COMPOSITION COMPRISING MELATONIN OR ITS DERIVATIVES WITH COENZYME Q10 AND USE THEREOF AGAINST AGEING OF THE SKIN

Abstract

The invention relates to a composition comprising melatonin, a metabolite or derivative thereof and coenzyme Q10 and to use thereof for the production of a pharmaceutical or cosmetic composition for the treatment of the skin, said composition potentiating the movement of both molecules into the mitochondrion and facilitating percutaneous absorption, in which both the melatonin and the CoQ10 can reach all of the strata of the skin.

Claims

1. Use of a composition comprising: a. coenzyme Q10 at a concentration of 0.2 to 1.5% w/v with respect to the final composition, b. melatonin at a concentration of 1 to 5% w/v with respect to the final composition and c. at least one melatonin antioxidant at a concentration of 0.25 to 0.75% w/v with respect to the final composition, for the production of a medicinal product or a cosmetic composition in a form that is suitable for topical administration thereof.

2. Use of the composition according to claim 2, where the melatonin is at a concentration of 1.5 to 3% w/v with respect to the final composition

3. Use of the composition according to claim 2, where the melatonin is at a concentration of 2% w/v with respect to the final composition.

4. Use of the composition according to any of the preceding claims, where the coenzyme Q10 is at a concentration of 0.3 to 1.0% w/v with respect to the final composition.

5. Use of the composition according to claim 4, where the coenzyme Q10 is at a concentration of 0.5% w/v with respect to the final composition.

6. Use of the composition according to claim 1, where the antioxidant is selected from the list comprising tocopherol, ascorbic acid, sodium ascorbate, tartaric acid, butylhydroxyanisole, citric acid, vitamin A and vitamin E.

7. Use of the composition according to any of the preceding claims, where it furthermore comprises at least one preservative.

8. Use of the composition according to the preceding claim, where the preservative is selected from the list comprising benzoic acid, sodium benzoate, ascorbic acid, potassium sorbate, methylparaben, ethylparaben or butylparaben.

9. Use of the composition according to any of the preceding claims, furthermore comprising at least one gelling agent.

10. Use of the composition according to claim 9, where the gelling agent is selected from the list comprising a polyethylene and polypropylene copolymer, cellulose and guar gum.

11. Use of the composition according to any of the preceding claims, furthermore comprising at least one pharmaceutically or cosmetically acceptable vehicle.

12. Use of the composition according to claim 11, where the pharmaceutically or cosmetically acceptable vehicle is selected from the list comprising lysosomes, millicapsules, microcapsules, nanocapsules, sponges, millispheres, microspheres, nanospheres, milliparticles, microparticles and nanoparticles.

13. Use of the composition according to any of the preceding claims, furthermore comprising at least one pharmaceutically or cosmetically acceptable excipient or adjuvant.

14. Use of the composition according to claim 13, where the pharmaceutically or cosmetically acceptable excipient or adjuvant is selected from the list comprising dibasic calcium phosphate, starches, sugars, celluloses, essences of cinnamon, of lemon, of orange, of mandarin and of vanilla.

15. Use of the composition according to any of the preceding claims, furthermore comprising at least other additives such as emulsifiers, emollients and antifoaming agents.

16. Use of the composition according to claim 15, where the additives can be at a concentration of 2.5 to 7% w/v with respect to the final composition.

17. Use of the composition according to any of claim 15 or 16, where the emulsifier that is selected from the list comprising Montanov 68, glycerol, sodium lauroyl glutamate, sodium cocoyl glutamate, PEG-26 jojoba acid, PEG-26 jojoba alcohol, PEG-11 avocado glycerides, PEG-30 almond glycerides, caprylic compound and triethylhexanoin.

18. Use of the composition according to any of claim 15 or 16, where the antifoaming agent is selected from the list comprising dimethicone, dimethiconol, phenethyl disiloxane, tetramethyl decynediol, phenyl trimethicone, polysilicone 7, isopropyl alcohol, hexyl alcohol, propyl alcohol, hexamethyl-disiloxane, bisphenyl hexamethicone and trimethyl-siloxy silicate.

