WO1991018589A1 - COSMETIC SKIN-LIGHTENING COMPOSITION BASED ON A HYDROQUINONE/2,6-DIMETHYL-β-CYCLODEXTRIN COMPLEX - Google Patents

COSMETIC SKIN-LIGHTENING COMPOSITION BASED ON A HYDROQUINONE/2,6-DIMETHYL-β-CYCLODEXTRIN COMPLEX Download PDF

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Publication number
WO1991018589A1
WO1991018589A1 PCT/FR1990/000372 FR9000372W WO9118589A1 WO 1991018589 A1 WO1991018589 A1 WO 1991018589A1 FR 9000372 W FR9000372 W FR 9000372W WO 9118589 A1 WO9118589 A1 WO 9118589A1
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WO
WIPO (PCT)
Prior art keywords
hydroquinone
dimethyl
dimeb
cyclodextrin
skin
Prior art date
Application number
PCT/FR1990/000372
Other languages
French (fr)
Inventor
Vassiliki Tsomi
Original Assignee
Vassiliki Tsomi
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Filing date
Publication date
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Publication of WO1991018589A1 publication Critical patent/WO1991018589A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/02Preparations for care of the skin for chemically bleaching or whitening the skin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34Alcohols
    • A61K8/347Phenols
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73Polysaccharides
    • A61K8/738Cyclodextrins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/56Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms

Definitions

  • the first indication of complex formation is based on the following observation: A - In a saturated aqueous solution of DIMEB (57% at
  • the hydroquinone is added with stirring in a cris ⁇ rate and the hydroquinone is solubilized at a rate of 46.5% (the solubility of HQ in water at 25 ° C is 7, 14%).
  • the mixture is kept in solution at 4 ° C for 8 days. There is then no coloration of the solution, which signifies the absence of oxidation of the hydroquinone. Since the aqueous solution is already saturated with DIMEB, the solubilization of the HQ crystals can only be due to the formation of a complex.
  • mice have the particularity of having a highly pigmented tail and this particularity has been used to test the depigmentation power of our preparations intended for cosmetic use.
  • mice We made up 5 lots of 5 mice each.
  • mice At the start of the applications, the mice weighed 25 + 1 g. At the end of the applications, the mice weighed 27 + 1 g.
  • This batch received no treatment.
  • mice are placed in cages, in pairs or in pairs.
  • each group is transferred to a plastic bowl, 4 times more spacious than the cage, with the bottom lined with shavings.
  • the product to be tested is applied in excess over the entire surface of the tail; a light massage is then carried out and the animals are left for 30 minutes. Then remove the excess product with a cellulose pad and return the animals to their cages.
  • the products to be tested were applied once a day, every day, for 31 days. After the sacrifice of each animal, the skin of the tail is removed over its entire length. About 1 cm from each end is removed and the remainder is divided into three for the preparation of 3 slides.
  • L-DOPA L-3 (3 - 4 hydroxy) phenyl alanine
  • the epidermis has scales of highly pigmented circular shape, regularly arranged on parallel lines and separated by non-pigmented areas.
  • the number of melanocytes per scale was read with an enlargement factor of 150.
  • the treatment being likely to modify the elasticity of the skin and consequently to induce errors on an estimate based on the number of melanocytes per unit of surface, we took as criterion the number of mela ⁇ nocytes per scale, which represents a well-defined entity even after treatment.
  • the number of melanocytes per scale observed in each batch is deducted from the number of melanocytes per scale in the Placebo batch and the difference expressed in percent of inhibited melanocytes.
  • the VEGA commercial cream produces substantially the same melanogenesis inhibiting effect as the cream prepared by our laboratories with a 2% hydroquinone content, ie 30%.
  • Photos 1, 2, 3, 4 illustrate the condition of the skin after treatment of lots A, B, C, D respectively.
  • Photo 5 was taken at the end of the treatment of the animals. The difference is visible between Placebo (A) and lots B, C, D, treated with skin lightening products.

Abstract

A cosmetic skin-lightening composition containing the hydroquinone (HQ)/2,6-dimethyl-β-cyclodextrin (DIMEB) complex. These compositions have greater stability with respect to coloration caused by hydroquinone oxidation, and have a greater depigmentation effect than that of cosmetic compositions having the same hydroquinone content. The cosmetic composition may be a cream or a gel and can be applied on human skin.

