heated to boiling temperature and 400 milliliters of fresh distilled water are added thereto. While maintaining the temperature at 85° C and while stirring the mixture, 23.63 grams of para- aminobenzoyldiethylaminoethanol are added. The reaction mixture is then treated as described in Example 1. About 70 grams of crystalline monohydrochloride of di(1-) asparate of (1-)arginine para-aminobenzoyl- diethylaminoethanol are obtained.
EXAMPLE 7
The tri-glutamate of di-arginine para-aminobenzoyl-diethylaminoethanol (M.P.: 235°-238° C) and the hydrochloride thereof are prepared by the procedure described in Examples 1, 2 and 3, except that two moles of di-arginine glutamate per mole of para-aminobenzoyl- diethylaminoethanol are used.
EXAMPLE 8
The tri-aspartate of di-arginine para-aminobenzoyl-diethylaminoethanol (M.P.: 205°-208° C) and the hydrochloride thereof are prepared by the procedure described in Examples 4, 5 and 6, except that two moles of di-arginine aspartate per mole of para-aminobenzoyl- diethylaminoethanol are used.
The compounds of the general formula I and the hydrochlorides thereof are soluble in water. All that is necessary is to apply topically the compounds of the general formula I in an effective amount of the compound sufficient to alleviate the folds and wrinkles of the skin.
The hydrating cosmetic compositions for external use according to this invention, which contain, as active ingredients, at least one compound of formula I, may take various forms and may be used on the human skin. Said compositions may take the form of fatty or non fatty creams, milky suspensions or emulsions of the water-in-oil or oil-in-water types, lotions, gels or jellies, colloidal or non colloidal aqueous or oily solutions, pastes, soaps, aerosols, soluble tablets (to be dissolved in a fluid, such as water) or sticks.
The amount of active ingredient contained in the hydrating cosmetic compositions according to the invention applied to the skin may vary between wide limits, depending from the formulating and from the frequency of use of said compositions. Generally, said compositions contain from 0.1% to 2%, by weight of the composition of active ingredient of the formula I.
The hydrating cosmetic compositions used in the method according to the invention may contain not only one or more active ingredients of the formula I but also conventional vehicles or carriers, such as solvents, fats, oils and mineral waxes, fatty acids and derivatives thereof, alcohols and derivatives thereof, glycols and derivatives thereof, glycerol and derivatives thereof, sorbitol and derivatives thereof, surface-active agents of the anionic, cationic or non ionic type, emulsifying agents, preserving agents, perfumes, etc.
A few examples of hydrating cosmetic agents used in the method according to this invention are given hereafter. These examples are only illustrative and must not be considered as limiting the scope of the invention. In said examples, the percentages are by weight.
EXAMPLE I
Hydrating Milk Mono and diglycerides of fatty acids 5 to 6% (palmitic and stearic acids) Condensate of polyglycol and saturated 2.5 to 3% fatty alcohol ethers with polyoxyethylene Isopropyleneglycol 5 to 15% Perhydrosqualene 5 to 15% Amniotic fluid 2 to 10% Tri-aspartate of di-arginine-para- aminobenzoyl diethylaminoethanol 0.5 to 1% Distilled water q.s.ad. 100%
EXAMPLE II
Hydrating Milk High fatty alcohols (such as cetyl, stearyl, myristyl alcohols) 5 to 6% Condensate of polyglycol and saturated fatty alcohol ethers with polyoxyethylene 2.5 to 3% Isopropyleneglycol 5 to 15% Perhydrosqualene 5 to 15% Amniotic fluid 2 to 10% Tri-aspartate of di-arginine-para- aminobenzoyl-diethylaminoethanol 0.5 to 1% Distilled water q.s.ad. 100%
EXAMPLE III
