Sunscreen Composition

Abstract

It is disclosed an improved transdermal sunscreen composition including porphyrin, porphyrin analogues and/or porphyrin precursors (particularly 5-aminolevulinic acid, ALA) in a subtherapeutic dose in combination with vitamin D3 or its analogues/derivatives in a transdermal carrier or carrier system to generate biomedical effects on reducing photodamaged skin conditions, inducing skin rejuvenation and compensating vitamin D3 for sunscreen-mediated vitamin D3 reduction/deficiency while simultaneously blocking harmful UV radiation from reaching and harming DNA in the cells of the skin.

Claims

1. A composition comprising: (a) 5-aminolevulinic acid (5-ALA) or an acid addition salt thereof; (b) vitamin D3; and (c) a UVA and/or UVB protective agent, wherein said 5-ALA or acid addition salt thereof is present in an amount of 0.1 to 2.0 wt % of the composition.

2. The composition according to claim 1, wherein said 5-ALA or an acid addition salt thereof is present in an amount of 0.1 to 1.0 wt % of the composition.

3. The composition according to claim 1, wherein said 5-ALA or an acid addition salt thereof is present in an amount of 0.1 to 0.5 wt % of the composition.

4. The composition according to claim 1, wherein said 5-ALA or an acid addition salt thereof is present in an amount of 1 to 2 wt % of the composition.

5. The composition according to claim 1, wherein said vitamin D3 is present in an amount of 0.0001 to 0.005 wt % of the composition.

6. The composition according to claim 1, wherein said 5-ALA acid addition salt is the hydrochloride salt of 5-aminolevulinic acid (ALA-HCl).

7. The composition according to claim 1, wherein said vitamin D3 is Cholecalciferol.

8. A sunscreen composition according to comprising: (a) 5-aminolevulinic acid (5-ALA) or an acid addition salt thereof, present in an amount of 0.1 to 2.0 wt % of the composition; (b) vitamin D3; and (c) a UVA and/or UVB protective agent, and (d) one or more skin conditioning agents, preservatives, skin penetration enhancers, thickeners, viscosity modifying agents, gelling agents, sequestering agents, pH adjusting agents, waxes, drying agents, anti-itch agents, anti-foaming agents, buffers, neutralizing agents, colouring agents, discolouring agents, emulsifying agents, emulsion stabilizers, odorants, antioxidants, diluents, carriers, and/or propellants.

9. (canceled)

10. A method of treating or preventing skin ageing, which comprises applying a composition to a subject's skin, wherein the composition comprises: (a) 5-aminolevulinic acid (5-ALA) or an acid addition salt thereof, present in an amount of 0.1 to 2.0 wt % of the composition; (b) vitamin D3; and (c) a UVA and/or UVB protective agent.

11. The method of claim 10, wherein said 5-ALA or an acid addition salt thereof is present in an amount of 0.1 to 1.0 wt % of the composition or 0.1 to 0.5 wt % of the composition.

12. (canceled)

13. A method of treating or preventing actinic keratosis which comprises applying a composition to a subject's skin, wherein the composition comprises: (a) 5-aminolevulinic acid (5-ALA) or an acid addition salt thereof, present in an amount of 0.1 to 2.0 wt % of the composition; (b) vitamin D3; and (c) a UVA and/or UVB protective agent.

14. A method of increasing the elasticity, increasing the density, reducing the presence of fine lines and/or wrinkles, and/or increasing the firmness/reducing the laxity of a subject's skin, which comprises applying to the subject's skin a composition, wherein the composition comprises: (a) 5-aminolevulinic acid (5-ALA) or an acid addition salt thereof, present in an amount of 0.1 to 2.0 wt % of the composition; (b) vitamin D3; and (c) a UVA and/or UVB protective agent.

15. The method of claim 14, wherein said 5-ALA or an acid addition salt thereof is present in an amount of 0.1 to 1.0 wt % of the composition or in an amount of 0.1 to 0.5 wt % of the composition.

16. The method of claim 13, wherein said 5-ALA or an acid addition salt thereof is present in an amount of 0.1 to 1.0 wt % of the composition or in an amount of 0.1 to 0.5 wt % of the composition.

17. The sunscreen of claim 8, wherein said 5-ALA or an acid addition salt thereof is present in an amount of 0.1 to 1.0 wt % of the composition or in an amount of 0.1 to 0.5 wt % of the composition.

