Combination of a MC1R receptor agonist and UVB for the treatment and/or prevention of pigmentation disorders

Abstract

A system comprising a combination of at least one MCI R receptor agonist and a source of NB-UVB, wherein said system is adapted for simultaneous or sequential use of said MC1R receptor agonist and said NB-UVB in amounts effective for the treatment and/or prevention of dermatological conditions linked to a hypopigmentation.

Claims

1. A system comprising a combination of at least one MC1R receptor agonist and a source of NB-UVB, wherein said system is adapted for simultaneous or sequential use of said MC1R receptor agonist and said NB-UVB in amounts effective for the treatment of dermatological conditions linked to a hypopigmentation, wherein said MC1R agonist is N-[((R)-2-[3-(4-hydroxybutoxy)-3-o-tolyl-azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxo-ethyl]-3-(1H-imidazol-4-yl)-propionamide or N[(R)-2-(3-cyclopropylmethoxy-3-o-tolyl-azetidin-1-yl)-1-(4-methoxybenzyl)-2-oxo-ethyl]-3-(5-methyl-1H-imidazol-4-yl)-propionamide, and wherein said source of NB-UVB has a wavelength between 280 nm and 315 nm.

2. The system according to claim 1, wherein said MC1R agonist is present in a composition applied topically or administered orally.

3. The system according to claim 2, wherein said composition comprises, in a cosmetically acceptable medium, at least one MC1R agonist.

4. The system according to claim 2, wherein said MC1R agonist is present in the composition at a concentration between about 0.001% and 10% by weight based on the total weight of the composition comprising it.

5. The system according to claim 1, wherein the skin disease associated with hypopigmentation is selected from the group consisting of vitiligo, albinism, hypomelanoses, depigmentation by physical or chemical agents, post-inflammatory hypopigmentation, phenomenon of Sutton and other hypopigmentation lesions.

6. A method of treating a dermatological condition linked to a hypopigmentation, the method comprising administering to an individual subject in need thereof a composition comprising at least one MC1R receptor agonist in combination with NB-UVB, wherein said MC1R agonist is N-[(R)-2-[3-(4-hydroxybutoxy)-3-o-tolyl-azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxo-ethyl]-3-(1H-imidazol-4-yl)-propionamide or N[(R)-2-(3-cyclopropylmethoxy-3-o-tolyl-azetidin-1-yl)-1-(4-methoxybenzyl)-2-oxo-ethyl]-3-(5-methyl-1H-imidazol-4-yl)-propionamide, and wherein said source of NB-UVB has a wavelength between 280 nm and 315 nm.

7. A method of treating a dermatological condition linked to hypopigmentation, the method comprising applying to an affected or susceptible area, a combination of at least one MC1R receptor agonist and NB-UVB for simultaneous or sequential in time treatment of the dermatological condition, wherein said MC1R agonist is N-[((R)-2-[3-(4-hydroxybutoxy)-3-o-tolyl-azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxo-ethyl]-3-(1H-imidazol-4-yl)-propionamide or N[(R)-2-(3-cyclopropylmethoxy-3-o-tolyl-azetidin-1-yl)-1-(4-methoxybenzyl)-2-oxo-ethyl]-3-(5-methyl-1H-imidazol-4-yl)-propionamide, and wherein said source of NB-UVB has a wavelength between 280 nm and 315 nm.

8. The method according to claim 7, wherein the skin disease associated with hypopigmentation is selected from the group consisting of vitiligo, albinism, hypomelanoses, depigmentation by physical or chemical agents, post-inflammatory hypopigmentation, phenomenon of Sutton and other hypopigmentation lesions.

9. A product containing a composition comprising at least one MC1R receptor agonist for use in combination with NB-UVB, as a medicament for simultaneous or sequential in time treatment of dermatological conditions linked to a hypopigmentation, wherein said MC1R agonist is N-[((R)-2-[3-(4-hydroxybutoxy)-3-o-tolyl-azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxo-ethyl]-3-(1H-imidazol-4-yl)-propionamide or N[(R)-2-(3-cyclopropylmethoxy-3-o-tolyl-azetidin-1-yl)-1-(4-methoxybenzyl)-2-oxo-ethyl]-3-(5-methyl-1H-imidazol-4-yl)-propionamide, and wherein said source of NB-UVB has a wavelength between 280 nm and 315 nm.