19. Use of the composition according to any of claim 15 or 16, where the emollient is selected from the list comprising perhydrosqualene, lanolin, petroleum jelly, rosehip oil, borage oil, sweet almond oil, peach kernel oil, olive oil, beeswax, paraffin waxes, stearyl alcohol and cetyl alcohol.

20. Use of the composition according to any of the preceding claims, furthermore comprising at least one antimicrobial agent.

21. Use of the composition according to claim 20, where the antimicrobial agent is selected from the list comprising 2-phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben, methyl parahydroxybenzoate, propyl parahydroxybenzoate, benzalkonium chloride and imidazolidinyl-urea.

22. Use of the composition according to any of claim 20 or 21, where the antimicrobial agent is at a concentration of 0.4 to 1.0% w/v with respect to the final composition.

23. Use of the composition according to any of the preceding claims, where said composition is presented in the form of cream, emulsion, lotion, gel or aerosol.

24. Use of the composition according to claim 23, where said composition is presented as an O/W emulsion.

25. Use of the composition described according to any of claims 1 to 24 for the production of a medicinal product for the treatment and/or prevention of cell damage caused by oxidative stress.

26. Use of the composition described according to any of claims 1 to 24 for the production of a medicinal product for the treatment and/or prevention of cellular ageing.

27. Use of the composition according to claim 26, where cellular ageing is due to exposure to the sun in the skin.

28. A cosmetic method for anti-ageing of the skin, characterized in that it consists of the topical application of an effective amount of the composition described according to any of claims 1 to 24.

29. The cosmetic method of claim 28, where the ageing of the skin is caused by the exposure of the skin to the sun's rays.

30. A sunscreen comprising a composition containing: a. at least one agent acting as filter for UV-B and UV-A rays, b. coenzyme Q10, and c. at least one compound of general formula (I), ##STR00003## where: n is an integer between 1 and 4; R.sub.1 is a straight or branched (C.sub.1-C.sub.4) alkyl group; R.sub.2 is hydrogen, straight or branched (C.sub.1-C.sub.4) alkyl, a C(O)ORa group or a C(O)N(H)Ra group, wherein Ra is a straight or branched (C.sub.1-C.sub.4) alkyl group; and R.sub.3 is a hydrogen or a straight or branched (C.sub.1-C.sub.4) alkyl group.

31. The sunscreen according to claim 30, where the compound of formula (I) is melatonin or N-acetylserotonin.

32. The sunscreen according to claim 31, where the compound is melatonin.

33. The sunscreen according to any of claim 30 or 31, where the compound of general formula (I) is at a concentration of 1 to 5% w/v with respect to the final composition.

34. The sunscreen according to claim 33, where the compound of general formula (I) is at a concentration of 2% w/v with respect to the final composition.

35. The sunscreen according to any of claims 30-34, where the coenzyme Q10 is at a concentration of 0.2 to 1.5% w/v with respect to the final composition.

36. The sunscreen according to claim 35, where the coenzyme Q10 is at a concentration of 0.5% w/v with respect to the final composition.

37. The sunscreen according to any of claims 30-36, where it furthermore comprises at least one antioxidant.

38. The sunscreen according to claim 37, where the antioxidant is selected from the list comprising tocopherol, ascorbic acid, sodium ascorbate, tartaric acid, butylhydroxyanisole, citric acid, vitamin A and vitamin E.

39. The sunscreen according to any of claim 37 or 38, where the antioxidant is at a concentration of 0.25 to 0.75% w/v with respect to the final composition.

40. The sunscreen according to any of claims 30-39, where it furthermore comprises at least one preservative.

41. The sunscreen according to the preceding claim, where the preservative is selected from the list comprising benzoic acid, sodium benzoate, ascorbic acid, potassium sorbate, methylparaben, ethylparaben or butylparaben.

42. The sunscreen according to any of claims 30-41, furthermore comprising at least one gelling agent.

43. The sunscreen according to claim 42, where the gelling agent is selected from the list comprising a polyethylene and polypropylene copolymer, cellulose and guar gum.

