WO2006114338A1

WO2006114338A1 - Topical skin care composition

Info

Publication number: WO2006114338A1
Application number: PCT/EP2006/004947
Authority: WO
Inventors: Hitoshi Masaki; Nobuhiro Ando
Original assignee: Chanel Parfums Beaute SAS; Nikko Chemicals Co Ltd
Current assignee: Chanel Parfums Beaute SAS; Nikko Chemicals Co Ltd
Priority date: 2005-04-26
Filing date: 2006-04-26
Publication date: 2006-11-02
Anticipated expiration: 2007-10-26
Also published as: TW200719920A; JP4723899B2; JP2006306744A

Abstract

The present invention relates to a cosmetic or dermatological topical composition, containing tranexamic acid ester and/or a salt thereof (Component A), and silicone oil (Component B).

Description

TOPICAL SKIN CARE COMPOSITION

BACKGROUND

The present invention relates to a topical skin care composition (a composition for epicutaneous external use) ; specifically to a dermatological or cosmetic topical composition, in which stability of application onto the skin and continuity of long term release to skin of tranexamic acid ester and/or a salt thereof have been improved.

Tranexamic acid is known to possess the activity of decreasing the activity of plasminolytic or fibrinolytic enzyme (antiplasmin activity) , and such effects as antiallergic, antiedematous and anti-inflammatory effects are anticipated. Currently, tranexamic acid is administered clinically by oral administration, intravenous injection and intramuscular injection, with the objective of inhibiting erythema, itching and the like of the skin and mucous membrane. In particular, internal administration of tranexamic acid is known to be effective for skin disease.

Meanwhile, a variety of effects in addition to those mentioned above are also known for tranexamic acid, such as, for instance, anti-pigmentation agent and skin roughness improvement agent, percutaneous administration being common when used in such applications.

For instance, an anti-pigmentation agent for external use with tranexamic acid ester and salt thereof as an active ingredient (effective component) is disclosed in Japanese Patent Application Laid-open No. H04-46144, as agent for external use (composition for external use) for such percutaneous administration. In addition, a dermatological topical composition containing a stress handling agent containing tranexamic acid and/or a derivative thereof is disclosed in Japanese Patent Application Laid-open No. 2002-234836.

However, in the above-mentioned conventional dermatological topical composition, stability of application onto the skin and percutaneous penetrability of tranexamic acid ester and salts thereof, which are active ingredients, were insufficient. That is, in conventional dermatological topical compositions, it was difficult to supply stably over a long time period sufficient quantity of tranexamic acid ester and salt thereof to the skin, such that there was still room for improvement.

The present invention was devised in view of such a situation, and it is an object of the invention to provide a dermatological or cosmetic topical composition allowing stability of application onto the skin and percutaneous penetrability of tranexamic acid ester and a derivative thereof to be improved.

SUMMARY

As a result of studies on the solubility of tranexamic acid ester in solvents to solve the above- mentioned issues, the present inventor found a component having excellent compatibility with tranexamic acid ester and/or a derivative thereof, and at the same time, discovered that when a tranexamic acid ester composition wherein that component is admixed is used, the effect of tranexamic acid ester persisted over a long time period, leading to completion of the present invention.

That is to say, a dermatological or cosmetic topical composition according to the present invention contains tranexamic acid ester and/or a salt thereof (Component A) and silicone oil (Component B) .

According to such constitution, as the compatibility between Component A and Component B is increased, the solubility of both components A and B in the topical composition is increased, thereby increasing the content of both components in the topical composition, and increasing homogeneity in the topical composition.

The above-mentioned Component (A) is preferably a compound having the following Formula (1) and/or a salt thereof.

In Formula (1), R represents a saturated or unsaturated aliphatic hydrocarbon group having a linear chain or a branched chain with 1 to 22 carbons, wherein one or several hydrogen atoms in R may be independently substituted by a hydroxyl group or an amino group.

In addition, the mixing ratio of the Component A and the Component B is preferably 0.01:100 to 100:0.01, and even more preferably 20:80 to 80:20, by weight. Furthermore, the topical composition according to the present invention is particularly useful if used as cosmetics .

According to the present invention, since the main active component, Component A, is used together with

Component B, which is silicone oil, stability of application onto the skin and continuity of long term release of Component A can be improved.

