RU2336867C2 - Composition for dermal application with photoprotective and antierythemal effect, containing sun filtre ant dimethylsulphone - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: declared composition contains sun filtre and dimethylsulphone, where the quantity of dimethylsulphone is from 0.5 wt % to 50 wt %, and the sun filtre - from 1 wt % to 20 wt %. The declared composition to prevent or redoce or inhibit excitation, inflammation and dermal erythema, triggered by sun radiation or ultraviolet light. Dimethylsulphone, present in the composition, allows to eliminate negative influence of ultraviolet light, that is not block by sun filtre.

EFFECT: elimination of negative influence of ultraviolet light.

10 ex, 3 dwg

Description

FIELD OF THE INVENTION

The object of the present invention is a new composition for cosmetic or pharmaceutical use intended for external use by applying to both intact and damaged skin or mucous membranes in order to reduce or inhibit irritation, inflammation and skin erythema caused by exogenous phenomena (irritations caused by chemicals, pharmaceutical, cosmetic ingredients, physical agents, such as, for example, solar radiation, ultraviolet radiation, ionizing radiation, X-rays, gamma rays, laser radiation; bacterial agents, viral agents, etc.), and for photoprotection of the skin from sunlight and, in particular, from damage caused by ultraviolet radiation of types A, B and C.

State of the art

Erythema is a reddening of the skin caused by increased blood delivery to the blood vessels of the superficial dermis. Erythema is defined as active when it reflects the expansion of arterial vessels: it can be detected by the appearance of bright red skin color and an increase in local temperature. Passive erythema is caused by venous stasis, is detected by the bluish-red color of the skin with a decrease in local temperature. Erythema has various sizes, shapes and localizations; disappears with vitropression due to interruption of blood flow. It can appear on its own due to physical (mechanical, thermal, radiation), chemical, infectious (mycosis, initial exanthematous diseases), emotional (sudden redness localized on the face and neck, which occurs in awkward situations) reasons, or it can be caused by medications, vitamin deficiency, endocrine dysfunction or even appear in the process of an allergic reaction.

Inflammation is the body's defensive response to tissue damage by biological agents (microorganisms), chemicals, physical and mechanical agents (e.g., trauma, radiation), or due to disease. It has a biological function of bringing into an ineffective state or destroying harmful factors of a chemical, physical, biological nature and sequentially recovering possible damage to tissue affected by injuries. Various vascular phenomena are determined by chemical mediators (inflammatory mediators), such as histamine, leukotrienes, prostaglandins, thromboxanes, interleukins.

Photo protection consists in taking measures that can reduce the harmful effects of ultraviolet radiation on the skin.

Inflammation and oxidative species

Reactive oxygen compounds (ROS) are toxic and highly reactive molecules that play an important role in the onset and maintenance of inflammatory processes. The superoxide radical (O ₂ ^· ) is produced by monocytes and macrophages, cells involved in inflammatory processes, and plays a role in enhancing the process itself.

The hydroxyl radical ^(· OH) radicals and hydrogen peroxide (H ₂ O ₂₎ intervene in the inflammatory processes and are released during the metabolism of prostaglandins and in particular during the enzymatic metabolism of arachidonic acid.

Inflammatory processes are localized at the dermal level.

The problem on which the present invention is based is the creation of a suitable cosmetic and / or pharmaceutical composition for the treatment and / or prevention of inflammation, irritation and skin erythema and for photoprotection of the skin from sunlight and, in a more specific sense, from damage caused by types of ultraviolet radiation A, B and C. Such a problem is solved with the help of compositions containing dimethyl sulfone, such as those described in the attached claims.

Brief Description of the Drawings

Figure 1 shows the reflection spectra of the skin obtained before (curve a) and after (curve b) exposure to type B ultraviolet radiation;

figure 2 shows the changes in the erythema index (ΔI.E.) as a function of time obtained in the case of untreated (control) plots and plots treated with SALDMS 5;

figure 3 shows the percentage inhibition of cutaneous erythema (P.I.E.) obtained with the composition SALDMS 5 according to the invention and with placebo.

Description of the present invention

The present invention relates to the use of dimethyl sulfone, which is given the properties of a carrier, for topical use, for the prevention and / or treatment of skin irritations caused by chemical, physical, bacterial and viral agents. According to the present invention, dimethyl sulfone is used to inhibit erythema caused by physical agents, such as, but not limited to, ultraviolet radiation (solar radiation), especially when associated with solar filters, ionizing radiation, x-rays, gamma rays, laser radiation ( any intensity and nature).