Hydrating Milk Mono and diglycerides of palmitic and stearic acids 5 to 6% Condensate of polyglycol and saturated fatty alcohol ethers with polyoxyethylene 2.5 to 3% Glycerol 5 to 15% Ester of stearic acid and octyldodecanol 5 to 15% Amniotic fluid 2 to 10% Tri-glutamate of di-arginine para- aminobenzoyl diethylaminoethanol 0.5 to 1% Distilled water q.s.ad. 100%
EXAMPLE IV
Cream of the Oil-in-Water Type Liquid paraffin 40 to 60% White wax 5 to 10% Solid paraffin 2 to 8% Borax 0.1 to 0.5% Di-aspartate of arginine para-amino- benzoyl diethylaminoethanol 0.5 to 1% Distilled water q.s.ad. 100%
EXAMPLE V
Cream of the Water-in-Oil Type Liquid paraffin 30 to 50% Ozokerite 3 to 8% Solid paraffin 1 to 3% Lanoline 1.5 to 4% Mono-diglycerides of fat-forming fatty acids with not more than 1/100 of 1% butylated anisole, 1/100 of 1% butylated hydroxy toluene, and 1/100 of 1% citric acid in propylene glycol added as a preservative (Arlacel 186-Atlas Chemical Industries-Wilmington, Delaware, U.S.A.) 1 to 2% Polysorbate 80, an ester of sorbitan etherified with polyethylene glycol (Tween 80 - Atlas Chemical Industries) 0.1 to 0.3% Di-glutamate of arginine para- aminobenzoyl-diethylaminoethanol 0.5 to 1% Water q.s.ad. 100%
EXAMPLE VI
Hydrating Lotion Triethanolamine lauryl sulfate 1 to 5% Isopropanol 40 to 60% Cetiol V (decylic ester of oleic acid- Dehydag Deutsche Hydrierwerke, Dusseldorf, Germany) 2 to 6% Triglutamate of di-arginine para-amino- benzoyl diethylaminoethanol 0.5 to 1% Water q.s.ad. 100%
EXAMPLE VII
Cream of the Water-in-Oil Type Amphocerine K (Dehydag), a mixture of fatty alcohols and waxy esters of animal origin 40 to 60% Placenta extract 5 to 15% Tri-aspartate of di-arginine para- aminobenzoyl diethylaminoethanol 0.5 to 1% Water q.s.ad. 100%
EXAMPLE VIII
Hydrating Aerosol
The cream of the oil-in-water of Example IV and 8% by weight of a mixture of 40% dichlorodifluoromethane and 60% dichlorotetrafluoromethane are introduced into an aerosol container.
To the formulations described in Examples I to VIII, perfumes (such as rose, orange, jasmine oil and the like), dyes or pigments (such as zinc oxide, titanium oxide, ochre and the like), as well as preserving or antioxidizing agents (such as butylhydroxy toluene, butylhydroxy anisole, sorbic acid, methyl para-hydroxybenzoate, and the like) may be added in suitable amounts, as well known in cosmetology.
Tests have been made in vivo with the hydrating cosmetic compositions according to the invention. These tests have clearly shown that said compositions have remarkable hydrating properties when topically applied to the skin.
These tests have shown the hydrating properties of the compounds of formula I as well as the synergistic effect of these compounds on already known hydrating products (such as amniotic fluid, placenta extract and the like), when they are used jointly with these known products.
The tests have been made by applying on the human face (forehead and cheeks) masks for taking impressions of the relief of the skin before and after treatment by means of various hydrating compositions. For taking such impressions, compositions of the Laboratory of Dr. Renaux (Paris, France) containing rubber or plastic materials, which cure in contact with the skin, have been used. The masks obtained after curing or hardening on the face of the rubber or plastic-based compositions and after removing the hardened layers from the face may be used for determining objectively the effectiveness of the hydrating compositions according to the invention for reducing or alleviating the skin wrinkles, manly by hydrating the skin. The effect of reducing or alleviating the skin wrinkles is determined by counting with an approximation of ±1% the impressions of the wrinkles on surfaces of an area of 3cm 2 of the masks.