DESCRIPTION OF DRAWINGS

[Fig. 1] Graph showing the measurement results of the amount of moisture on the skin surface.

[Fig. 2] Graph showing the measurement results of transepidermal water loss (TEWL) .

[Fig. 3] Graph showing the measurement results of skin color. [Fig. 4] Graph showing the measurement results of skin elasticity.

[Fig. 5] Graph showing the measurement results of cell area (stratum corneum cell area) .

[Fig. 6] Graph showing the measurement results of degree of multi-layer peeling.

[Fig. 7] Graph showing the measurement results of nucleated cell ratio.

[Fig. 8] Graph showing the measurement results of degree of SH staining. [Fig. 9] Graph showing the measurement results of wrinkle depth.

DETAILED DESCRIPTION In the following, the present invention will be described in detail. The topical composition according to the present invention contains a Component A and a Component B.

(Component A)

Component A is tranexamic acid ester and/or a salt thereof and is not limited to a particular component ; however, a compound represented by the following Formula (1) or a derivative thereof is preferred.

In Formula (1), R represents a saturated or unsaturated aliphatic hydrocarbon group having a linear chain or a branched chain with 1 to 22, preferably 8 to 20, and more preferably 12 to 18 carbon atoms. In addition, one or several hydrogen atoms in R may be independently substituted by a hydroxyl group or an amino group.

Specifically, examples of tranexamic acid esters include, for instance, tranexamic acid lauryl ester, tranexamic acid myristyl ester, tranexamic acid cetyl ester, tranexamic acid stearyl ester and the like. Among these, tranexamic acid cetyl ester and tranexamic acid stearyl ester are particularly preferred from the view point of higher effect of the present invention.. In addition, salts of tranexamic acid ester are not limited in particular as long as they are salts that are physiologically acceptable, more specifically pharmaceutically and/or cosmetically acceptable, and examples include, for instance, inorganic salts such as phosphate, hydrochloride, hydrobromide and sulphate, and salts with organic acids such as α-hydroxy acid (glycolic acid, lactic acid, malic acid, citric acid and the like) , acidic amino acid, long-chain fatty acid (palmitic acid, stearic acid, linoleic acid and the like) . These may be used singly, or used by combining two species or more.

Tranexamic acid cetyl ester hydrochloride is preferred according to this invention.

(Component B)

Those silicone oils used in general for make-up preparations and agents for external use may be used as Component B. Examples include, for instance :

polyorganosiloxanes, such as polydimethylsiloxanes (dimethicones) , which may be chosen from the group consisting of tetramethyldisiloxane, hexamethyltri- siloxane, octamethyltetrasiloxane and polydimethyl- siloxanes of higher molecular weights such as those sold by GOLDSCHMIDT under the trade name ABIL ; polyalkylcyclosiloxanes, such as polydimethyl- cyclosiloxanes (cyclomethicones) , which may be chosen from the group consisting of : octamethylcyclotetra- siloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane, such as those sold by DOW CORNING under the trade names DC 200, DC 244, DC 245, DC 344 et DC 345 or by GENERAL ELECTRIC under the trade names SF-1204, SF-1202, GE 7207 and GE 7158 or by SWS SILICONES under the trade name SWS-03314 ; - polyalkylphenylsiloxanes such as polymethylphenyl- siloxanes (phenyldimethicones) as sold for instance by RHODIA CHIMIE under the trade name MIRASIL PTM; polyether-modified polysiloxanes, amino-modified polysiloxanes, alcohol-modified polysiloxanes, acryl-modified polysiloxanes, - crosslinked or non-crosslinked organopolysiloxanes such as crosslinked polymers obtained by reacting, in the presence of a catalyst, a polysiloxane having at least one reactive group (such as hydrogen or a vinyl, alkoxy, acetoxy or amino group) and bearing a C₁-C₂₀ alkyl (such as methyl) and/or phenyl side and/or terminal groups, with an organosilicone such as an organohydrogenpolysiloxane, among which one may mention the polymers sold by SHIN ETSU under the trade names KSG-β, KSG-16, KSG-31, KSG-32, KSG-41, KSG-42, KSG-43 and KSG-44, the polymers sold by DOW CORNING under the trade names DC 9040 and DC 9041 and the polymer sold by DOW CORNING as an emulsion under the trade name HMW-2220, and the like.