Description

COMPOSITION COSMETIQUE A ACTIVITE ECLAIRCISSANTE DE LA PEAU, A BASE DE COMPLEXE HYDROQUINONE ET 2,6 DIMETHYL-β-CYCLODEXTRINE COSMETIC COMPOSITION WITH SKIN LIGHTENING ACTIVITY, BASED ON HYDROQUINONE COMPLEX AND 2.6 DIMETHYL-β-CYCLODEXTRIN
DESCRIPTION DE L'INVENTIONDESCRIPTION OF THE INVENTION
Complexe hydroquinone (HQ) et 2,6 diméthyl-E-cyclodextrine (DIMEB)Hydroquinone (HQ) and 2,6 dimethyl-E-cyclodextrin (DIMEB) complex
De nombreuses études scientifiques concernant des molécules complexées avec la DIMEB ont démontré que la complexation favorise leur absorption percutanée et con¬ tribue à une meilleure régulation de leur biodisponibilité Par conséquent on doit obtenir une efficacité meilleure avec une dose inférieure.Numerous scientific studies concerning molecules complexed with DIMEB have demonstrated that complexation promotes their percutaneous absorption and contributes to better regulation of their bioavailability. Consequently, better efficacy must be obtained with a lower dose.
D'autres études ont prouvé que ce type de complexa¬ tion protège les molécules sensibles à l'oxydation et ou photosensibles.Other studies have shown that this type of complexa¬ protects molecules sensitive to oxidation and or photosensitive.
(KANETO UEKAMA AND TETSUMI IRIE(KANETO UEKAMA AND TETSUMI IRIE
Pharmaceutical applications of Methylated Cyclodextrin Derivatives - pp 393-441 in CYCLODEXTRINS IN THE INDUSTRIAL USE Ed. de Santé - Paris, 1987).Pharmaceutical applications of Methylated Cyclodextrin Derivatives - pp 393-441 in CYCLODEXTRINS IN THE INDUSTRIAL USE Ed. De Santé - Paris, 1987).
L'efficacité bien connue de 1'hydroquinone sur l'inhibition de la mélanogenèse fait qu'elle représente la molécule de choix pour les préparations cosmétiques éclair- cissantes de la peau. Malheureusement la dose efficace pour l'inhibition de la mélanogenèse est très proche de la dose toxique des mélanocytes avec les effets indésirables consécutifs.The well-known efficacy of hydroquinone on the inhibition of melanogenesis makes it the molecule of choice for cosmetic skin lightening preparations. Unfortunately, the effective dose for the inhibition of melanogenesis is very close to the toxic dose of melanocytes with the consequent undesirable effects.
Pour toutes ces raisons, la formulation d'un complexe HQ-DIMEB serait tout à fait souhaitable.For all these reasons, the formulation of an HQ-DIMEB complex would be highly desirable.
La première indication de formation de complexe est basée sur l'observation suivante : A - Dans une solution aqueuse saturée de DIMEB (57 % àThe first indication of complex formation is based on the following observation: A - In a saturated aqueous solution of DIMEB (57% at
25°C) on ajoute sous agitation 1 'hydroquinone en cris¬ taux et l'on arrive à solubiliser 1 'hydroquinone à un taux de 46,5 % (la solubilité de HQ dans l'eau à 25°C est de 7,14 %). Le mélange se maintient en solution à 4°C pendant 8 jours. On n'observe alors pas de colora¬ tion de la solution ce qui signifie l'absence d'oxyda¬ tion de 1'hydroquinone. Etant donné que la solution aqueuse est déjà saturée en DIMEB, la solubilisation des cristaux de HQ ne peut être due qu'à la formation d'un complexe.25 ° C) the hydroquinone is added with stirring in a cris¬ rate and the hydroquinone is solubilized at a rate of 46.5% (the solubility of HQ in water at 25 ° C is 7, 14%). The mixture is kept in solution at 4 ° C for 8 days. There is then no coloration of the solution, which signifies the absence of oxidation of the hydroquinone. Since the aqueous solution is already saturated with DIMEB, the solubilization of the HQ crystals can only be due to the formation of a complex.
B - Pour les besoins de notre formulation cosmétique et à la suite de nombreux essais, nous avons adopté les conditions suivantes :B - For the needs of our cosmetic formulation and following numerous tests, we have adopted the following conditions:
Dans 6 ml d'eau à température ambiante, sous agitation on dissout 1,6 g de DIMEB. On commence à chauffer et, toujours sous agitation, on ajoute 2,0 g de HQ en cristaux. A 45°C toute la quantité de HQ est solubi¬ lisée et reste en solution si le mélange revient à la température ambiante. Ce mélange est utilisé pour 100g de crème HQ-D.In 6 ml of water at room temperature, with stirring, 1.6 g of DIMEB are dissolved. Heating is started and, still with stirring, 2.0 g of crystal HQ are added. At 45 ° C the whole quantity of HQ is solubi¬ lized and remains in solution if the mixture returns to room temperature. This mixture is used for 100g of HQ-D cream.
Une goutte de ce mélange, évaporée sur un verre de montre et observée sous le microscope présente des cristaux caractéristiques.A drop of this mixture, evaporated on a watch glass and observed under the microscope has characteristic crystals.
- La complexation de HQ avec la DIMEB est démontrée par spectroscopie RMN (Résonance Magnétique Nucléaire). Les spectres des solutions A et B ainsi que ceux des molécules HQ et DIMEB sont présentés aux figures 1, 2, 3, 4 respectivement.- The complexation of HQ with DIMEB is demonstrated by NMR spectroscopy (Nuclear Magnetic Resonance). The spectra of solutions A and B as well as those of the molecules HQ and DIMEB are presented in Figures 1, 2, 3, 4 respectively.
- Le rapport des surfaces HQ/DIMEB montre qu'il a environ : Mélange A : 4,4 moles HQ/1 mole DIMEB.- The ratio of HQ / DIMEB surfaces shows that it has approximately: Mixture A: 4.4 moles HQ / 1 mole DIMEB.
Mélange B : 6,3 moles HQ/1 mole DIMEB. Les spectres RMN ont été réalisés dans le service du Professeur M. PLAT. Laboratoire de Chimie Thérapeutique UNIVERSITE PARIS-SUD, FACQLTE DE PHARMACIE, CHATENAY- MALABRY, FRANCE. EXEMPLES DE FORMULATION AVEC LE COMPLEXE HQ-DIMEBMixture B: 6.3 moles HQ / 1 mole DIMEB. NMR spectra were performed in the service of Professor M. PLAT. Laboratory of Therapeutic Chemistry UNIVERSITE PARIS-SUD, FACQLTE DE PHARMACIE, CHATENAY- MALABRY, FRANCE. FORMULATION EXAMPLES WITH THE HQ-DIMEB COMPLEX
CREME HQ-DHQ-D CREAM
MATIERES PREMIERES %RAW MATERIALS %
A - Glyceryl Stéarate et PEG-lOO Stéarate 9,00A - Glyceryl Stearate and PEG-lOO Stearate 9.00
Polyoxyéthylène (20) Stéaryl éther 2,00Polyoxyethylene (20) Stearyl ether 2.00
PEG - (5) - Stéarate de Stéaryl 2,00PEG - (5) - Stearyl stearate 2.00
Beurre de Karité 2,50Shea Butter 2.50
Octyl-méthoxycinnamate 2,50Octyl-methoxycinnamate 2.50
DL-< -tσcophérol (acétate) 0,20DL- <-tσcopherol (acetate) 0.20
Pal itate d'Isopropyle -. . 3,00Isopropyl Pal itate -. . 3.00
Polydiméthylsiloxane 1500 0,20Polydimethylsiloxane 1500 0.20
B - Eau déminéralisée 61,50B - Demineralized water 61.50
Propylène glycol 4,00Propylene glycol 4.00
1,1' - méthylène - bis (3-(3-(hydroxyméthyl)-1,1 '- methylene - bis (3- (3- (hydroxymethyl) -
2,4- dioxo - 5 - imidazolidinyl)•) urée 0,402,4- dioxo - 5 - imidazolidinyl) •) urea 0.40
Acide sorbique 0,20Sorbic acid 0.20
Sel disodique de l'acide éthylenediamine tétra-acétique 0,10Disodium salt of ethylenediamine tetraacetic acid 0.10
Hydroxyéthyl cellulose QP 300 0,80Hydroxyethyl cellulose QP 300 0.80
C - Eau déminéralisée 6,00C - Demineralized water 6.00
2,6 diméthyl-p-cyclodextrine (DIMEB) 1,602.6 dimethyl-p-cyclodextrin (DIMEB) 1.60
Hydroquinone 2,00Hydroquinone 2.00
D - Parfum 0,30D - Perfume 0.30
POE - (45) - Huile de ricin 0,30POE - (45) - Castor oil 0.30
E - Métabisulfite de Sodium 0,40E - Sodium metabisulfite 0.40
Eau déminéralisée 1,00 MODE OPERATOIRE :Demineralized water 1.00 PROCEDURE:
- Porter la phase grasse A à 75°C, ajouter l'antimousse 1500 dispersé dans le palmitate d'isopropyle à chaud (75°C) et bien mélanger.- Bring the fatty phase A to 75 ° C, add the antifoam 1500 dispersed in hot isopropyl palmitate (75 ° C) and mix well.
- A température ambiante mélanger tous les ingrédients de la phase aqueuse B et sous agitation vive disperser la cellulose. Continuer l'agitation pendant 30 minutes. Chauffer. A 75°C le mélange doit être clair et transparent.- At room temperature mix all the ingredients of the aqueous phase B and, with vigorous stirring, disperse the cellulose. Continue agitation for 30 minutes. Heat. At 75 ° C the mixture must be clear and transparent.
