Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/34—Alcohols
  • A61K8/347—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/63—Steroids; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders

Definitions

• the invention relates to a depigmenting composition for the skin, comprising, in a physiologically acceptable medium, adapalene (6- [3- (1-adamantyl) -4-methoxyphenyl] - 2-naphthanoic acid) , at least one depigmenting agent and at least one anti-inflammatory agent, and to its pharmaceutical or cosmetic use.
• adapalene 6- [3- (1-adamantyl) -4-methoxyphenyl] - 2-naphthanoic acid
• A.M. Kligman describes, in US Patent 3,856,934, a depigmenting composition comprising hydroquinone, reti- noic acid and a corticosteroid. This type of combination allows good depigmentation of the skin but causes substantial adverse effects such as irritation and itching.
• Retinoic acid is known to have, on its own, a skin depigmenting activity (Guevara I.A. and Pandya A. G. Int. J. Dermatol. 40, 210-215 (2001)).
• tretinoin used at 0.01% or 0.03%, induces depigmentation of the tail which begins from the first week of treatment and progresses to reach a clear depigmentation at 6 weeks.
• the dose of 0.03% is capable of inhibiting the induction of pigmentation by UVB radiation, whereas the lower dose has no effect.
• Tretinoin is therefore a depigmenting agent on its own.
• adapalene has no depigmenting activity, as is shown in Example 5 hereinafter. Due to its lack of depigmenting activity in particular, nothing therefore encouraged those skilled in the art to combine it with a depigmenting agent in a depigmenting composition possibly containing an anti-inflammatory agent.
• the Applicant has discovered, surprisingly, that the combination of adapalene, a depigmenting agent and an anti-inflammatory agent makes it possible to obtain a much more rapid depigmenting response than that obtained with the depigmenting agent alone.
• the Applicant has also discovered, surprisingly, that good tolerance of the skin is obtained with the combination of adapalene, a depigmenting agent and an anti-inflammatory agent, at the same time keeping a considerable depigmenting activity.
• the invention therefore relates to a depigmenting composition for the skin, comprising, in a physiologically acceptable medium, adapalene, at least one depigmenting agent distinct from adapalene, and at least one anti-inflammatory agent distinct from adapalene.
• the composition according to the invention therefore comprises at least three different active ingredients .
• physiologically acceptable medium is intended to mean a medium which is compatible with the skin, the mucous membranes and/or the integuments.
• depigmenting agent is intended to mean any active agent having skin-depigmenting activity. This activity makes it possible to decrease the pigmentation of the skin that already exists and also to prevent any additional pigmentation above the natural pigmentation.
• phenolic derivatives such as hydroquinone, hydroquinone monoethyl ether, hydro- quinone monobenzyl ether or 4-hydroxyanisole, kojic acid and its derivatives, azelaic acid and its derivatives, linoleic acid, resorcinol and its derivatives, ellagic acid, hydroxy acids such as glycolic acid, ascorbic acid, zinc peroxide, and mercury chloride.
• the depigmenting composition for the skin may comprise, as depigmenting agent, a phenolic derivative, in particular hydroguinone .
• the invention also relates to a depigmenting composition for the skin, comprising, in a physiologically acceptable medium, adapalene, at least one depigmenting agent distinct from adapalene and at least one anti-inflammatory agent distinct from adapalene.
• the composition according to the invention advantageously comprises between 0.0001% and 20% by weight of adapalene relative to the total weight of the composition, and between 0.0001% and 20% by weight of depigmenting agent relative to the total weight of the composition, and preferably, respectively, between 0.001% and 10% by weight of adapalene relative to the total weight of the composition, and between 0.025% and 5% by weight of depigmenting agent relative to the total weight of the composition.
• the composition comprises at least one steroidal or non-steroidal anti-inflammatory agent in preferential concentrations ranging from 0.001% to 20.00% by weight relative to the total weight of the composition.
• steroidal anti-inflammatory agents mention may be made, by way of non-limiting example, of clobetasone butyrate, clobetasol propionate, clobetasol dipropio- nate, hydrocortisone, cortisone, prednisolone, miconazole, prednisone, triamcinolone acetonide, methyl- prednisolone, fluometholone, fluocinolone acetonide, desonide, betamethasone, dexamethasone, or mixtures thereof .
• non-steroidal anti-inflammatory agents mention may be made, by way of non-limiting example, of indole derivatives, arylcarboxylic derivatives such as ibu- profen, oxicams, pyrazole compounds, salicylic acid and selective COX-2 inhibitors.
• the depigmenting composition for the skin may comprise fluocinolone acetonide as antiinflammatory agent .
• the composition may also comprise any additive normally used in the cosmetics or pharmaceutical field, such as sequestering agents, antioxidants, sunscreens, preserving agents, fillers, electrolytes, humectants, dyes, common inorganic or organic bases or acids, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self- tanning compounds, and skin calmative and protective agents such as allantoin.
• any additive normally used in the cosmetics or pharmaceutical field such as sequestering agents, antioxidants, sunscreens, preserving agents, fillers, electrolytes, humectants, dyes, common inorganic or organic bases or acids, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self- tanning compounds, and skin calmative and protective agents such as allantoin.
• any additive normally used in the cosmetics or pharmaceutical field such as sequestering agents, antioxidants, sunscreens, preserving agents, fillers, electrolytes,
• additives may be present in the composition in a proportion of from 0.001% to 20% by weight relative to the total weight of the composition.
• EDTA ethylenediaminetetraacetic acid