These may be used singly, or two species or more may be combined for use. Among these, for instance, when using dimethicones, cyclomethicones and phenyl dimethicones, adhesiveness is inhibited, and the "sticky" feeling or the oily feeling (oiliness) of the skin can be attenuated. Note that these silicone oils can be used by selecting one species, two species, or more. Herein, a cosmetic or dermatological topical composition is a collective name for a composition that is administered to the skin by external use. Such a composition can be used as, for instance, medicine or skin- care for epicutaneous use, such as whitening preparation, cleansing preparation, bath agent, disinfectant for epicutaneous use, bactericide for epicutaneous use and the like, and can preferably be used in particular as a whitening preparation.

The topical composition of the present invention can be in the form of an ointment, cream, fluid, milky lotion, cosmetic water, lotion, serum, gel, facial mask, lipstick, powder, and the like. In all cases, it generally includes a pharmaceutically or cosmetically acceptable carrier adapted for a topical application onto skin. Preferably, this composition includes water. More preferably, it is in the form of a gel or oil-in-water emulsion.

Various additives can be provided in this topical composition and in particular, any type of agent used in a common medicinal product, quasi drug, cosmetic and the like.

For instance, examples of carrier materials included in the topical composition include well known raw materials such as animal and plant oils, mineral oils, synthetic oils, ester oils, waxes, linear higher alcohols, fatty acids, surfactants, phospholipids, gelling and/or thickening agents (including taurate homopolymers and copolymers, either crosslinked or not, which may be hydrophobized, including Simulgel NS from SEPPIC, and Aristoflex AVC and HMB from CLARIANT ; and polyacrylamide homo- and copolymers, including Sepigel 305 from SEPPIC) ) , alcohol, polyols (including glycerine and propylene glycol) , fillers such as clay minerals, soft-focus powders, preservatives, fragrances, pigments and purified water.

In addition, the topical composition of the present invention may suitably contain various active agents which may be chosen from the group consisting of:

- antioxidants, such as ascorbic acid and its derivatives, including ascorbyl palmitate, ascorbyl tetraisopalmitate, ascorbyl glucoside, magnesium ascorbyl phosphate, sodium ascorbyl phosphate and ascorbyl sorbate ; tocopherol and its derivatives, such as tocopheryl acetate, tocopheryl sorbate and others esters of tocopherol ; BHT and BHA ; and plant extracts, for instance from Chondrus cripsus, Rhodiola, Thermus thermophilus, mate leaf, oak wood, kayu rapet bark, sakura leaves and ylang ylang leaves ; - anti-ageing agents, such as acyl aminoacids (for instance Maxilip, Matrixyl 3000 or Biopeptide CL from SEDERMA or Sepilift from SEPPIC) , Pisum sativum extracts, hydrolyzed soy proteins, methylsilanol derivatives such as methylsilanol mannuronate, hydrolyzed cucurbita pepo seedcake, Scenedesmus extract ; anti-pollution agents such as Moringa pterygosperma seed extracts ; keratolytic agents, such as α-hydroxyacids (for instance, glycolic, lactic, citric, malic, mandelic or tartaric acid) and β-hydroxyacids (for instance, salicylic acid) , and their esters, including C₁₂-₁₃ alkyl lactate, and plant extracts containing these hydroxyacids, such as Hibiscus sabdriffa extracts ; astringents such as hamamelis extracts ; moisturizers, including plant extracts such as Castanea sativa extracts, hydrolyzed hazelnut proteins, Polyanthes tuberosa polysaccharides and Argania spinosa kernel oil ; homo- and copolymers of 2- methacryloyloxyethylphosphorylcholine, such as Lipidure HM and Lipidure PBM from NOF ; saccharides such as glucose, fructose, mannose or trehalose; glycosaminoglycanes and their derivatives such as hyaluronic acid, sodium hyaluronate and acetylated hyaluronic acid ; panthenol ; allantoin ; aloe vera ; free amino acids and their derivatives ; glucosamine ; citric acid ; urea and its derivatives and ceramides; emollients such as glyceryl polymethacrylate ; depigmenting agents such as ascorbic acid and its derivatives, including ascorbyl palmitate, ascorbyl tetraisopalmitate, ascorbyl glucoside, magnesium ascorbyl phosphate, sodium ascorbyl phosphate and ascorbyl sorbate ; plant extracts including Narcissus tazetta extracts and licorice extracts ; arbutin ; kojic acid and ellagic acid ; anti-inflammatory agents, such as bisabolol, allantoin, tranexamic acid, zinc oxide, sulfur oxide and its derivatives, chondroitin sulfate, glycyrrhizinic acid and its derivatives such as glycyrrhizinates ; and their mixtures.