Dimethyl sulfone is also used to reduce skin irritation caused by chemicals such as carboxylic acids, dicarboxylic acids, tricarboxylic acids, monocarboxylic alpha hydroxy acids, dicarboxylic alpha hydroxy acids, tricarboxylic alpha hydroxy acids, monocarboxylic beta-hydroxy beta, hydroxy beta-hydroxy acids, -hydroxy acids, resorcinol, phenol, retinoic acid, adapalene, azelaic acid, salicylic acid, trichloroacetic acid, benzyl peroxide, etc. Gia substances which can be used in cosmetic and / or pharmaceutical field and which are characterized as potential irritants.

Dimethyl sulfone is also used for a special photoprotective effect, able to reduce damage caused by solar radiation and ultraviolet radiation of types A, B and C, both natural and artificial origin.

This invention relates, in particular, to a composition for the above use, which is characterized in that it comprises dimethyl sulfone used in an amount of from 0.5 to 90 wt.%, Preferably from 5 to 60 wt.%, Even more preferably from 8 to 30 wt.%. The percentage of dimethyl sulfone used usually depends on the typology of use and on the fact whether the intended use is for the prevention or treatment of the above skin manifestations.

The scope of the present invention includes both compositions containing dimethyl sulfone as the sole active ingredient in association with cosmetic and / or pharmaceutical excipients, and compositions in which dimethyl sulfone is used in combination with various types of agents, such as keratolytic agents, to effect chemical peeling or solar filters or tanning compounds or pharmaceutical substances that should counteract potential irritation.

When dimethyl sulfone is the sole active ingredient of the composition, the above composition being anti-erythema or anti-irritant, it includes it in various amounts from 0.5 to 80 wt.%, Preferably from 1 to 20 wt.%.

When dimethyl sulfone is in combination with a keratolytic agent, the amount of dimethyl sulfone is from 1 to 60 wt.% And the amount of keratolytic agent is from 5 to 70 wt.%.

When dimethyl sulfone is in combination with a solar filter (e.g. p-aminobenzoic acid (PABA), Homosalate, Camphor, benzalkonium, methosulfate, benzophenone-3, phenylbenzimidazole sulfonic acid, butylmethoxybenzoylmethoxy-aminomethylene-phenylmethoxy-phenylmethoxy-phenylmethoxy-aminomethylene-sulfonamide-phenylmethoxy-aminomethylene-sulfonamide-aminomethoxy-aminomethylene-sulfonamide-aminomethoxy-aminomethylene sulfonamide octyl salicylate, octyldimethyl PABA, isoamyl p-methoxy cinnamate, benzophenones-4, 3-benzylidene camphor, 4-methylbenzylidene camphor, isopropyl benzyl salicylate, octyl triazonesia), quant of dimethyl sulfone is from 0.5 to 50 wt.% and the amount of solar filters are comprised between 1 to 20 wt.%, and in any case within the limits for use imposed by the various regulations at the international level.

When dimethyl sulfone is in combination with a pharmaceutically active ingredient that is irritating to the skin (e.g. retinoic acid, salicylic acid, azelaic acid, adapalene, benzoyl peroxide, metronidazole, antibiotics, sulfamides, including their respective salts and dextrorotatory and / or esters or levorotatory forms, racemic mixtures and cis or trans forms), the amount of dimethyl sulfone is from 1.0 to 60.0 wt.% and the amount of irritant is from 5.0 to 70 wt.%.

A mass balance of up to 100% in the compositions of this invention can be achieved by the addition of solvents such as water (in particular demineralized water), alcohols (such as ethanol) or glycols (e.g. ethylene glycol or propylene glycol), and / or excipients, such as emulsifiers, antioxidants, lipid-based excipients (liquid lipids or solid lipids), consistency factors, sequestrants, preservatives. Such excipients, used in particular for the preparation of emulsions, gels, creams, ointments, etc., are widely known to the person skilled in the art and therefore will not be described in further detail.

experimental part

In support of the present invention, experiments are described relating to the evaluation of the photoprotective effect and to the effect of inhibition of erythema induced by ultraviolet radiation.

Type B ultraviolet radiation that causes cutaneous erythema is considered to be a suitable model for assessing damage to the skin caused by both constant and strong exposure to solar radiation.