The count of impressions on the masks taken before the treatment by means of hydrating compositions is used as base for the subsequent counts. A value of 100% is given to the number of wrinkle impressions counted on the mask taken before the treatment by means of the hydrating compositions.
As control, a hydrating cream containing only water as the hydrating ingredient has been used.
Said control cream had the following composition. Formulation A Mono- and di-glycerides of palmitic and stearic acids 6% Condensate of polyglycol and saturated fatty alcohols with polyoxyethylene 3% Ester of stearic acid and diethyldodecanol 10% Preserving agent and perfume q.s. Water q.s.ad. 100%
For one series of tests, 1% of tri-aspartate of arginine para-aminobenzoyl-diethylaminoethanol (Formulation B) was added to said base or control cream.
For another series of tests, 20% of amniotic fluid, 10% of human placenta extract and 0.1% of choline chloride (Formulation C) was added to the control cream, these three known products being commonly used in hydrating creams of good quality.
For still another series of tests, 20% of amniotic fluid, 10% of human placenta extract, 0.1% of choline chloride and 1% of tri-aspartate of arginine para-aminobenzoyl-diethylaminoethanol (Formulation D) were added to the control cream.
Finally, for the last series of tests, a cream (Formulation E) similar to Formulation D was used, except that it contained 10% in place of 20% of amniotic fluid, 5% in place of 10% of placenta extract and 0.05% in place of 0.1% of choline chloride (i.e., 50% less of these active ingredients than in Formulation D), the proportion of tri-aspartate of arginine paraaminobenzoyldiethylaminoethanol remaining identical (1%).
The various tests were each made on fifteen 40 to 50 years old patients before and after daily treatments, in the evening, with the various creams (Formulations A to E) during 30 days, on the forehead or on the cheeks, of the patients.
The control cream A and the creams B to E were applied respectively on the lefthand part of the forehead or the lefthand cheek and on the righthand part of the forehead or righthand cheek. a. First series of tests
An impression of the face skin of 15 patients was taken by means of a mask and the number of impressed wrinkles was counted. A value of 100% was given to the average of the total number of impressed wrinkles.
The patients were then treated, during 30 days, by means of the control cream (Formulation A) and by means of the cream (Formulation B) according to the invention.
After said treatment, a new impression of the face of the 15 patients was taken and the number of remaining wrinkle impressions was counted. By taking the average number of remaining wrinkle impressions, the percentage of the remaining wrinkles was determined in comparison with the percentage (100%) determined before the treatment.
The following results were obtained:
TABLE I Treated Before After Treatment Skin Treatment Part Formula- Formula- tion A tion B ____________________________________________________________ _____________ _ Forehead 100% 90%(±1%) 49%(±1%) Cheeks 100% 88%(±1%) 45%(±1%) ____________________________________________________________ _____________ _
This table shows clearly the significant anti-wrinkle effect obtained with cream B containing only 1% of tri-aspartate of arginine para-aminobenzoyl diethylaminoethanol, when applied to the skin. b. Second series of tests
The procedure was the same as in the first series of tests, except that creams C and D were used and the results were compared to the results obtained with cream A.
The following results were obtained:
TABLE II Treated After Treatment Skin Part Formulation A Formulation C Formulation D ____________________________________________________________ _____________ _ Forehead 100% 50%(±1%) 31%(±1%) Cheeks 100% 46%(±1%) 28%(±1%) ____________________________________________________________ _____________ _
This table shows that by adding only 1% of tri-aspartate of arginine para-aminobenzoyl diethylaminoethanol to cream C, the anti-wrinkle effect of cream C is surprisingly increased of 18% and 19%, whereas the known active ingredients (amniotic fluid, placenta extract and choline chloride) have themselves, at the indicated doses, an anti-wrinkle effect which is substantially equivalent to that of the tri-aspartate of arginine para-aminobenzoyl diethylaminoethanol, as shown by a comparison of the results obtained with cream B (Table I) and cream C (Table II) c. Third series of tests
The procedure was the same as in the first series of tests, except that creams D and E were used and that the results were compared to those obtained with control cream A.