- Sous agitation forte, ajouter B dans A. Continuer l'agitation pendant 15 minutes.- With vigorous stirring, add B to A. Continue stirring for 15 minutes.
- Examiner l'émulsion au microscope.- Examine the emulsion under a microscope.
- Refroidir sous agitation lente et à 50°C ajouter C goutte à goutte.- Cool with slow stirring and at 50 ° C add C drop by drop.
- Préparation de C : A la température ambiante, sous agitation, mettre la 2,6 diméthyl-p-cyclodextrine en solu¬ tion dans l'eau. Commencer à chauffer et toujours sous agitation, ajouter 1'hydroquinone qui doit se solubiliser complètement. Ne pas dépasser 50°C.- Preparation of C: At room temperature, with stirring, put the 2,6 dimethyl-p-cyclodextrin in solution in water. Begin to heat and still with stirring, add the hydroquinone which must dissolve completely. Do not exceed 50 ° C.
- A 30°C, ajouter D. Le parfum est préalablement émul- sionné dans la POE -(45)- huile de ricin (mélange limpide).- At 30 ° C, add D. The perfume is emulsified beforehand in the POE - (45) - castor oil (clear mixture).
- A 25°C ajouter E qu'on doit mettre en solution extem- poranément.- At 25 ° C add E which must be dissolved immediately.
- Continuer l'agitation lente pendant 30 minutes.- Continue the slow agitation for 30 minutes.
- Cette formule a été testée pour sa stabilité à 40°C pendant 3 mois.- This formula has been tested for its stability at 40 ° C for 3 months.
- Cette formule a été testée IN VIVO pour son efficacité inhibitrice de la mélanogenèse sur souris de souche C3H / OUJ. GEL HQ-D MATIERES PREMIERES %- This formula has been tested IN VIVO for its inhibitory efficacy against melanogenesis on mice of C3H / OUJ strain. RAW MATERIAL HQ-D GEL
A - Eau déminéralisée 57,00A - Demineralized water 57.00
1,1'-méthylène-bis(3-(3-(hydroxyméthyl)-2,4- dioxo-5-imidazolidinyl) ) urée 0,301,1'-methylene-bis (3- (3- (hydroxymethyl) -2,4- dioxo-5-imidazolidinyl)) urea 0.30
Sel disodique de l'acide éthylènediamine tétra-acétique 0,10Disodium salt of ethylenediamine tetraacetic acid 0.10
Hexylène glycol 1 ,00Hexylene glycol 1.00
Propylène glycol 12,00Propylene glycol 12.00
Acide sorbique 0,10Sorbic acid 0.10
Hydroxyéthyl cellulose QP 300 2,80Hydroxyethyl cellulose QP 300 2.80
B - Eau déminéralisée 6,00B - Demineralized water 6.00
2,6 diméthyl-p-cyclodextrine (DIMEB) 1,602.6 dimethyl-p-cyclodextrin (DIMEB) 1.60
Hydroquinone 2,00Hydroquinone 2.00
C - Propylène glycol 3,00C - Propylene glycol 3.00
Butyl Hydroxy Anisol (B.H.A.) 0,05Butyl Hydroxy Anisol (B.H.A.) 0.05
Mono Tertiaire-Butylhydroquinone (T.B.H.Q.). 0,05Mono Tertiary-Butylhydroquinone (T.B.H.Q.). 0.05
MODE OPERATOIRE :PROCEDURE:
- A température ambiante, mélanger tous les ingrédients de la phase A, et, sous agitation moyenne, disperser la cellulose. Continuer l'agitation lente pendant 30 minutes. Chauffer. A 50°C le mélange doit être clair et transparent. Maintenir la température à 50°C.- At room temperature, mix all the ingredients of phase A, and, with moderate stirring, disperse the cellulose. Continue slow agitation for 30 minutes. Heat. At 50 ° C the mixture must be clear and transparent. Maintain the temperature at 50 ° C.
- Préparation du B : à température ambiante, sous agita¬ tion, solubiliser la DIMEB dans l'eau. Commencer à chauf¬ fer et, toujours sous agitation, ajouter 1'hydroquinone qui doit se solubiliser complètement.- Preparation of B: at room temperature, with stirring, dissolve the DIMEB in water. Start heating and, while stirring, add the hydroquinone which must dissolve completely.
Ne pas dépasser 50 °C.Do not exceed 50 ° C.
- Les phases A et B étant à 50°C, sous agitation lente, ajouter goutte à goutte B dans A. Bien homogénéiser et ajouter C. Le gel doit être clair et transparent.- Phases A and B being at 50 ° C, with slow stirring, add drop by drop B to A. Mix well and add C. The gel must be clear and transparent.
EMENT TEST IN VIVO POUR L'EFFICACITE DE LA CREME HQ-D SUR LA DEPIGMENTATION DE LA PEAU.EMENT IN VIVO TEST FOR THE EFFECTIVENESS OF THE HQ-D CREAM ON DEPIGMENTATION OF THE SKIN.
PROTOCOLE EXPERIMENTALEXPERIMENTAL PROTOCOL
MATERIEL ANIMALANIMAL MATERIAL