Description

[0132] The effect of the compositions according to the invention upon the skin is illustrated through the results presented in the following figures, wherein:

[0133] FIG. 1 shows the wavelength peak in nm of the ingredients in a composition according to the present invention including 2% ALA (as the hydrochloride salt) (at 3-hours after application on human skin) or 10 M PpIX (corresponding to 0.56 mg % (w/v) PpIX) measured as the maximum relative fluorescence intensity versus a range of wavelengths spanning 580-740 nm. The measurements were conducted on separate compositions including: I) 10 M PpIX (water solution with 0.1% (w/w) TWEEN 20); II) 2% (w/w) ALA (3-h application on human skin) and III) as a control autofluorescence of human skin without ALA application. FIG. 1 shows a peak at a wavelength range of 620-650 nm, with a clear maximum peak at 635 nm, being the wavelength selected for conducting measurements in the subsequent tests;

[0134] FIGS. 2 to 7 show PpIX fluorescence intensities as a function of time after topical facial application of ALA at various concentrations (as indicated) in 6 volunteers (FIGS. 2, 3, 7) and 2 volunteers (FIGS. 4-6) of both sexes (male/female). The filled circles indicate the measurements at the photodamaged skin areas; while the unfilled cycles are normal skin areas; Thus,

[0135] FIG. 2, i.e. FIG. 2A and FIG. 2B, shows PpIX fluorescence intensities as a function of time after topical facial application of 2% ALA in 6 different volunteers, where the filled circles indicate the measurements at the photodamaged skin areas; while the unfilled cycles are normal skin areas;

[0136] FIG. 3, i.e. FIG. 3A and FIG. 3B, shows PpIX fluorescence intensities as a function of time after topical facial application of 0.5% ALA in 6 different volunteers, where the filled circles indicate the measurements at the photodamaged skin areas; while the unfilled cycles are normal skin areas;

[0137] FIG. 4 shows PpIX fluorescence intensities as a function of time after topical facial application of 0.4% ALA in 2 different volunteers, where the filled circles indicate the measurements at the photodamaged skin areas; while the unfilled cycles are normal skin areas;

[0138] FIG. 5 shows PpIX fluorescence intensities as a function of time after topical facial application of 0.3% ALA in 2 different volunteers, where the filled circles indicate the measurements at the photodamaged skin areas; while the unfilled cycles are normal skin areas;

[0139] FIG. 6 shows PpIX fluorescence intensities as a function of time after topical facial application of 0.2% ALA in 2 different volunteers, where the filled circles indicate the measurements at the photodamaged skin areas; while the unfilled cycles are normal skin areas;

[0140] FIG. 7, i.e. FIG. 7A and FIG. 7B, shows PpIX fluorescence intensities as a function of time after topical facial application of 0.12% ALA in 6 different volunteers, where the filled circles indicate the measurements at the photodamaged skin areas; while the unfilled cycles are normal skin areas; and

[0141] FIG. 8 shows information regarding the heme pathway.

EXAMPLES

[0142] In all of the Examples, ALA was used in the hydrochloride salt form (ALA-HCl) and the wt % indicated is the wt % of ALA-HCl, rather than the wt % of free ALA.

Example 1

[0143] The example relates to a sun-blocking composition according to the present invention comprising of ALA in a concentration of 0.12% (w/w) (calculated on the basis of the total weight of the composition). The ALA together with Vit. D3 was included in a carrier composition of methylvinylether-maleic anhydride and poly(ethyleneglycol) included in a water solution with 0.1% (w/w) TWEEN 20. (La Roche-Posay Anthelios xl)

Example 2

[0144] This example concerns a composition like the composition of Example 1, but with an ALA concentration of 0.2% (w/w).

Example 3

[0145] This example concerns a composition like the composition of Example 1, but with a ALA concentration of 0.3% (w/w).

Example 4

[0146] This example concerns a composition like the composition of Example 1, but with a ALA concentration of 0.4% (w/w).

Example 5

[0147] This example concerns a composition like the composition of Example 1, but with a ALA concentration of 0.5% (w/w).

Example 6

[0148] This example concerns a composition like the composition of Example 1, but with a ALA concentration of 2.0% (w/w).

