Title of Invention

"DEPIGMENTING COMPOSITION FOR THE SKIN"

Abstract Depigmenting composition for the skin, comprising 0.0001 to 20% by weight of adapalene and 0.0001 to 20% by weight of 4-hydroxyanisole in a physiologically acceptable vehicle of the kind such as herein described.
Full Text 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) and at least one depigmenting agent and its pharmaceutical or cosmetic use. The composition according to the invention may also contain a sunscreen.
A. M. Kligman describes, in patent US 3,856,934, a depigmenting composition comprising hydroquinone, retinoic acid and a corticosteroid. This type of combination allows good depigmentation of the skin but causes substantial undesirable effects such as irritation and itching.
Retinoic acid (tretinoin) 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) unlike adapalene which has no depigmenting activity as is shown in Example 6 below. By virtue of its lack of depigmenting activity in particular, nothing therefore encouraged persons skilled in the art to combine it with a depigmenting agent in a depigmenting composition containing a sunscreen or not.
However, the applicant has discovered, surprisingly, that the combination of adapalene and a depigmenting agent made it possible to obtain a much

more rapid depigmenting response than that obtained with the depigmenting agent alone.
The invention therefore relates to a depigmenting composition for the skin comprising, in a physiologically acceptable medium, adapalene and at least one depigmenting agent.
The expression physiologically acceptable medium is understood to mean a medium compatible with the skin, the mucous membranes and/or the superficial body growths.
The expression depigmenting agent is understood to mean any active agent having a skin depigmenting activity. This activity makes it possible to reduce the already existing pigmentation of the skin and also to prevent any additional pigmentation above the natural pigmentation.
There may be mentioned, as depigmenting agent, by way of nonlimiting example, phenolic derivatives, such as hydroquinone, hydroguinone monoethyl ether, hydroquinone 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 and its derivatives, in particular ascorbyl glucoside; zinc peroxide; and mercury chloride, arbutin and its derivatives such as those described in applications

EP-895 779 and EP-524 109; aminophenol derivatives such as those described in applications WO 99/10318 and WO 99/32077, and in particular N-cholesteryloxy-carbonyl-para-aminophenol and N-ethyloxycarbonyl-para-aminophenol; iminophenol derivatives, in particular those described in application WO 99/22707; L-2-oxothiazolidine-4-carboxylic acid or procysteine, and its salts and esters; and extracts of plants, in particular of liquorice, mulberry and skullcap.
In particular, the depigmenting composition for the skin can comprise, as depigmenting agent, a phenolic derivative, in particular hydroquinone or 4-hydroxyanisole.
The invention also relates to a depigmenting composition for the skin comprising, in a physiologically acceptable medium, adapalene, at least one depigmenting agent and at least one sunscreen.
To give an order of magnitude, 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 10% by weight of

depigmenting agent relative to the total weight of the composition.
The composition may also comprise at least one sunscreen in preferential concentrations ranging from 0.001 to 30.00% by weight relative to the total weight of the composition.
Among the sunscreens, there may be mentioned, by way of nonlimiting example, physical sunscreens such as titanium dioxide, zinc oxide, and chemical sunscreens such as octocrylene, ethylhexyl methoxycinnamate, octyl salicylate, avobenzone, oxybenzone, ecamsule or drometrizole trisiloxane or mixtures thereof. Each sunscreen may be added at a concentration ranging from 0.001 to 20% by weight relative to the total weight of the composition.
The compositions according to the invention may additionally comprise any additive customarily used in the cosmetic or pharmaceutical field, such as sequestrants, antioxidants, preservatives, fillers, electrolytes, humectants, colourings, customary inorganic or organic bases or acids, perfumes, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, skin soothing and protecting agents such as allantoin. Of course, persons skilled in the art will be careful to choose this or these optional additional compounds, and/or their quantity, such that

the advantageous properties of the composition according to the invention are not, or not substantially, impaired.
These additives may be present in the composition in an amount of 0.001 to 20% by weight relative to the total weight of the composition.
There may be mentioned as example of sequestering agents: ethylenediaminetetraacetic acid (EDTA), and its derivatives or its salts, dihydroxyethylglycine, citric acid and tartaric acid.
There may be mentioned as examples of preservatives benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea and parabens.
There may be mentioned as examples of humectants: glycerin and sorbitol.
The 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 cosmetic field.
Compositions of the invention are particularly suitable for the treatment and prevention of hyperpigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, vitiligo, freckles, postinflammatory hyperpigmentations due to an abrasion, a burn, a scar, a dermatosis, a contact allergy; naevi,

hyperpigmentations with a genetic determinism, hyperpigmentations of metabolic or drug origin, melanomas or any other hyperpigmentary lesions.
The compositions according to the invention also find application in the cosmetic field, in particular in protection against the harmful effects of the sun, for preventing and/or combating photoinduced or chronologic ageing of the skin and of the superficial body growths.
The invention also relates to a method for a nontherapeutic cosmetic treatment for beautifying the skin and/or for improving its surface appearance, characterized in that a composition comprising adapalene and at least one depigmenting agent is applied to the skin and/or its superficial body growths.
The examples of formulations below make it possible to illustrate the compositions according to the invention, without however limiting the scope thereof. Examples illustrating the depigmenting activity of the various compositions according to the invention are also described.
In the compositions below (Examples 1 to 5), the proportions of the various constituents are expressed as a percentage by weight relative to the total weight of the composition.

Example 1:
(Table Removed)

This composition should be applied twice per day until complete depigmentation is obtained for the treatment of lentigines. Example 2;
(Table Removed)




This composition should be applied once per day until complete depigmentation is obtained for the treatment of melasma. Example 3;
(Table Removed)
This composition should be applied twice per day until complete depigmentation is obtained for the treatment of melasma. Example 4;
(Table Removed)


This composition should be applied twice per day until complete depigmentation is obtained for the treatment of melasma.