In this experiment, using the protocol already described in the literature, we determined the ability of a composition based on 5% dimethyl sulfone (SALDMS 5) to inhibit cutaneous erythema induced in healthy volunteers by exposure to type B ultraviolet radiation. For a more objective and quantitative assessment of the erythematogenic course of the disease, we monitored using a non-invasive method, such as reflective spectrophotometry.

Experimental protocol

To assess the photoprotective and anti-erythema ability of the composition based on 5% dimethyl sulfone, twelve healthy volunteers were used, previously informed about the nature of the experiment and the methods used. Volunteers who required written consent were selected from subjects having phototypes II and III.

Cutaneous erythema was induced using a UVM-57 model UV lamp (UVP, San Gabriel, Calif.) Capable of emitting radiation in the range 290-320 nm with a maximum at 302 nm. For each subject, the minimum erythematogenic dose (MED) was preliminarily determined and, therefore, on the central part of each forearm, six 1 cm ² skin sites were identified and delimited, which were irradiated to provoke erythema at exposure times equal to the double MED corresponding to each subject.

After exposure to type B ultraviolet radiation, two sections were used as control and therefore were not treated, and the remaining sections were treated twice with 100 mg of the composition per test (SALDMS 5). The compositions were applied to skin areas using appropriate chambers (Hill Top Chambers - Hill Top, Cincinnati, OH) for a period of three hours.

At the end of the treatment period (three hours), each area, after being removed from Hill Top Chambers, was washed with water to remove residual composition and left alone for 30 minutes. Erythema at each site was monitored over the next 60 hours with an X-Rite Model 968 reflective spectrophotometer. The instrument was calibrated according to the “white” standard of the National Bureau of Standards using a type C light source and viewing angle. equal to 2 ^about . The spectrophotometer is connected to a personal computer, which, when using the software supplied with the measuring instrument (Spectrostart), is capable of processing the reflection spectra of the skin in the region of 400-700 nm.

Figure 1 shows the reflection spectra relating to the same skin area before (curve a) and after (curve b) exposure to type B ultraviolet radiation. As can be established from curve b, the reflection spectrum of the skin area after exposure to ultraviolet type B shows two absorption bands: a singlet at about 400 nm, and the other a doublet, from 540 to 580 nm, related to the absorption of hemoglobin.

From the spectral data obtained using the device, it is possible to calculate in time for each tested skin area and using the following equation:

erythema index (I.E.), which is an essential parameter proposed by Dawson for the quantitative monitoring of cutaneous erythema.

According to the above equation, the logarithms of the inverse reflectance values are summed up at those wavelengths (540 nm, 560 nm, 580 nm) at which the absorption peaks of hemoglobin are confirmed, while the corresponding values at wavelengths (510 nm and 610 nm) at which optical density corresponds mainly to the presence of melanin.

The basic EI values established for each section before exposure to type B ultraviolet radiation are subtracted from the EI values calculated at different time periods for the same section, thus obtaining typical curves (ΔE.I. - time; see figure 2) from which the corresponding areas under the curves (AUC) are calculated. AUC values are of particular importance in assessing erythema, as they are inversely proportional to the intensity and duration of erythema itself and, therefore, the ability of the product to inhibit erythema formation.

Therefore, for a better comparison of the effectiveness of individual compositions, the percentage of inhibition of erythema (P.I.E.) was calculated using the formula below:

The values of AUC mean the area under the curves ΔE.I. - time curves of the treated plots [AUC (T)] or control plots [AUC (C)]. Statistical analyzes of the results were carried out using the Student t-test.

results

Figure 2 shows several typical curves related to subject 1 obtained by recording changes in the erythema index as a function of time, both in the case of untreated sections (control) and in the case of sections treated with SALDMS 5.

From the change in the erythematogenic course of the disease shown in FIG. 2, the inhibitory effect is manifested, manifested, to various degrees, by the tested compositions, in comparison with erythema caused by type B ultraviolet radiation.

Table 1 presents the average AUC values obtained from the ΔE.I. curves — time curves for dimethyl sulfone-based compositions and for individual subjects.

From the obtained results, it is obvious that the SALDMS 5 composition is significantly effective in inhibiting cutaneous erythema caused by type B ultraviolet radiation. In order to quantify the erythema inhibition ability of the products being evaluated, the percent erythema inhibition (PIE) was calculated, which are presented in FIG. 3 .

As a result, from the results obtained in this experiment, the SALDMS 5 composition has a photoprotective effect of interest suitable for protecting the skin from degenerative effects caused by exposure to ultraviolet radiation.