[0149] In the compositions relating to Examples 1-6 the Vit. D3 was present at a fixed concentration of 250 g/g. The active ingredients were included in a carrier composition (La Roche-Posay Anthelios xl). Example 6 was conducted in the same manner as Example 1.

[0150] These studies relating to Examples 1-6 were aimed at finding out an optimal ALA concentration to generate sub-therapeutic PpIX-mediated photodynamic effects with no acute phototoxic reactions. The carrier creams containing ALA and Vit. D3 were topically applied to the human facial skin for 3 hours, during which the ALA-PpIX fluorescent signals were clearly detected by spectrophotometry as discussed in relation to FIG. 1. The facial skin was then subjected to sun-exposure for a time of 120 minutes. The results in all 6 tested volunteers show a clear improvement of the skin conditions such as increased suppleness of the treated skin, reduced scar-tissue formation of the treated skin at the locations where the compositions had been applied, as assessed by medical experts visually at 1-, 4- and 8-week afterwards.

Example 7

[0151] This example relates to the results shown in FIG. 2 concerning a test conducted with the La RochePosay Anthelios x1 conventional sunscreen composition including the ingredients 2% (w/w) ALA applied to the facial skin of 6 volunteers for 3 hours, during which time the ALA-PpIX fluorescent signals at the photodamaged skin areas of all 6 volunteers were clearly detected by spectrophotometry. Some ALA-PpIX fluorescent signals were also detected at the normal skin areas.

Example 8

[0152] This example is relating to the results presented in FIG. 3, and relates to a test conducted with the La Roche-Posay Anthelios xl sunscreen including the ingredient ALA/PpIX at 0.5% (w/w) applied to the facial skin of 6 volunteers for 3 hours, during which the ALA-PpIX fluorescent signals at the photodamaged skin areas of 3 volunteers were clearly detected by spectrophotometry. Some ALA-PpIX fluorescent signals were also detected at the normal skin areas.

Example 9

[0153] This example relating to the results shown in FIG. 4, relates to a test conducted with the La Roche-Posay Anthelios xl sunscreen including the ingredient 0.4% (w/w) ALA/PpIX applied to the facial skin of 2 volunteers for 3 hours, during which the ALA-PpIX fluorescent signals at the photodamaged skin areas of the two volunteers were clearly detected by spectrophotometry. Some ALA-PpIX fluorescent signals were also detected at the normal skin areas.

Example 10

[0154] This example relates to the results shown in FIG. 5 and relates to a test conducted with the La Roche-Posay Anthelios xl sunscreen including the ingredient 0.3% (w/w) ALA/PpIX applied to the facial skin of 2 volunteers for 3 hours, during which the ALA-PpIX fluorescent signals at the photodamaged skin areas of the two volunteers were clearly detected by spectrophotometry. Some ALA-PpIX fluorescent signals were also detected at the normal skin areas.

Example 11

[0155] This example relates to the results shown in FIG. 6 and relates to a test conducted with the La Roche-Posay Anthelios xl sunscreen including the ingredient ALA/PpIX 0.2% (w/w) applied to the facial skin of 2 volunteers for 3 hours, during which the ALA-PpIX fluorescent signals at the photodamaged skin areas of one of the two volunteers were clearly detected by spectrophotometry. Some ALA-PpIX fluorescent signals were also detected at the normal skin areas.

Example 12

[0156] This example relates to the results shown in FIG. 7 and relates to a test conducted with the La Roche-Posay Anthelios xl sunscreen including the ingredient ALA/PpIX 0.12% (w/w) applied to the facial skin of 6 volunteers for 3 hours, during which no ALA-PpIX fluorescent signals in the photodamaged and also normal skin areas of all volunteers were detected by spectrophotometry.

Example 13

[0157] Comparison of skin improvement between 5-aminolevulinic acid alone and 5-aminolevulinic acid plus Vitamin D3 (Cholecalciferol) in a sunscreen product after daylight exposure.

[0158] Aim of the Study:

[0159] The aim of the study was to investigate the effect on human skin of low (sub-therapeutic) concentrations of ALA alone or in combination with vitamin D3 in a commercial sunscreen product

Study Design:

Products

[0160] (a) A commercial FPS-50 sunscreen product (La Roche-Posay Anthelios xl) supplemented with ALA (0.2 wt %) [0161] (b) A commercial FPS-50 sunscreen product (La Roche-Posay Anthelios xl) supplemented with ALA (0.2 wt %) plus vitamin D3 (cholecalciferol) (0.0001 wt %) [0162] (c) A commercial FPS-50 sunscreen product (La Roche-Posay Anthelios xl, Actinica Galderma 50+, or Cosmica 50) without any modifications.