Nous avons utilisé des souris de souche C3H/OUJ. Elles ont pour particularité de posséder une queue fortement pigmentée et cette particularité a été mise à profit pour tester le pouvoir de dépigmentation de nos préparations destinées à usage cosmétique.We used C3H / OUJ strain mice. They have the particularity of having a highly pigmented tail and this particularity has been used to test the depigmentation power of our preparations intended for cosmetic use.
La formule complète de la crème HQ-D a fait l'objet essentiel de la première étude.The complete formula of HQ-D cream was the main focus of the first study.
CONSTITUTION DES LOTSCONSTITUTION OF LOTS
Nous avons constitué 5 lots de 5 souris chacun.We made up 5 lots of 5 mice each.
Au début des applications, les souris avaient un poids de 25 + 1 g. A la fin des applications les souris avaient un poids de 27 + 1 g.At the start of the applications, the mice weighed 25 + 1 g. At the end of the applications, the mice weighed 27 + 1 g.
LOT - A (placebo) :LOT - A (placebo):
Dans la crème pour le traitement du lot placebo, tous les ingrédients de la formule HQ-D ont été introduits, à l'exclusion de 1'hydroquinone (HQ) et de la 2,6 diméthyl- p-cyclodextrine (DIMEB).In the cream for the treatment of the placebo batch, all the ingredients of the formula HQ-D have been introduced, with the exception of hydroquinone (HQ) and 2,6 dimethyl-p-cyclodextrin (DIMEB).
LOT - B (hydroquinone) :LOT - B (hydroquinone):
Dans la crème pour le traitement du lot hydroquinone, tous les ingrédients de la formule HQ-D ont été introduits à l'exclusion de la 2,6 diméthyl-p-cyclodextrine (DIMEB).In the cream for the treatment of the hydroquinone batch, all the ingredients of the formula HQ-D have been introduced with the exclusion of 2,6 dimethyl-p-cyclodextrin (DIMEB).
LOT - C (HQ - DIMEB) :LOT - C (HQ - DIMEB):
Le traitement de ce lot a été effectué avec la formule complète HQ-D. LOT - D (Vega) :The treatment of this batch was carried out with the complete formula HQ-D. LOT - D (Vega):
Le traitement de ce lot a été effectué avec une crème éclaircissante commercialisée depuis plusieurs années et à notre connaissance ayant une teneur en hydroquinone 2%.The treatment of this batch was carried out with a lightening cream marketed for several years and to our knowledge having a hydroquinone content 2%.
LOT - E (témoins) :LOT - E (witnesses):
Ce lot n'a reçu aucun traitement.This batch received no treatment.
MODE D'APPLICATION ET DUREE D'APPLICATIONMETHOD OF APPLICATION AND DURATION OF APPLICATION
Les souris sont placées dans des cages, par deux ou par trois. Pour l'application, chaque groupe est transféré dans une cuvette en plastique, 4 fois plus spacieuse que la cage, avec le fond garni de copeaux. A l'aide des doig- tiers, le produit à tester est appliqué en excès sur toute la surface de la queue; on pratique ensuite un léger mas¬ sage et on laisse les animaux pendant 30 minutes. Puis on enlève l'excès de produit avec un tampon de cellulose et on remet les animaux dans leurs cages.The mice are placed in cages, in pairs or in pairs. For the application, each group is transferred to a plastic bowl, 4 times more spacious than the cage, with the bottom lined with shavings. Using the fingers, the product to be tested is applied in excess over the entire surface of the tail; a light massage is then carried out and the animals are left for 30 minutes. Then remove the excess product with a cellulose pad and return the animals to their cages.
Les produits à tester ont été appliqués 1 fois par jour, tous les jours, pendant 31 jours. Après sacrifice de chaque animal, la peau de la queue est prélevée sur toute sa longueur. Environ 1 cm de chaque extrémité est éliminé et le restant est partagé en trois pour la préparation de 3 lames.The products to be tested were applied once a day, every day, for 31 days. After the sacrifice of each animal, the skin of the tail is removed over its entire length. About 1 cm from each end is removed and the remainder is divided into three for the preparation of 3 slides.
SEPARATION EPIDERME/DERMEEPIDERMIS / DERMIS SEPARATION