The high anti-erythema and photoprotective ability of the SALDMS 5 composition makes it possible to effectively use this active ingredient in cosmetic and pharmaceutical fields and, in particular, to prevent and protect against damage caused by ultraviolet radiation.

AUC values obtained for control (untreated) sites and for sites treated with a composition based on 5% dimethyl sulfone Subject The control SALDMS 5 A 1580.2 828.4 B 1468.5 726.3 C 1698.3 864.1 D 1152.4 952.7 E 1338.2 764.5 F 1637.5 686.7 G 1212.5 921.54 H 1692.3 623.7 I 1547.8 721.6 L 1463.0 864.9 M 1865.5 786.3 N 1545.3 505.1 average value 1516.8 770.5 S.D. 206.3 128.2 P.I.E. * - 49.2 * Percent inhibition of erythema p <0.01: SALDMS 5 compared to control

Examples of compositions

Preparation 1 - Lotion / Solution

No. Title Wt.% / Wt. each 01 Dimethyl isosorbide 40.00 02 Pyruvic acid 50.00 03 Dimethyl sulfone 10.00

Preparation: Dissolve 03 in 01, the resulting solution is mixed with 02.

Preparation 2 - Lotion / Solution

No. Title Wt.% / Wt. each 01 Dimethyl isosorbide 40.00 02 Trichloroacetic acid 50.00 03 Dimethyl sulfone 10.00

Preparation: Dissolve 03 in 01, the resulting solution is mixed with 02.

Preparation 3 - Lotion / Solution

No. Title Wt.% / Wt. each 01 Dimethyl isosorbide 20.00 02 Glycolic acid 50.00 03 Dimethyl sulfone 20.00 04 Water 10.00

Method of preparation: dissolve 03 + 02 in 01; the resulting solution is mixed with 04.

Preparation 4 - Oil-in-Water Emulsion

No. Title Wt.% / Wt. each Phase A 01 Steareth 2 3.00 02 Steareth 21 2.00 03 Polypropylene glycol stearyl ether 15 10.00 04 Tocopheryl acetate 1.00 05 Jojoba oil 2.00 06 Butyloxytoluene (Bht) 0.01 07 Ascorbyl palmitate 0.10 08 Octylmethoxycinnamate 5.00 09 4-methylbenzylidene camphor 2.00 Phase B 10 Propylene glycol 2.00 eleven Retinoic acid 0,025 12 Demineralized water 10.00 Phase C 13 Dimethyl sulfone 10.00 fourteen Propylene glycol 2.00 fifteen Disodium EDTU 0,07 16 Glycerol 5.00 17 Phenoxyethanol 1.00 eighteen Methylparaben 0.10 19 Ethylparaben 0.10 twenty Propylparaben 0.10 21 Demineralized water Up to 100

Method of preparation: phase A) is heated to 75 ° C; phase C) is heated to + 75 ° C; combine phase A) with phase C) with stirring until a homogeneous solution is formed; cooled to + 45 ° C; then add phase B) with constant stirring and cooling to 25 ° C.

Preparation 5 - Oil-in-Water Emulsion

No. Title Wt.% / Wt. each Phase A 01 Steareth 2 3.00 02 Steareth 21 2.00 03 Polypropylene glycol stearyl ether 15 10.00 04 Tocopheryl acetate 1.00 05 Jojoba oil 2.00 06 Butyloxytoluene 0.01 07 Ascorbyl palmitate 0.10 08 Ethyl lactate 5.00 Phase B 09 Propylene glycol 2.00 10 Azelaic acid 15.0 eleven Demineralized water 10.00 Phase C 12 Dimethyl sulfone 10.00 13 Propylene glycol 2.00 fourteen Disodium EDTU 0,07 fifteen Glycerol 5.00 16 Phenoxyethanol 1.00 17 Methylparaben 0.10 eighteen Ethylparaben 0.10 19 Propylparaben 0.10 twenty Demineralized water Up to 100

Method of preparation: phase A) is heated to 75 ° C; phase C) is heated to + 75 ° C; combine phase A) with phase C) with constant stirring until the solution is homogenized; cooled to + 45 ° C; then combined with phase B) with constant stirring and cooling to 25 ° C.