Selection of Subjects

[0163] Subjects all signed an informed consent agreement before the study started.

Ethic Approvals

[0164] The Regional Ethic Committee and National Medicinal Authority both regarded the study as a non-pharmaceutical study due to the low concentrations of the active substances.

Application of Compositions

[0165] Topical application of the compositions to each side of the face was made daily for 6-12 weeks followed by daylight exposure. All subjects recorded the frequency of the use of the creams and daylight exposure and only subjects using the creams and daylight at least 5 days per week were included in this study.

Examination

[0166] A survey was performed and the subjects reported daily the subjective and objective effects and side effects on their facial skin during the first week and weekly thereafter. No side-effects were reported by any of the subjects.

Example 13 A

[0167] The effect of the composition on Actinic Keratosis (AK) was assessed. AK is an erythematous lesion of the skin with a fine or thick scale. Clinical and photographic assessments of AK were made before and after the daily use of the creams for 6-12 weeks.

[0168] Clinical grading of erythema (E): Grade 0: no erythema; Grade 1: pink; Grade 2: moderate redness; Grade 3: intense redness.

[0169] Clinical Grading of AK according to the Olsen classification 1991 (T).sup.1,2:

[0170] Grade 0: no actinic keratosis; Grade 1: single or few lesions, better felt than seen; Grade 2: moderate thick lesions (hyperkeratotic), easily felt and seen; Grade 3: thick hyperkeratotic lesions.

[0171] The clinical evaluation was performed independently by two experienced senior dermatologists, one by clinical examination on the subjects; while the other (blinded) on photographs only. Their evaluation is represented in table 1.

[0172] In addition, a specialised ultrasound device (Derma Lab, Skin Lab Combo, Cortex Technology, 9560 Hadsund, Denmark) was employed to measure the thickness, intensity and elasticity in the bilateral temple areas of the skin.

Results and Conclusions

[0173]

TABLE-US-00001 TABLE 1 Clinical evaluation of the skin improvement # test Right side 0.2% ALA Left side 0.2% ALA + vit D3 subject Before After Before After No 1 E 2 E 1.5 E 2.5 E 1 T 2 T 2 T 2 T 1 No 2 E 2.5 E 2 E 1.5 E 0 T 2 T 2 T 1 T 0 No 3 E 0 E 0 E 1.5 E 1 T 0 T 0 T 2 T 1 No 4 E 2 E 1 E 1 E 1 T 2 T 2 T 2 T 1 Note: T = Thickness (Olsen) grade 1-3; E = Erythema grade 1-3

[0174] Conclusion: ALA plus vitamin D3 was superior as compared to ALA alone regarding both reduction of erythema and thickness of AK.

Example 13B

[0175] The effect of the compositions on cosmetic factors such as skin thickness and elasticity was assessed by Dermalab equipment. Visco Elasticity (VE) represents a parameter where both the elevation phase and the retraction phase are taken into account.

[0176] VE=Young's modulus/R normalized where R normalized=R/260 ms

[0177] VE with the unit MPa (Mega Pascal) can be measured by the Derma Lab ultrasound device. A reduction of VE represents an increase in the skin elasticity.

TABLE-US-00002 TABLE 2 Ultrasound measurements of the skin elasticity before and after cream use and presented as difference in percentage Thickness of dermis Elasticity (VE) Left side Left side #test Right side ALA 0.2% + Right side ALA 0.2% + subject 0.2% ALA vit D3 0.2% ALA vit D3 No 1 5% +18% 44% 64% No 2 21% +25% +16% 45% No 3 +8% +23% 0% 62% No 4 +6% +19% 17% 17%

[0178] Conclusion: The composition ALA+vitamin D3 is superior as compared to ALA alone regarding the increase in thickness of the dermis, as well as increase in elasticity of the skin (indicated by a negative VE).

REFERENCES

[0179] 1. Primary Care Dermatology Society (PCDS) guidelines 2012 [0180] 2. De Berker D et al. British Journal of Dermatology 2007; 158:222-230