Méthode chimique au Bromure de Sodium.Sodium Bromide chemical method.
Immerger le lambeau de peau dans une solution aqueuse de bromure de sodium 2M. Laisser en contact deux heures à la température ambiante. A l'aide de pinces au bout arron¬ di, détacher avec précaution l'épiderme du derme et rincer l'épiderme par passage dans une solution tampon pïï = 7,3.Immerse the skin flap in a 2M aqueous sodium bromide solution. Leave in contact for two hours at room temperature. Using tweezers, carefully detach the epidermis from the dermis and rinse the epidermis by passing it through a buffer solution = 7.3.
Cette technique permet la séparation de l'épiderme et du derme, juste à la jonction dermo-épidermique, sans dété¬ rioration des mélanocytes. L-DOPA - réaction :This technique allows the separation of the epidermis and the dermis, just at the dermo-epidermal junction, without deterioration of the melanocytes. L-DOPA - reaction:
Préparer extemporanément une solution de L-DOPA (L-3 (3 - 4 hydroxy) phényl alanine) à 0,1 pour cent dans un tampon (pH 7,3). Laisser en contact environ 20 minutes à l'abri de la lumière.Prepare a 0.1 percent solution of L-DOPA (L-3 (3 - 4 hydroxy) phenyl alanine) extemporaneously in a buffer (pH 7.3). Leave in contact for about 20 minutes, protected from light.
- Immerger l'épiderme dans cette solution de L-DOPA pen¬ dant 30 minutes à 37°C.- Immerse the epidermis in this L-DOPA solution for 30 minutes at 37 ° C.
- Renouveler la solution de -L-DOPA et laisser l'épiderme en contact pendant deux heures trente minutes à 37°C.- Renew the -L-DOPA solution and leave the epidermis in contact for two hours and thirty minutes at 37 ° C.
PREPARATION DES LAMES :PREPARING THE BLADES:
A la fin de la DOPA-réaction, rincer l'épiderme par passage dans une solution tampon CBS (pH 7,3), déshydrater et dégraisser par passages successifs dans :At the end of the DOPA-reaction, rinse the epidermis by passage through a CBS buffer solution (pH 7.3), dehydrate and degrease by successive passages in:
* solution formaidéhyde à 4 %* 4% formaldehyde solution
* éthanol 50 %* 50% ethanol
* éthanol 70 %* 70% ethanol
* éthanol absolu* absolute ethanol
* toluène* toluene
Placer bien à plat le lambeau de l'épiderme ainsi traité entre lame et lamelle avec une goutte de solution polymérisante (EUKIT). Poser sur la lamelle un poids de plomb (3x2x2). Laisser sécher pendant 24 heures.Place the flap of the epidermis thus treated between the blade and coverslip well flat with a drop of polymerizing solution (EUKIT). Place a lead weight (3x2x2) on the strip. Leave to dry for 24 hours.
LECTURE AU MICROSCOPE :MICROSCOPE READING:
Au microscope, l'épiderme présente des écailles de forme circulaire fortement pigmentées, disposées réguliè¬ rement sur des lignes parallèles et séparées par des zones non pigmentées. La lecture du nombre de mélanocytes par écaille a été effectuée avec un facteur d'agrandissement de 150.Under the microscope, the epidermis has scales of highly pigmented circular shape, regularly arranged on parallel lines and separated by non-pigmented areas. The number of melanocytes per scale was read with an enlargement factor of 150.
Pour chaque lame, la lecture a été effectuée sur 20 écailles différentes, soit 60 écailles par souris et 300 écailles par groupe d'animaux et par produit testé. EVALUATION DE L'ACTIVITE DEPIGMENTANTE :For each slide, the reading was taken on 20 different scales, ie 60 scales per mouse and 300 scales per group of animals and per product tested. EVALUATION OF DEPIGMENTING ACTIVITY:
Plusieurs paramètres permettent d'estimer la capacité fonctionnelle des mélanocytes. Ce sont :Several parameters are used to estimate the functional capacity of melanocytes. Those are :
- le nombre de mélanocytes par unité de surface de peau,- the number of melanocytes per unit of skin area,
- la distance intermélanocytaire,- the intermelanocytic distance,
- le nombre de dendrites,- the number of dendrites,
- la longueur des dendrites.- the length of the dendrites.