44. The sunscreen according to any of claims 30-43, furthermore comprising at least one pharmaceutically or cosmetically acceptable vehicle.

45. The sunscreen according to claim 44, where the pharmaceutically or cosmetically acceptable vehicle is selected from the list comprising lysosomes, millicapsules, microcapsules, nanocapsules, sponges, millispheres, microspheres, nanospheres, milliparticles, microparticles and nanoparticles.

46. The sunscreen according to any of claims 30-45, furthermore comprising at least one pharmaceutically or cosmetically acceptable excipient or adjuvant.

47. The sunscreen according to claim 46, where the pharmaceutically or cosmetically acceptable excipient or adjuvant is selected from the list comprising dibasic calcium phosphate, starches, sugars, celluloses, essences of cinnamon, of lemon, of orange, of mandarin and of vanilla.

48. The sunscreen according to any of claims 30-47, furthermore comprising at least other additives such as emulsifiers, emollients and antifoaming agents.

49. The sunscreen according to claim 48, where the additives can be at a concentration of 2.5 to 7% w/v with respect to the final composition.

50. The sunscreen according to any of claim 48 or 49, where the emulsifier that is selected from the list comprising Montanov 68, glycerol, sodium lauroyl glutamate, sodium cocoyl glutamate, PEG-26 jojoba acid, PEG-26 jojoba alcohol, PEG-11 avocado glycerides, PEG-30 almond glycerides, caprylic compound and triethylhexanoin.

51. The sunscreen according to any of claim 48 or 49, where the antifoaming agent is selected from the list comprising dimethicone, dimethiconol, phenethyl disiloxane, tetramethyl decynediol, phenyl trimethicone, polysilicone 7, isopropyl alcohol, hexyl alcohol, propyl alcohol, hexamethyl-disiloxane, bisphenyl hexamethicone and trimethyl-siloxy silicate.

52. The sunscreen according to any of claim 48 or 49, where the emollient is selected from the list comprising perhydrosqualene, lanolin, petroleum jelly, rosehip oil, borage oil, sweet almond oil, peach kernel oil, olive oil, beeswax, paraffin waxes, stearyl alcohol and cetyl alcohol.

53. The sunscreen according to any of claims 30-52, furthermore comprising at least one antimicrobial agent.

54. The sunscreen according to claim 53, where the antimicrobial agent is selected from the list comprising 2-phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben, methyl parahydroxybenzoate, propyl parahydroxybenzoate, benzalkonium chloride and imidazolidinyl-urea.

55. The sunscreen according to any of claim 53 or 54, where the antimicrobial agent is at a concentration of 0.4 to 1.0% w/v with respect to the final composition.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0089] FIG. 1 shows levels of CoQ10 in cytosol of the skin of mice treated with cream comprising melatonin, cream comprising CoQ10, and cream comprising melatonin+CoQ10. Controls (C), mice treated with cream comprising melatonin (aMT), mice treated with cream comprising CoQ10 (CoQ), and mice treated with cream comprising melatonin+CoQ 10 (aMT+CoQ). ***p<0.001 compared to C; +p<0.05 compared to CoQ10, ###P<0.001 compared to melatonin.

[0090] FIG. 2 shows levels of CoQ10 in mitochondrion of the skin of mice treated with cream comprising melatonin, cream comprising CoQ10, and cream comprising melatonin+CoQ10. Controls (C), mice treated with cream comprising melatonin (aMT), mice treated with cream comprising CoQ10 (CoQ), and mice treated with cream comprising melatonin+CoQ 10 (aMT+CoQ). ***p<0.001 compared to C; ++p<0.01 compared to CoQ10, ###P<0.001 compared to melatonin.