These results are given in the following table:
TABLE III Treated After Treatment Skin Part Formulation A Formulation D Formulation E ____________________________________________________________ _____________ _ Forehead 100% 31%(±1%) 30%(±1%) Cheeks 100% 28%(±1%) 26%(±1%) ____________________________________________________________ _____________ _
This table shows clearly the synergistic effect of the tri-aspartate of arginine para-aminobenzoyl diethylaminoethanol on conventional ingredients (amniotic fluid, placenta extract and choline chloride), since the results obtained when the percentage of these three known active ingredients is reduced by 50% and when the percentage (1%) of the above tri-aspartate is maintained are nearly the same and even slightly better than the results obtained with a twofold percentage of these three active ingredients.
Tests made with hydrating compositions containing other compounds of the formula I have given similar results.
The appearance of the skin depends from the complexion, brightness, ruggedness (folds and wrinkles) and wear thereof. As is known, the relief of the skin may be influenced by hydrating cosmetic compositions containing, as active ingredients, singly or combined, various products such as extracts (embryo, tissues or placenta), animal serums or plasmas, amniotic fluid, plant extracts, lecithines, amino-alcohols, such as choline and the salts and derivatives thereof, and the like.
This invention relates to cosmetic compositions having a significant hydrating activity when topically applied to human skin, due to the presence in the cosmetic compositions of amine compounds as defined hereafter which have a hydrating activity which was unknown heretofore and which have not been used in cosmetology until now. These amine compounds may also be added to known hydrating cosmetic compositions, in which they increase surprisingly the hydrating activity of the known hydrating ingredients.
SUMMARY OF THE INVENTION
The invention concerns a method for substantially reducing the folds and wrinkles in skin by topically applying hydrating cosmetic compositions containing, as active ingredient, at least one amine compound, which may be represented by the following general formula: ##SPC1## In which R represents an alkylene group --(CH 2 ) n where n = 1 or 2, and m represents 1 or 2.
DETAILED DESCRIPTION OF THE INVENTION
When each R in the above described formula represents a methylene group (--CH 2 --) and m is 1, the compound of the general formula I is the diaspartate of arginine para-aminobenzoyl-diethylaminoethanol.
When each R represents an ethylene group --(CH 2 ) 2 -- and m is 1, the compound of the general formula I is the di-glutamate of arginine para-aminobenzoyl-diethylaminoethanol.
When each R represents a methylene group (--CH 2 --) and m is 2, the compound of the general formula I is the tri-aspartate of di-L-arginine para-aminobenzoyl-diethylaminoethanol.
When each R represents an ethylene group --(CH 2 ) 2 -- and m is 2, the compound of the general formula I is the tri-glutatmate of di-L-arginine para-aminobenzoyl-diethylaminoethanole
The compounds of the general formula I are crystallizable and have similar physico-chemical and biological properties. They can be used in their dextrogyre (D), levogyre (L) or racemic (DL) forms and also as acid addition salts, such as the hydrochlorides.
The compounds of the general formula I may be prepared by reaction of one or two moles of arginine glutamate or aspartate with one mole of para-aminobenzoyl-diethylamino-ethanol in a solvent, such as distilled water, at the reflux boiling temperature of the reaction medium. After evaporation under reduced pressure, the product is crystallized at a temperature of less than 0° C or is dried in a drying closet. Crystalline pure products, which are clearly distinguished from mere mixtures of the starting reactants, are thus obtained with a yield of 98 to 99%.
The preparation of the compounds of formula I is described with more details in the following examples.
EXAMPLE 1
To 46.82 grams of dry (1-) arginine di-(1+) glutamate dissolved in 500 millilitres of fresh distilled water, heated at 80° C, 23.63 grams of para-aminobenzoyl-diethylaminoethanol are added, while stirring.