The topical composition can also include organic and/or inorganic sunscreens. Among organic sunscreens, mention can be made of dibenzoylmethane derivatives such as butyl methoxydibenzoylmethane (Parsol 1789 from HOFFMANN LA ROCHE) , cinnamic acid derivatives such as ethylhexyl methoxycinnamate (Parsol MCX from HOFFMANN LA ROCHE), salicylates, para-aminobenzoic acids, β- β'- diphenylacrylate derivatives, benzophenone derivatives, benzylidenecamphor derivatives such as terephtalylidene dicamphor sulphonic acid, phenylbenzimidazole derivatives, triazine derivatives, phenylbenzotriazole derivatives, anthranilic derivatives, all of which may be coated or encapsulated. Among inorganic photoprotective agents, mention can be made of pigments or alternatively nanopigments formed from coated or uncoated metal oxides, such as, for example, titanium oxide, iron oxide, zinc oxide, zirconium oxide or cerium oxide nanopigments; which are all UV photoprotective agents well known per se.

The mixing ratio of Component A and Component B in the topical composition is not restricted in particular. However, from the view point of higher whitening, anti- aging, and skin roughness prevention effects, preferably 0.01:100 to 100:0.01, and more preferably 20:80 to 80:20 by mass criteria are desirable. If this mixing ratio is less than the lower limit value (that is to say, with respect to 100 mass parts of Component B, Component A is less than 0.01 mass parts), whitening, anti-aging, and skin roughness prevention effects tend to not improve enough. On the other hand, if this mixing ratio exceeds the upper limit value (that is to say, with respect to 0.01 mass parts of Component B, Component A exceedslOO mass parts), dispersing and mixing Component A homogeneously in the topical composition tend to be difficult. Note that, such mixing ratio is particularly useful when using the composition for epicutaneous use according to the present invention as an anti-aging agent.

In addition, when combining a cyclic silicone oil (cyclomethicone) and a linear silicone oil for use as Component B, a mixing ratio of cyclic silicone oil and linear silicone oil of preferably 0.01:100 to 100:0.01 and more preferably 1:100 to 100:1 by mass criteria is optimum. If this mixing ratio is less than the lower limit value (that is to say, with respect to 100 mass parts of linear silicone oil, cyclic silicone oil is less than 0.01 mass parts) the effect of using silicone oil as Component B tend to not be exerted enough. On the other hand, if this mixing ratio exceeds the upper limit value (that is to say, with respect to 0.01 mass parts of linear silicone oil, cyclic silicone oil exceeds 100 mass parts) , dispersing and mixing Component B homogeneously in the dermatological topical composition tend to be difficult.

Moreover, Component A is preferably mixed in the topical composition in an amount of from 0.5 to 10%, more preferably 1 to 6% by weight, when the total of all the components of the topical composition is taken as 100%.

On the other hand, Component B is preferably mixed in the topical composition in an amount of from 0.5 to 50%, more preferably 0.5 to 30%, even more preferably 3 to 20% by weight, when the total of all the components of the topical composition is taken as 100%. If this mixing proportion is less than 0.5 weight %, depending on the circumstance, the desired effect of improving the feeling upon use sometimes cannot be obtained; in addition, if 50 weight % is exceeded, depending on the circumstance, a "sticky" feeling can sometimes occur. In other words, if the quantity of Component B mixed is within the above- mentioned optimum range, feelings upon use of the topical composition such as spread, non-sticky feeling and smooth feeling become further satisfactory, and, solubility of Component A in the composition for epicutaneous use can be increased even more, increasing the stability of application onto the skin and continuity of long term release even more.