• dihydroxyethylglycine citric acid and tartaric acid.
• preserving agents mention may be made of benzalkonium chloride, phenoxyethanol , benzyl alcohol, diazolidinylurea and parabens .
• humectants examples include: glycerol and sorbitol .
• a subject of the present invention is also the composition according to the invention as described above, as a medicament.
• the invention also relates to the use of the composition according to the invention as described above, in the pharmaceutical and cosmetics field.
• compositions of the invention are particularly- suitable for the treatment and prevention of hyperpig- mentary disorders such as melasma, chloasma, lenti- gines, senile lentigo, freckles, post-inflammatory hyperpigmentations due to an abrasion, a burn, a scar, a dermatosis, a contact allergy; naevi, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or drug-related origin, melanomas or any other hyperpigmentary lesions .
• hyperpig- mentary disorders such as melasma, chloasma, lenti- gines, senile lentigo, freckles, post-inflammatory hyperpigmentations due to an abrasion, a burn, a scar, a dermatosis, a contact allergy; naevi, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or drug-related origin,
• compositions according to the invention also find application in the cosmetics field, in particular in protection against the harmful effects of the sun, for preventing and/or for combating photo-induced or chronological ageing of the skin and of the integuments .
• This composition should be applied once a day until complete depigmentation is obtained, for the treatment of chloasma.
• This composition should be applied twice a day until complete depigmentation is obtained, for the treatment of lentigines.
• This composition should be- applied once a day until complete depigmentation is obtained, for the treatment of melasma.
• This composition should be applied twice a day until complete depigmentation is obtained, for the treatment of lentigines.
• Example 5 Measurement of the depigmenting activity of the combination of adapalene and a depigmenting agent
• the evaluation of the depigmenting and/or anti-pigment- ing activity of 3% hydroquinone and of 0.1% adapalene, alone or in combination for 8 weeks, is carried out on the tail of an SKH:HR2 mouse irradiated with ultraviolet B radiation, or not irradiated.
• the tail of the SKH-.HR2 mouse is naturally pigmented and this pigmentation increases under the effect of repeated UVB irradiation.
• the depigmenting activity is measured on the natural pigmentation after application of the test product to the tail of non-irradiated animals.
• the anti-pigmenting activity is measured by the inhibition of the induction of the UV-induced pigmentation: the test product is applied to the tail of UVB-irradiated animals .
• the treatment is carried out 5 days a week for 8 weeks. 20 ⁇ l of test product diluted in acetone are applied to the tail with a gap between applications: the hydroquinone is applied in the morning and the adapalene 4 h later. On the days of irradiation, the treatment is applied after irradiation.
• the animals are irradiated 3 times a week for 8 weeks (Monday, Wednesday, Friday) at the dose of 90 mJ/cm 2 of UVB.
• the pigmentation is evaluated once a week before irradiation, by means of a score on a scale of 0 to 4.
• the scores are divided up as follows:
• Depigmentation scale scores -1 to -4.
• Figure 1 represents the kinetics of the mouse tail skin pigmentation scores as a function of treatment time with or without ultraviolet B irradiation (up to 8 weeks of treatment) with ( ⁇ ) UVB + acetone, ( ⁇ ) UVB + adapalene, M) UVB + hydroquinone, (•) UVB + hydroquinone + adapalene, (D) skin not irradiated + acetone, ( ⁇ ) skin not irradiated + adapalene, (o) skin not irradiated + hydroquinone, (V) skin not irradiated + hydroquinone + adapalene.
• Figure 2 represents the scores for pigmentation on the tail at the end of the study (D57) with (D) acetone
• Depigmenting activity Hydroquinone alone at 3% induces a depigmentation which is clinically visible from the 6th week of treatment (D43) and statistically significant at the end of the study.
• Adapalene alone does not modify the natural pigmentation. When adapalene is combined with hydroquinone, it potentiates its depigmenting activity.
• Anti-pigmenting activity In the animals irradiated and treated concomitantly, hydroquinone shows an anti- pigmenting effect at the 6th and at the 7th week (D50) , which becomes less marked at the end of the study. On the other hand, the adapalene + hydroquinone combination inhibits the pigmentation induced by UVB irradiation as soon as it appears and until the end of the study, where the difference is statistically significant (**, p ⁇ 0.01).
• hydroquinone + adapalene combination exhibits a strong anti-pigmenting activity and significantly inhibits the pigmentation induced by UVB irradiation as soon as it appears and until the end of the study.
• the hydroquinone + adapalene combination exhibits a significant benefit as a depigmenting agent, with respect to hydroquinone alone .
• Example 6 Measurement of the tolerance with respect to the combination of adapalene, an antx-pigmenting agent and an anti-inflammatory agent
• adapalene trio hydroquinone + fluocinolone acetonide combination
• control trio combination retinoic acid
• tretinoin hydroquinone + fluocinolone acetonide
• the treatment is carried out 5 days a week for 4 weeks.
• the animals are irradiated 3 times a week for 4 weeks (Monday, Wednesday, Friday) at the dose of 90 mJ/cm 2 of UVB.
• the inflammation (erythema and squamae) is evaluated once a week before irradiation by means of a score on a scale of 0 to 4.
• the scores are divided up as follows:
• Figure 3 presents the overall clinical score for inflammation on the tail at the end of the 4 weeks of study after application either of the vehicle (A) , or of the adapalene trio ( ' BBl) , or of the control trio ⁇ ) .

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• 2006
  • 2006-08-31 CA CA002616915A patent/CA2616915A1/en not_active Abandoned
  • 2006-08-31 WO PCT/IB2006/003725 patent/WO2007052157A2/en active Application Filing
  • 2006-08-31 EP EP06842260A patent/EP1926484A2/de not_active Withdrawn

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