The mixture is maintained at the boiling temperature (40°-50° C) under reduced pressure and is then concentrated, by distillation of the aqueous solvent, until an opalescent product is obtained. The product is then crystallized at a temperature of less than 0° C and dried during 24 hours at 45° C in a drying closet. Yield: 98 to 99%. About 69 grams of crystalline di-(1+) glutamate of (1-) arginine para-aminobenzoyl-diethylaminoethanol are thus obtained. Melting Point: 172°-173° C.
EXAMPLE 2
To a solution of 50.45 grams of the monohydrochloride of (1-) arginine di-(1+) glutamate dissolved in 450 millilitres of fresh distilled water, heated at 80° C, 23.63 grams of para-aminobenzoyl- diethylaminoethanol are added, while stirring the reaction medium. By treating this medium as described in Example 1. 72.5 grams of crystalline di-(1+) glutamate of (1-) arginine para-aminobenzoyl-diethylaminoethanol are obtained. This compound starts melting at 159° C with decomposition and melts until 170°-172° C.
EXAMPLE 3
100 millilitres of a 1N solution of hydrochloric acid are added to 46.82 grams of (1-) arginine di-(1+) glutamate. The obtained mixture is heated at boiling temperature and 350 millilitres of fresh distilled water are added thereto. The temperature is maintained at 80° C and 23.63 grams of para-aminobenzoyl-diethylaminoethanol are added, while stirring the reaction medium. This medium is then treated as described in Example 1. 72.5 grams of the crystalline monohydrochloride of di-(1+) glutamate of (1-) arginine para-aminobenzoyl-diethylaminoethanol are obtained as in Example 2.
EXAMPLE 4
To a boiling solution of 44 grams of dry (1-) arginine di-(1-) aspartate in 500 millilitres of fresh distilled water, 23.63 grams of para-aminobenzoyl-diethylaminoethanol are added while stirring. The reaction mixture is then treated as described in Example 1. About 66 grams of crystalline di-(1-) aspartate of (1-) arginine para-aminobenzoyl-diethylaminoethanol are obtained. Melting point: 144°-148° C.
EXAMPLE 5
To a boiling solution of 47.65 grams of the monohydrochloride of (1-) arginine de (1-)aspartate in 500 milliliters of fresh distilled water, 23.63 grams of para-aminobenzoyl-diethylaminoethanol are added while stirring. The reaction mixture is then treated as described in Example 1. About 70 grams of the crystalline monohydrochloride of di(1-) aspartate of (1-)arginine paraaminobenzoyl-diethylaminoethanol are obtained. This compound starts melting at 152° C (with decomposition).
EXAMPLE 6
100 milliliters of a 1N solution of hydrochloric acid are added to 44 grams of (1-) arginine di (1-) aspartate. The obtained solution is heated to boiling temperature and 400 milliliters of fresh distilled water are added thereto. While maintaining the temperature at 85° C and while stirring the mixture, 23.63 grams of para- aminobenzoyldiethylaminoethanol are added. The reaction mixture is then treated as described in Example 1. About 70 grams of crystalline monohydrochloride of di(1-) asparate of (1-)arginine para-aminobenzoyl- diethylaminoethanol are obtained.
EXAMPLE 7
The tri-glutamate of di-arginine para-aminobenzoyl-diethylaminoethanol (M.P.: 235°-238° C) and the hydrochloride thereof are prepared by the procedure described in Examples 1, 2 and 3, except that two moles of di-arginine glutamate per mole of para-aminobenzoyl- diethylaminoethanol are used.
EXAMPLE 8
The tri-aspartate of di-arginine para-aminobenzoyl-diethylaminoethanol (M.P.: 205°-208° C) and the hydrochloride thereof are prepared by the procedure described in Examples 4, 5 and 6, except that two moles of di-arginine aspartate per mole of para-aminobenzoyl- diethylaminoethanol are used.