[0091] FIG. 3 shows levels of CoQ10 in the plasma of mice treated with cream comprising melatonin, cream comprising CoQ10, and cream comprising melatonin+CoQ10. Controls (C), mice treated with cream comprising melatonin (aMT), mice treated with cream comprising CoQ10 (CoQ), and mice treated with cream comprising melatonin+CoQ 10 (aMT+CoQ). ***p<0.001 compared to C; +++p<0.001 compared to CoQ10, ###P<0.001 compared to melatonin.

[0092] FIG. 4 shows levels of melatonin in cytosol of the skin of mice treated with cream comprising melatonin, cream comprising CoQ10, and cream comprising melatonin+CoQ10. Controls (C), mice treated with cream comprising melatonin (aMT), mice treated with cream comprising CoQ10 (CoQ10), and mice treated with cream comprising melatonin+CoQ 10 (aMT+CoQ 10). ***p<0.001 compared to C; +++p<0.001 compared to CoQ10, ###P<0.001 compared to melatonin.

[0093] FIG. 5 shows levels of melatonin in mitochondrion of the skin of mice treated with cream comprising melatonin, cream comprising CoQ10, and cream comprising melatonin+CoQ10. Controls (C), mice treated with cream comprising melatonin (aMT), mice treated with cream comprising CoQ10 (CoQ), and mice treated with cream comprising melatonin+CoQ 10 (aMT+CoQ). ***p<0.001 compared to C; +++p<0.001 compared to CoQ10, ###P<0.001 compared to melatonin.

[0094] FIG. 6 shows levels of melatonin in the plasma of mice treated with cream comprising melatonin, cream comprising CoQ10, with cream comprising melatonin+CoQ10. Controls (C), mice treated with cream comprising melatonin (aMT), mice treated with cream comprising CoQ10 (CoQ), and mice treated with cream comprising melatonin+CoQ 10 (aMT+CoQ). ***p<0.001 compared to C; +++p<0.001 compared to CoQ10, ###P<0.001 compared to melatonin.

EMBODIMENTS

[0095] The following examples provided in this patent document serve to illustrate the nature of the present invention. These examples are included only for illustrative purposes and must not be interpreted as limitations to the invention herein claimed. Therefore, the examples described below illustrate the invention without limiting the field of application thereof.

[0096] The invention will be illustrated below by means of tests performed by the inventors which clearly show the usefulness of the cream comprising melatonin plus CoQ10 for potentiating the movement of these compounds into cells, primarily into the mitochondrion, and favoring percutaneous absorption, allowing these compounds to reach all of the layers of the skin.

Example 1

[0097] The following example provides formulations of cream comprising melatonin, cream comprising CoQ10 and cream comprising melatonin together with CoQ10 and the method of producing them:

TABLE-US-00001 CREAM 1: MELATONIN (aMT) PHASE A: 70 C. Montanov 68 5% Perhydrosqualene 5% Long-chain TG 5% Dimethicone 5% Phenopip 0.80% Vitamin E 0.50% PHASE B: 75 C. Glycerol 5% H.sub.2O qsf Melatonin 2% in 30% PG CREAM 2: CoQ10 PHASE A: 70 C. Montanov 68 5% Perhydrosqualene 5% Long-chain TG 5% Dimethicone 5% Phenopip 0.80% Vitamin E 0.50% PHASE B: 75 C. Glycerol 5% H.sub.2O qsf CoQ10 0.5% in 5% PG The solution comprising CoQ is added to the emulsion at 60 C. CREAM 3: CoQ10 + aMT PHASE A: 70 C. Montanov 68 5% Perhydrosqualene 5% Long-chain TG 5% Dimethicone 5% Phenopip 0.80% Vitamin E 0.50% PHASE B: 75 C. Glycerol 5% H2O qsf Melatonin 2% in 30% PG CoQ10 0.5% in 5% PG The solution comprising CoQ is added to the emulsion at 60 C.
where: TG triglyceride; PG propylene glycol.

[0098] The method for producing the creams 1, 2 and 3 was carried out by means of the following steps:

Cream 1:

[0099] PHASE A: all the components of phase A are mixed and it is heated until reaching the temperature of 70 C.