In addition, the desirable pH of the topical composition of the present invention is 4 to 8, and preferably 4.5 to 7, from the view point of obtaining a sufficient effectiveness at the same time as increasing safety.

Since the solubility of Component A with respect to the topical composition can be increased by mixing it with Component B, Component A can be dispersed substantially homogeneously in the dermatological topical composition. Consequently, stability of application onto the skin and continuity of long term release can be improved. Further, since the properties of Component A provoke cosmetic effects such as whitening, anti-aging, skin roughness prevention effects, if the topical composition according to the present invention is used as a cosmetic, excellent synergistic effects between make-up effect and cosmetic effect can be obtained.

[Example]

< Example 1 and Comparative Examples 1 to 5 > Creams whose compositions are shown in the following Table 2 were prepared as a topical composition according to established methods well known from the skilled artisan.

[Table 2] Unit: weight %

1) KF-96H-1, 000, 000 CS, manufactured by Shin-Etsu Chemicals Co., LTD

2) KF-995, manufactured by Shin-Etsu Chemicals Co., LTD

< Evaluation >

For the creams (topical compositions) of Example 1 and Comparative Examples 1 to 5, the effects of action exerted on the skin such as amelioration of skin condition and amelioration of wrinkles, were measured and evaluated by the test indicated below.

(Test)

Test Subjects

Each cream described in Table 1 was applied to a group of ten males (age: 35 to 40 year old) having wrinkles identifiable by direct observation at the corner of their eyes. Since there was also one non-application group (hereinafter referred to as " blank") wherein no cream was applied, a total of seven groups were thus constituted. Sample Application Method

The test sample was applied over the face of the test subjects of each group in suitable amounts, twice daily, in the morning and at night.

Test Period

The test was performed continuously for 8 weeks, and the following items were measured as skin conditions immediately before the beginning of the test, 4 weeks after and 8 weeks after.

Measurement Items

(1) Amount of moisture on the skin surface (2) Transepidermal water loss (TEWL)

(3) Skin color

(4) Skin elasticity

(5) Diagnosis of peeled stratum corneum

(6) Measurement of wrinkle depth

Method of Measurement

The test subjects were placed in a room with constant temperature and humidity (22°C; relative humidity: 45%), acclimatized to the environment by resting for 15 minutes, whereafter the measurements were carried out according to the procedures shown in (1) to (6) below. Note that in all cases mentioned below in (1) to (6), a significant difference test was performed for each measurement value by the Student t test or the Wilcoxson test, to evaluate the difference between the blank non-application group and the group with the topical compositions applied. (1) Amount of moisture on the skin surface Electric conductivity per unit area (mS/cm²) was measured using the skin surface hydrometer SKICON200

(manufactured by I. B. S. Co., Ltd.)- The measurement was carried out 5 times, and the mean value of 3 stable measurement values among these was taken as the amount of moisture on the skin surface at that site. Note that an increase in the amount of moisture on the skin surface is one indication representing an improvement of the skin condition. The results of the measurements are shown in Fig. 1. In the figures, measurement data of the blank and Example 1 are shown in black filled squares, and black filled circles. In addition, measurement data of each Comparative Example are shown in white empty circles. The solid lines and broken lines in the figures are line guides that connect each plotted data per blank, Example and Comparative Example. Furthermore, solid line B, solid line El, and broken lines Cl to C5 represent respectively the blank, Example 1 and Comparative Examples 1 to 5 (hereinafter, same for Fig. 2 to 9) .

(2) Transepidermal water loss (TEWL) Transepidermal water loss (TEWL) was measured using the dual channel transepidermal water loss meter AS-TW2 (manufactured by ASAHI BIOMED) . The measurement was carried out 3 times, and the mean value thereof was taken as TEWL (g/cm²/h) . Note that a decrease in the TEWL value is one indication representing an improvement of the skin condition. The measurement results are shown in Fig. 2.

(3) Skin color

Skin color was measured using the contact type colorimeter CM-2022 (manufactured by Minolta) using the . _{* *}, _*

Lab table color system. The measurement of the L value was carried out 3 times, and the mean value thereof was taken as the L^* value. An increase in the L^* value is one indication representing a whitening of the skin color. The measurement results are shown in Fig. 3.