The compounds of the general formula I and the hydrochlorides thereof are soluble in water. All that is necessary is to apply topically the compounds of the general formula I in an effective amount of the compound sufficient to alleviate the folds and wrinkles of the skin.
The hydrating cosmetic compositions for external use according to this invention, which contain, as active ingredients, at least one compound of formula I, may take various forms and may be used on the human skin. Said compositions may take the form of fatty or non fatty creams, milky suspensions or emulsions of the water-in-oil or oil-in-water types, lotions, gels or jellies, colloidal or non colloidal aqueous or oily solutions, pastes, soaps, aerosols, soluble tablets (to be dissolved in a fluid, such as water) or sticks.
The amount of active ingredient contained in the hydrating cosmetic compositions according to the invention applied to the skin may vary between wide limits, depending from the formulating and from the frequency of use of said compositions. Generally, said compositions contain from 0.1% to 2%, by weight of the composition of active ingredient of the formula I.
The hydrating cosmetic compositions used in the method according to the invention may contain not only one or more active ingredients of the formula I but also conventional vehicles or carriers, such as solvents, fats, oils and mineral waxes, fatty acids and derivatives thereof, alcohols and derivatives thereof, glycols and derivatives thereof, glycerol and derivatives thereof, sorbitol and derivatives thereof, surface-active agents of the anionic, cationic or non ionic type, emulsifying agents, preserving agents, perfumes, etc.
A few examples of hydrating cosmetic agents used in the method according to this invention are given hereafter. These examples are only illustrative and must not be considered as limiting the scope of the invention. In said examples, the percentages are by weight.
EXAMPLE I
Hydrating Milk Mono and diglycerides of fatty acids 5 to 6% (palmitic and stearic acids) Condensate of polyglycol and saturated 2.5 to 3% fatty alcohol ethers with polyoxyethylene Isopropyleneglycol 5 to 15% Perhydrosqualene 5 to 15% Amniotic fluid 2 to 10% Tri-aspartate of di-arginine-para- aminobenzoyl diethylaminoethanol 0.5 to 1% Distilled water q.s.ad. 100%
EXAMPLE II
Hydrating Milk High fatty alcohols (such as cetyl, stearyl, myristyl alcohols) 5 to 6% Condensate of polyglycol and saturated fatty alcohol ethers with polyoxyethylene 2.5 to 3% Isopropyleneglycol 5 to 15% Perhydrosqualene 5 to 15% Amniotic fluid 2 to 10% Tri-aspartate of di-arginine-para- aminobenzoyl-diethylaminoethanol 0.5 to 1% Distilled water q.s.ad. 100%
EXAMPLE III
Hydrating Milk Mono and diglycerides of palmitic and stearic acids 5 to 6% Condensate of polyglycol and saturated fatty alcohol ethers with polyoxyethylene 2.5 to 3% Glycerol 5 to 15% Ester of stearic acid and octyldodecanol 5 to 15% Amniotic fluid 2 to 10% Tri-glutamate of di-arginine para- aminobenzoyl diethylaminoethanol 0.5 to 1% Distilled water q.s.ad. 100%
EXAMPLE IV
Cream of the Oil-in-Water Type Liquid paraffin 40 to 60% White wax 5 to 10% Solid paraffin 2 to 8% Borax 0.1 to 0.5% Di-aspartate of arginine para-amino- benzoyl diethylaminoethanol 0.5 to 1% Distilled water q.s.ad. 100%
EXAMPLE V
Cream of the Water-in-Oil Type Liquid paraffin 30 to 50% Ozokerite 3 to 8% Solid paraffin 1 to 3% Lanoline 1.5 to 4% Mono-diglycerides of fat-forming fatty acids with not more than 1/100 of 1% butylated anisole, 1/100 of 1% butylated hydroxy toluene, and 1/100 of 1% citric acid in propylene glycol added as a preservative (Arlacel 186-Atlas Chemical Industries-Wilmington, Delaware, U.S.A.) 1 to 2% Polysorbate 80, an ester of sorbitan etherified with polyethylene glycol (Tween 80 - Atlas Chemical Industries) 0.1 to 0.3% Di-glutamate of arginine para- aminobenzoyl-diethylaminoethanol 0.5 to 1% Water q.s.ad. 100%