Example 5:
(Table Removed)


This composition should be applied once per day until complete depigmentation is obtained for the treatment of chloasma.
Example 6 - Measurement of the depigmenting activity of the combination of adapalene and a depigmenting agent
The evaluation of the depigmenting and/or anti-pigmenting activity of hydroquinone 3% and Adapalene 0.1% alone or in combination for 8 weeks is

carried out on the tail of SKH HR2 mice which is irradiated or not with ultraviolet B. 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 nonirradiated 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 animals irradiated with UVB.
The treatment is carried out for 5 days per week for 8 weeks. 2 0 ul of test product, diluted in acetone, are applied to the tail in a deferred manner: hydroquinone in the morning and adapalene 4 h later. On the days for irradiation, the treatment is applied after irradiation.
The animals are irradiated 3 times per week for 8 weeks (Monday, Wednesday, Friday) at the dose of 90 mJ/cm2 of UVB.
The evaluation is made by different clinical observations: once per week before irradiation, the pigmentation is evaluated by virtue of a score on a scale from 0 to 4. The distribution of the scores is the following: 0: natural pigmentation depigmentation scale: scores -1 to -4

-1: light depigmentation -2: moderate depigmentation -3: marked depigmentation -4: total depigmentation pigmentation scale: scores 1 to 4 1: light pigmentation 2: moderate pigmentation 3: marked pigmentation 4: intense pigmentation
The results are represented in Figures 1 and 2.
Figure 1 represents the kinetics for the scores of pigmentation of the mouse skin as a function of the treatment time with or without irradiation with ultraviolet B (up to 8 weeks of treatment) with (♦) UVB + acetone, (►) UVB + Adapalene, (◄) UVB + hydroquinone, (•) UVB+hydroquinone+adapalene, (D] non-irradiated skin + acetone, (A) nonirridiated skin + adapalene (o) nonirradiated skin + hydroquinone (V) nonirradiated skin + hydroquinone + adapalene.
Figure 2 represents the pigmentation scores at the end of the study (D57) with (D] acetone, (j%&) hydroquinone, (■) adapalene, (■) adapalene + hydroquinone with or without ultraviolet B irradiation. Depigmenting activity: hydroquinone alone at 3% induces a clinically visible depigmentation from the 6th week of treatment (D43) and a statistically significant

depigmentation 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 from its appearance and up to the end of the study where the difference is statistically significant (**,p After 8 weeks of topical treatment on the tail of SKH:HR2 mice, it is noted that the hydroquinone + adapalene combination exhibits a high antipigmenting activity and significantly inhibits the pigmentation induced by UVB irradiation from its appearance and up to the end of the study. The hydroquinone + adapalene combination has a significant benefit as depigmenting agent in relation to hydroquinone alone.




WE CLAIM;
1. Depigmenting composition for the skin, comprising 0.000 1 to 20% by weight of adapalene and 0.0001 to 20% by weight of 4-hydroxyanisole in a physiologically acceptable vehicle of a kind such as herein described.
2. Depigmenting composition as claimed in claim 1, wherein it also optionally contains at least one sunscreen.
3. Depigmenting composition as claimed in claim 1 or claim 2, wherein it additionally contains at least one cosmetic or pharmaceutical additive of the kind such as herein described.
4. Depigmenting composition whenever utilized for the prevention or treatment of hyperpigmentary disorders such as melasma, chloasma, lentigines, vitiligo, freckles, post-inflammatory hyper pigmentations due to an abrasion, a burn, a scar, a dermatosis, a contact allergy; naevi, hyperpigmentations of metabolic or drug origin, melanomas or any other hyperpigmentary lesions, harmful effects of the sun, photoinduced or chronologic ageing of the skin and of the superficial body growths and for beautifying the skin and/or for improving its surface appearance.


Documents:

935-delnp-2005-abstract.pdf

935-DELNP-2005-Claims.pdf

935-delnp-2005-complete specification ( as files).pdf

935-delnp-2005-complete specification (granted).pdf

935-delnp-2005-correspondence-others.pdf

935-delnp-2005-correspondence-po.pdf

935-DELNP-2005-Description (Complete).pdf

935-delnp-2005-drawings.pdf

935-delnp-2005-form-1.pdf

935-delnp-2005-form-18.pdf

935-DELNP-2005-Form-2.pdf

935-delnp-2005-form-3.pdf

935-delnp-2005-form-5.pdf

935-delnp-2005-gpa.pdf

935-delnp-2005-pct-210.pdf

935-delnp-2005-pct-409.pdf

935-delnp-2005-petition-137.pdf

935-delnp-2005-petition-138.pdf


Patent Number 237994
Indian Patent Application Number 935/DELNP/2005
PG Journal Number 4/2010
Publication Date 22-Jan-2010
Grant Date 15-Jan-2010
Date of Filing 10-Mar-2005
Name of Patentee GALDERMA RESEARCH & DEVELOPMENT
Applicant Address 635, ROUTE DES LUCIOLES, SOPHIA ANTIPOLIS, F-06560, FRANCE.
Inventors:
# Inventor's Name Inventor's Address
1 ISABELLE PELISSON RESIDENCE LA ROSERAIE BATIMENT B, 112 CHEMIN DES BRUQUETS, F-06220 VALLAURIS, FRANCE.
2 ANDRE JOMARD 20 BIS, AVENUE FRANCOIS GOBY, F-06460 SAINT VALLIER DE THIEY, FRANCE.
PCT International Classification Number A61K
PCT International Application Number PCT/EP2002/010692
PCT International Filing date 2003-09-01
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 02/11022 2002-09-05 France
2 60/411,350 2002-09-18 France