[0100] PHASE B: the 2% melatonin in 30% PG is prepared: 2 grams of melatonin are weighed and dissolved in 30 ml of PG for 100 ml of final composition. All the components are mixed and it is heated until reaching the temperature of 75 C.

[0101] Finally, phase B is added to phase A.

[0102] For creams 2 and 3, the method is the same as for cream 1.

[0103] Phase B is added to phase A. The solution comprising CoQ in PG is added when the temperature of this mixture reaches 60 C.

Example 2

[0104] Each of the creams described in the preceding example was administered to experimentation animals by topical route. Nude male mice 3 months of age (Harlan) were used. The animals were independently housed in conventional cages in an animal facility conditioned for that purpose in the Centro de Investigacin Biomdica (Biomedical Research Center), in sterile conditions and under a controlled light period (12:12 h) and temperature (221 C.) environment, and laboratory diet and water ad libitum. The study was conducted in samples of skin from the back of the mice.

[0105] The experimental groups included 6 mice each, and they were the following: [0106] Control group (C) [0107] Group treated with cream comprising 2% melatonin [0108] Group treated with cream comprising 0.5% CoQ10 [0109] Group treated with cream comprising 2% melatonin+0.5% CoQ10

[0110] Application of the different formulations of the cream was done in the dorsal area at a ratio of 15 mg/cm.sup.2/day (5 mg/cm.sup.2/administration).

[0111] Administration of the cream in the different groups was done twice a day (every 12 hours). The animals were sacrificed a month after starting treatment.

[0112] Blood samples are taken before the animals are sacrificed. The animals are anesthetized with chloroform and 1 ml of blood is taken by means of cardiac puncture. Plasma is separated from the red blood cells, which is used to measure levels of melatonin. After taking the blood sample and sacrificing the animals, samples of skin are taken from the back by means of surgical dissection. The skin is placed in a Petri dish with phosphate-buffered saline. The adipose tissue is removed, cut into pieces, and frozen at 80 C. until analysis. The method for extracting the epidermis and the histochemical technique are based on the protocol described by Scaletta and MacCalum, (Am J. Anat. 133:431-53, 1972).

[0113] These samples were used to evaluate levels of melatonin and CoQ10 in the cytosol and mitochondrion of the skin and in plasma.

[0114] By observing the results obtained in FIGS. 2 and 5, it is shown that melatonin potentiates the movement of CoQ10 into the mitochondrion, and conversely, CoQ10 potentiates the movement of melatonin into said organelle, since both compounds are at a significantly higher amount in the mitochondrion in the group in which they were jointly administered in the cream, compared with the administration of only melatonin or of only CoQ10. FIG. 2 shows that melatonin potentiates the movement of CoQ10 into the mitochondrion. FIG. 5 shows that CoQ10 potentiates the movement of melatonin into the cell in a very significant manner. A concentration of melatonin in the mitochondrion in the presence of CoQ10 is shown to be 4 times greater. These results are confirmed by what is shown in FIGS. 1 and 4, since in the case of FIG. 1, levels of CoQ10 in the cytosol are lower in the group of the joint administration of melatonin and CoQ10, than in the case of CoQ10 administered alone. Therefore, in the case of joint administration, CoQ10 began to be introduced into the mitochondrion from the cytosol. In the case of FIG. 4, CoQ10 potentiates in a very significant manner the movement of melatonin into the cell, and specifically into the mitochondrion. Additionally, despite the fact that CoQ10 increases movement of melatonin the into the mitochondrion, the melatonin continues to be very high in the cytosol, levels of this molecule in the cytosol being much higher when it is administered together with CoQ10 than when it is administered alone.

[0115] In addition to the movement of CoQ10 into the mitochondrion being potentiated, percutaneous absorption of this molecule is simultaneously favored as melatonin and CoQ10 are administered at the same time. This is reflected in the results shown by the group of joint administration in FIGS. 3 and 6, in which the levels of both CoQ10 and melatonin, respectively, are higher in plasma. Melatonin allows the absorption of CoQ through the dermis, which means that this molecule can reach all of the layers of the skin and does not remain only in the epidermis.