EXAMPLE VI
Hydrating Lotion Triethanolamine lauryl sulfate 1 to 5% Isopropanol 40 to 60% Cetiol V (decylic ester of oleic acid- Dehydag Deutsche Hydrierwerke, Dusseldorf, Germany) 2 to 6% Triglutamate of di-arginine para-amino- benzoyl diethylaminoethanol 0.5 to 1% Water q.s.ad. 100%
EXAMPLE VII
Cream of the Water-in-Oil Type Amphocerine K (Dehydag), a mixture of fatty alcohols and waxy esters of animal origin 40 to 60% Placenta extract 5 to 15% Tri-aspartate of di-arginine para- aminobenzoyl diethylaminoethanol 0.5 to 1% Water q.s.ad. 100%
EXAMPLE VIII
Hydrating Aerosol
The cream of the oil-in-water of Example IV and 8% by weight of a mixture of 40% dichlorodifluoromethane and 60% dichlorotetrafluoromethane are introduced into an aerosol container.
To the formulations described in Examples I to VIII, perfumes (such as rose, orange, jasmine oil and the like), dyes or pigments (such as zinc oxide, titanium oxide, ochre and the like), as well as preserving or antioxidizing agents (such as butylhydroxy toluene, butylhydroxy anisole, sorbic acid, methyl para-hydroxybenzoate, and the like) may be added in suitable amounts, as well known in cosmetology.
Tests have been made in vivo with the hydrating cosmetic compositions according to the invention. These tests have clearly shown that said compositions have remarkable hydrating properties when topically applied to the skin.
These tests have shown the hydrating properties of the compounds of formula I as well as the synergistic effect of these compounds on already known hydrating products (such as amniotic fluid, placenta extract and the like), when they are used jointly with these known products.
The tests have been made by applying on the human face (forehead and cheeks) masks for taking impressions of the relief of the skin before and after treatment by means of various hydrating compositions. For taking such impressions, compositions of the Laboratory of Dr. Renaux (Paris, France) containing rubber or plastic materials, which cure in contact with the skin, have been used. The masks obtained after curing or hardening on the face of the rubber or plastic-based compositions and after removing the hardened layers from the face may be used for determining objectively the effectiveness of the hydrating compositions according to the invention for reducing or alleviating the skin wrinkles, manly by hydrating the skin. The effect of reducing or alleviating the skin wrinkles is determined by counting with an approximation of ±1% the impressions of the wrinkles on surfaces of an area of 3cm 2 of the masks.
The count of impressions on the masks taken before the treatment by means of hydrating compositions is used as base for the subsequent counts. A value of 100% is given to the number of wrinkle impressions counted on the mask taken before the treatment by means of the hydrating compositions.
As control, a hydrating cream containing only water as the hydrating ingredient has been used.
Said control cream had the following composition. Formulation A Mono- and di-glycerides of palmitic and stearic acids 6% Condensate of polyglycol and saturated fatty alcohols with polyoxyethylene 3% Ester of stearic acid and diethyldodecanol 10% Preserving agent and perfume q.s. Water q.s.ad. 100%
For one series of tests, 1% of tri-aspartate of arginine para-aminobenzoyl-diethylaminoethanol (Formulation B) was added to said base or control cream.
For another series of tests, 20% of amniotic fluid, 10% of human placenta extract and 0.1% of choline chloride (Formulation C) was added to the control cream, these three known products being commonly used in hydrating creams of good quality.