10. The system according to claim 1, wherein the NB-UVB length wave is between 305 nm and 310 nm.

11. The system according to claim 1, wherein the NB-UVB length wave is between 307 nm and 309 nm.

12. The method according to claim 6, wherein the NB-UVB length wave is between 305 nm and 310 nm.

13. The method according to claim 6, wherein the NB-UVB length wave is between 307 nm and 309 nm.

14. The method according to claim 7, wherein the NB-UVB length wave is between 305 nm and 310 nm.

15. The method according to claim 7, wherein the NB-UVB length wave is between 307 nm and 309 nm.

Description

EXAMPLE

In Vivo Measure of Pro-Pigmenting Activity of 2 MC1R Agonists by Topical Route in Mice

(1) In mice, melanocytes are not present in the epidermis of hair-covered areas but are mainly present in the hair follicles. Pigmentation can be induced by irradiation with UVB in combination with topical or oral agents. The pigmentation changes can be quantified by various means such as clinical score pigmentation and pigmentation measurement by image analysis.

(2) The evaluation of the MC1R receptor agonists pro-pigmenting activity in combination with NB-UVB irradiation (60 mJ/cm2) is performed by topical application on the back of the mouse SKH2 during 43 days with MC1R agonist compound A at 8% or MC1R agonist compound B at 8% in combination with NB-UVB radiation.

(3) Practically, the animals were irradiated using the system Biospectra equipped NB-UVB lamps (peak emission maximum at 312 nm) irradiation at 3 times per week at 60 mJ/cm.sup.2 on Monday, Wednesday and Friday. The treatment is carried out 5 days a week and 50 l of the test product (compounds A or B) is diluted in the vehicle and applied on the back. In the case of associations with radiation, the compounds are administered after irradiation.

(4) Then, the pigmentation changes is quantified by clinical score pigmentation and pigmentation measurement by image analysis.

(5) Clinical Score of Pigmentation

(6) The clinical score of animals is performed 1 time per week before irradiation. The pigmentation is evaluated with a score on a scale of 0 to 4. The distribution of scores is as follows:

(7) 0: natural pigmentation

(8) 1: slight pigmentation

(9) 2: moderate pigmentation

(10) 3: marked pigmentation

(11) 4: intense pigmentation

(12) The following calculations are performed: Mean sem-clinical scores per week treatment group Aires under the curve (AUC) scores clinical animal J1 to J43. Index increased AUC for each combination group versus the non-irradiated group versus vehicle and vehicle-irradiated.

(13) The AUC is obtained by summing the areas of the rectangles between the first and last day of the study. The different treatment groups were compared to the vehicle group and UVB irradiated+vehicle group on this parameter using a Student t test.

(14) Quantification of Pigmentation by Image Analysis at the End of Study:

(15) At the end of the study, for each animal, two digital photographs of the skin of the back are made with a high quality dermascope and digital camera such as the LiteScope. The determination of the surface and the average pixel intensity is pigmented obtained by image analysis and the level of pigmentation is obtained by the product of two values.

(16) The following calculations are performed: Meansem of pigmentation by image analysis by treatment group Increased pigmentation Index by image analysis for each combination group versus the non-irradiated group versus vehicle and vehicle-irradiated.
Results:

(17) The results are shown in FIGS. 1, 2 and 3

(18) The results presented in FIGS. 1 and 2 show that repeated irradiation with NB-UVB (60 mJ/cm2) causes a moderate pigmentation on the backs of SKH2 mice. Treatment with the MC1R agonist A at 8% or MC1R agonist B at 8%, in combination with NB-UVB irradiation (60 mJ/cm2) significantly increases the pigmentation of the skin from the irradiated group treated with the vehicle.

(19) This synergistic effect is confirmed by the objective assessment of the pigmentation level at the end of the study by image analysis (FIG. 3) for MC1R agonist A compound.