(4) Skin elasticity

Skin elasticity was measured using the cutometer SEM575CK (manufactured by electronic Gmb.). In order to evaluate [the elasticity] as an indication of the skin tension, the R2 value (R2=Ua/Uf, where Ua: return of the skin upon release from aspiration; Uf: stretching of skin upon aspiration) was used. Note that an increase in the R2 value is one indication representing an improvement of the skin elasticity. The measurement results are shown in Fig. 4.

(5) Diagnosis of peeled stratum corneum

After wiping the skin clean with ethanol for disinfection, stratum corneum cells were peeled using a commercially available adhesive tape (30><24 mm). The peeled stratum corneum cells were transferred onto a slide glass and were used as samples for brilliant green/gentian violet

(BG) staining and N- (7-dimethylamino-4-methyl-3-coumarinyl) maleimide (DACM) staining. Stratum corneum cell area, stratum corneum cell peeling pattern (degree of multi-layer peeling) , nucleated cell ratio, and the degree of SH staining due to free SH groups were used as assessment parameters. Note that a decrease in the stratum corneum cell area is one indication representing the acceleration of the speed of epidermis turnover. In addition, a diminution of the stratum corneum cell peeling pattern, a diminution of nucleated cell ratio, and a diminution of the degree of SH staining are all one indication representing normal keratinization. Each of the measurement results is shown in Fig. 5 to Fig. 8.

(6) Wrinkle depth First, a template (replica) of the wrinkles present at the eye corners was obtained using a replica agent. Thereafter, against this template, the shadows of the wrinkles were generated by hitting with a light from a direction that is orthogonal to the direction in which the wrinkles predominantly run and 30° above. In addition, analyses were performed on the images thereof, to measure the depth of the shadows of the wrinkles that arose. Note that SILFLO (manufactured by Flexico. England) was used as the replica agent, which allows a from to be transferred finely, and has numerous performance reports for taking replica. The results are shown in Fig. 9.

Evaluation result

Figs. 1 to 9 reveal that the cream of Example 1 shows higher improvement effects than the creams of Comparative Examples 1 to 5 for all the measurement items described above. This demonstrates that the composition for epicutaneous use of the present invention significantly improves wrinkle and skin condition and can sufficiently accelerate whitening of the skin. In addition, it was revealed that the composition for epicutaneous use pertaining to the present invention can maintain high improvement effect even after a prescribed time period. This demonstrates that stability of application onto the skin, percutaneous penetrability, and continuity of long term release from skin, of tranexamic acid ester, are improved.

Claims

1. A cosmetic or dermatological topical composition, containing tranexamic acid ester and/or a salt thereof (Component A) , and silicone oil (Component B) .

2. The topical composition according to Claim 1, wherein said Component A is a tranexamic acid ester represented by the following Formula (1)

wherein R represents a saturated or unsaturated aliphatic hydrocarbon group having a linear chain or a branched chain with 1 to 22 carbons, wherein one or several hydrogen atoms in R may be independently substituted by a hydroxyl group or an amino group, and/or a salt thereof.

3. The topical composition according to Claim 2, wherein Component A is chosen from the group consisting of : tranexamic acid lauryl ester, tranexamic acid myristyl ester, tranexamic acid cetyl ester, tranexamic acid stearyl ester and their salts.

4. The topical composition according to Claim 3, wherein Component A is tranexamic acid cetyl ester hydrochloride.

5. The topical composition according to any of Claims 1 to

4, wherein Component B is chosen from the group consisting of : polyorganosiloxanes, such as polydimethylsiloxanes (dimethicones) ; polyalkylcyclosiloxanes, such as polydimethylcyclosiloxanes (cyclomethicones) ; polyalkyl- phenylsiloxanes such as polymethylphenylsiloxanes (phenyldimethicones) ; polyether-modified polysiloxanes ; amino-modified polysiloxanes ; alcohol-modified polysiloxanes ; acryl-modified polysiloxanes ; and crosslinked or non-crosslinked organopolysiloxanes .

6. The topical composition according to any of Claims 1 to 5, wherein the mixing ratio of Component A and Component B is 0.01:100 to 100:0.01 by weight.