For still another series of tests, 20% of amniotic fluid, 10% of human placenta extract, 0.1% of choline chloride and 1% of tri-aspartate of arginine para-aminobenzoyl-diethylaminoethanol (Formulation D) were added to the control cream.
Finally, for the last series of tests, a cream (Formulation E) similar to Formulation D was used, except that it contained 10% in place of 20% of amniotic fluid, 5% in place of 10% of placenta extract and 0.05% in place of 0.1% of choline chloride (i.e., 50% less of these active ingredients than in Formulation D), the proportion of tri-aspartate of arginine paraaminobenzoyldiethylaminoethanol remaining identical (1%).
The various tests were each made on fifteen 40 to 50 years old patients before and after daily treatments, in the evening, with the various creams (Formulations A to E) during 30 days, on the forehead or on the cheeks, of the patients.
The control cream A and the creams B to E were applied respectively on the lefthand part of the forehead or the lefthand cheek and on the righthand part of the forehead or righthand cheek. a. First series of tests
An impression of the face skin of 15 patients was taken by means of a mask and the number of impressed wrinkles was counted. A value of 100% was given to the average of the total number of impressed wrinkles.
The patients were then treated, during 30 days, by means of the control cream (Formulation A) and by means of the cream (Formulation B) according to the invention.
After said treatment, a new impression of the face of the 15 patients was taken and the number of remaining wrinkle impressions was counted. By taking the average number of remaining wrinkle impressions, the percentage of the remaining wrinkles was determined in comparison with the percentage (100%) determined before the treatment.
The following results were obtained:
TABLE I Treated Before After Treatment Skin Treatment Part Formula- Formula- tion A tion B ____________________________________________________________ _____________ _ Forehead 100% 90%(±1%) 49%(±1%) Cheeks 100% 88%(±1%) 45%(±1%) ____________________________________________________________ _____________ _
This table shows clearly the significant anti-wrinkle effect obtained with cream B containing only 1% of tri-aspartate of arginine para-aminobenzoyl diethylaminoethanol, when applied to the skin. b. Second series of tests
The procedure was the same as in the first series of tests, except that creams C and D were used and the results were compared to the results obtained with cream A.
The following results were obtained:
TABLE II Treated After Treatment Skin Part Formulation A Formulation C Formulation D ____________________________________________________________ _____________ _ Forehead 100% 50%(±1%) 31%(±1%) Cheeks 100% 46%(±1%) 28%(±1%) ____________________________________________________________ _____________ _
This table shows that by adding only 1% of tri-aspartate of arginine para-aminobenzoyl diethylaminoethanol to cream C, the anti-wrinkle effect of cream C is surprisingly increased of 18% and 19%, whereas the known active ingredients (amniotic fluid, placenta extract and choline chloride) have themselves, at the indicated doses, an anti-wrinkle effect which is substantially equivalent to that of the tri-aspartate of arginine para-aminobenzoyl diethylaminoethanol, as shown by a comparison of the results obtained with cream B (Table I) and cream C (Table II) c. Third series of tests
The procedure was the same as in the first series of tests, except that creams D and E were used and that the results were compared to those obtained with control cream A.
These results are given in the following table:
TABLE III Treated After Treatment Skin Part Formulation A Formulation D Formulation E ____________________________________________________________ _____________ _ Forehead 100% 31%(±1%) 30%(±1%) Cheeks 100% 28%(±1%) 26%(±1%) ____________________________________________________________ _____________ _
This table shows clearly the synergistic effect of the tri-aspartate of arginine para-aminobenzoyl diethylaminoethanol on conventional ingredients (amniotic fluid, placenta extract and choline chloride), since the results obtained when the percentage of these three known active ingredients is reduced by 50% and when the percentage (1%) of the above tri-aspartate is maintained are nearly the same and even slightly better than the results obtained with a twofold percentage of these three active ingredients.
Tests made with hydrating compositions containing other compounds of the formula I have given similar results.