Le traitement étant susceptible de modifier l'élasti¬ cité de la peau et par conséquent induire des erreurs sur une estimation basée au nombre de mélanocytes par unité de surface, nous avons pris comme critère le nombre de méla¬ nocytes par écaille, ce qui représente une entité bien délimitée même après traitement.The treatment being likely to modify the elasticity of the skin and consequently to induce errors on an estimate based on the number of melanocytes per unit of surface, we took as criterion the number of mela¬ nocytes per scale, which represents a well-defined entity even after treatment.
TABLEAU N° 1TABLE N ° 1
Nombre de Taux d'inhibition du Nbre mélanocytes de mélanocytes par rapport par écaille au groupe Placebo en %Number of inhibition rate of the number of melanocytes of melanocytes in relation to the Placebo group in%
Lot-A Placebo 122,1 ± 4,1Lot-A Placebo 122.1 ± 4.1
Lot-B Hydroquinone 85,4 + 5,9 30,0Lot-B Hydroquinone 85.4 + 5.9 30.0
Lot-C HQ - DIMEB 68,3 ± 8,1 44,0Lot-C HQ - DIMEB 68.3 ± 8.1 44.0
Lot-D VEGA 82,6 + 3,5 32,3Lot-D VEGA 82.6 + 3.5 32.3
Lot-E Témoins 120,0 ± 6,2Lot-E Witnesses 120.0 ± 6.2
RESULTATS ET DISCUSSION :RESULTS AND DISCUSSION :
Le tableau n°l présente nos résultats. On constate qu'il n'y a pas eu d'effet Placebo, ce lot ayant le même nombre de mélanocytes par écaille que le lot témoin.Table No. 1 presents our results. We note that there was no Placebo effect, this batch having the same number of melanocytes per scale as the control batch.
Pour l'évaluation du pouvoir éclaircissant des prépa¬ rations cosmétiques, le nombre de mélanocytes par écaille observée à chaque lot est déduit du nombre de mélanocytes par écaille du lot Placebo et la différence exprimée en pourcent de mélanocytes inhibés. Quantitativement, la crème commerciale VEGA produit sensiblement le même effet d'inhibition de mélanogenèse que la crème préparée par nos laboratoires à teneur d'hydroquinone 2 %, soit 30 %.For the evaluation of the lightening power of cosmetic preparations, the number of melanocytes per scale observed in each batch is deducted from the number of melanocytes per scale in the Placebo batch and the difference expressed in percent of inhibited melanocytes. Quantitatively, the VEGA commercial cream produces substantially the same melanogenesis inhibiting effect as the cream prepared by our laboratories with a 2% hydroquinone content, ie 30%.
De toute évidence, la crème HQ-D formule complète a exercé le meilleur pouvoir inhibiteur sur la capacité fonctionnelle des mélanocytes soit 44 %. Cette formule contient 2 % d'hydroquinone complexée préalablement avec la 2,6 diméthyl-p-cyclodextrine.Obviously, the complete formula HQ-D cream exerted the best inhibitory power on the functional capacity of melanocytes, ie 44%. This formula contains 2% of hydroquinone complexed beforehand with 2,6 dimethyl-p-cyclodextrin.
Dans cette formule, comme protection vis-à-vis de la pigmentation indirecte, un filtre UV-B, le octyl méthoxy- cinnamate est incorporé à un taux de 2,5 %.In this formula, as protection against indirect pigmentation, a UV-B filter, octyl methoxy cinnamate is incorporated at a rate of 2.5%.
Les photos 1, 2, 3, 4 illustrent l'état de la peau après traitement des lots A, B, C, D respectivement. La photo 5 a été réalisée à la fin du traitement des animaux. La différence est visible entre le Placebo (A) et les lots B, C, D, traités aux produits éclaircissants de la peau.Photos 1, 2, 3, 4 illustrate the condition of the skin after treatment of lots A, B, C, D respectively. Photo 5 was taken at the end of the treatment of the animals. The difference is visible between Placebo (A) and lots B, C, D, treated with skin lightening products.
Les expériences IN VIVO ont été réalisées dans le service du Docteur M. CESARINI. GROUPE DE RECHERCHE SUR L'ONCOGENESE, LES ULTRAVIOLETS ET LA PIGMENTATION CUTANEE HUMAINE. FONDATION OPHTALMOLOGIQUE ADOLPHE DE ROTHSCHILD, 25 - 29, rue Manin, PARIS. The IN VIVO experiments were carried out in the service of Doctor M. CESARINI. RESEARCH GROUP ON ONCOGENESIS, ULTRAVIOLETS AND HUMAN SKIN PIGMENTATION. FONDATION OPHTALMOLOGIQUE ADOLPHE DE ROTHSCHILD, 25 - 29, rue Manin, PARIS.

Claims

REVENDICATIONS
1 - Composition cosmétique éclaircissante de la peau, com¬ prenant une base contenant hydroquinone et 2,6 diméthyl-p- cyclodextrine.1 - Skin lightening cosmetic composition, comprising a base containing hydroquinone and 2.6 dimethyl-p- cyclodextrin.
2 --Composition cosmétique éclaircissante de la peau, selon la revendication 1, caractérisée en ce que 1'hydro¬ quinone est préalablement complexée avec la 2,6 diméthyl- p-cyclodextrine et ce complexe incorporé dans une base de crème.2 - Skin lightening cosmetic composition according to claim 1, characterized in that the hydro¬ quinone is previously complexed with 2,6 dimethyl-p-cyclodextrin and this complex incorporated in a cream base.
3 - Composition cosmétique éclaircissante de la peau, selon la revendication 1, caractérisée en ce que 1'hydro¬ quinone est préalablement complexée avec la 2,6 diméthyl- p-cyclodextrine et ce complexe incorporé dans une base de gel. 3 - Skin lightening cosmetic composition according to claim 1, characterized in that the hydro¬ quinone is previously complexed with 2,6 dimethyl-p-cyclodextrin and this complex incorporated in a gel base.
PCT/FR1990/000372 1988-12-08 1990-05-29 COSMETIC SKIN-LIGHTENING COMPOSITION BASED ON A HYDROQUINONE/2,6-DIMETHYL-β-CYCLODEXTRIN COMPLEX WO1991018589A1 (en)

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Publication number Priority date Publication date Assignee Title
FR2640136B1 (en) * 1988-12-08 1991-02-15 Tsomi Vassiliki COSMETIC COMPOSITION WITH SKIN LIGHTENING ACTIVITY, BASED ON HYDROQUINONE COMPLEX (HQ) -2,6 DIMETHYL- (BETA) -CYCLODEXTRIN (DIMEB)
US5296472A (en) * 1991-12-05 1994-03-22 Vyrex Corporation Methods for delipidation of skin and cerumen removal
FR2783714B1 (en) * 1998-09-29 2002-07-19 Led Evolution Dermatolog COMPOSITION BASED ON HYDROQUINONE AND METABISULPHITE FOR TOPICAL USE FOR DEPIGMENTATION OF THE SKIN

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FR2640136A1 (en) * 1988-12-08 1990-06-15 Tsomi Vassiliki Cosmetic composition having skin-lightening activity, based on the complex of hydroquinone [HQ] and 2,6-dimethyl- beta -cyclodextrin [DIMEB]

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US4692261A (en) * 1985-12-20 1987-09-08 Warner-Lambert Company Skin bleaching detergent bar
FR2640136A1 (en) * 1988-12-08 1990-06-15 Tsomi Vassiliki Cosmetic composition having skin-lightening activity, based on the complex of hydroquinone [HQ] and 2,6-dimethyl- beta -cyclodextrin [DIMEB]

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1174109A2 (en) * 2000-07-21 2002-01-23 Beiersdorf Aktiengesellschaft Combinations of active substances respectively adducts from cyclodextrins and at least a quinone and/or at least a hydroquinone and use of such combinations of active substances in cosmetic preparations
DE10035513A1 (en) * 2000-07-21 2002-01-31 Beiersdorf Ag Active substance combinations or adducts of cyclodextrins and at least one quinone and / or at least one hydroquinone and use of such active substance combinations in cosmetic preparations
EP1174109A3 (en) * 2000-07-21 2004-01-07 Beiersdorf Aktiengesellschaft Combinations of active substances respectively adducts from cyclodextrins and at least a quinone and/or at least a hydroquinone and use of such combinations of active substances in cosmetic preparations
US6825179B2 (en) 2000-07-21 2004-11-30 Beiersdorf Ag Active ingredient combinations or adducts of cyclodextrins and quinones

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FR2640136B1 (en) 1991-02-15

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