Preparation 6 - Oil-in-Water Emulsion

No. Title Wt.% / Wt. each Phase A 01 Steareth 2 3.00 02 Steareth 21 2.00 03 Polypropylene glycol stearyl ether 15 10.00 04 Tocopheryl acetate 1.00 05 Jojoba oil 2.00 06 Butyloxytoluene 0.01 07 Ascorbyl palmitate 0.10 08 Ethyl pyruvate 5.00 Phase B 09 Propylene glycol 2.00 10 Benzoyl peroxide 5.00 eleven Demineralized water 10.00 Phase C 12 Dimethyl sulfone 10.00 13 Propylene glycol 2.00 fourteen Disodium EDTU 0,07 fifteen Glycerol 5.00 16 Phenoxyethanol 1.00 17 Methylparaben 0.10 eighteen Ethylparaben 0.10 19 Propylparaben 0.10 twenty Demineralized water Up to 100

Method of preparation: phase A) is heated to 75 ° C; phase C) is heated to + 75 ° C; combine phase A) with phase C) with constant stirring until the solution is homogenized; cooled to + 45 ° C; then combined with phase B) with constant stirring and cooling to 25 ° C.

Preparation 7 - Oil-in-Water Emulsion

No. Title Wt.% / Wt. each Phase A 01 Steareth 2 3.00 02 Steareth 21 2.00 03 Polypropylene glycol stearyl ether 15 10.00 04 Tocopheryl acetate 1.00 05 Jojoba oil 2.00 06 Butyloxytoluene 0.01 07 Ascorbyl palmitate 0.10 08 Retinoic acid 0.02 Phase B 09 Propylene glycol 2.00 10 Lactic acid 10.00 eleven Demineralized water 10.00 Phase C 12 Dimethyl sulfone 10.00 13 Propylene glycol 2.00 fourteen Disodium EDTU 0,07 fifteen Glycerol 5.00 16 Phenoxyethanol 1.00 17 Methylparaben 0.10 eighteen Ethylparaben 0.10 19 Propylparaben 0.10 twenty Demineralized water Up to 100

Method of preparation: phase A) is heated to 75 ° C; phase C) is heated to + 75 ° C; combine phase A) with phase C) with constant stirring until the solution is homogenized; cooled to + 45 ° C; then combined with phase B) with constant stirring and cooling to 25 ° C.

Preparation 8 - Oil-in-Water Emulsion

No. Title Wt.% / Wt. each Phase A 01 Steareth 2 3.00 02 Steareth 21 2.00 03 Polypropylene glycol stearyl ether 15 10.00 04 Tocopheryl acetate 1.00 05 Jojoba oil 2.00 06 Butyloxytoluene 0.01 07 Ascorbyl palmitate 0.10 08 Ethyl pyruvate 5.00 Phase B 09 Propylene glycol 2.00 10 Adapalene 0.20 eleven Demineralized water 10.00 Phase C 12 Dimethyl sulfone 10.00 13 Propylene glycol 2.00 fourteen Disodium EDTU 0,07 fifteen Glycerol 5.00 16 Phenoxyethanol 1.00 17 Methylparaben 0.10 eighteen Ethylparaben 0.10 19 Propylparaben 0.10 twenty Demineralized water Up to 100

Method of preparation: phase A) is heated to 75 ° C; phase C) is heated to + 75 ° C; combine phase A) with phase C) with constant stirring until the solution is homogenized; cooled to + 45 ° C; then combined with phase B) with constant stirring and cooling to 25 ° C.

Preparation 9 - Oil-in-Water Emulsion

No. Title Wt.% / Wt. each Phase A 01 Steareth 2 3.00 02 Steareth 21 2.00 03 Polypropylene glycol stearyl ether 15 10.00 04 Tocopheryl acetate 1.00 05 Jojoba oil 2.00 06 Butyloxytoluene 0.01 07 Ascorbyl palmitate 0.10 08 Ethyl pyruvate 5.00 Phase B 09 Propylene glycol 2.00 10 Lactic acid 10.00 eleven Demineralized water 10.00 Phase C 12 Dimethyl sulfone 10.00 13 Propylene glycol 2.00 fourteen Disodium EDTU 0,07 fifteen Glycerol 5.00 16 Phenoxyethanol 1.00 17 Methylparaben 0.10 eighteen Ethylparaben 0.10 19 Propylparaben 0.10 twenty Demineralized water Up to 100

Method of preparation: phase A) is heated to 75 ° C; phase C) is heated to + 75 ° C; combine phase A) with phase C) with constant stirring until the solution is homogenized; cooled to + 45 ° C; then combined with phase B) with constant stirring and cooling to 25 ° C.

Preparation 10 - Oil-in-Water Emulsion

No. Title Wt.% / Wt. each Phase A 01 Steareth 2 3.00 02 Steareth 21 2.00 03 Polypropylene glycol stearyl ether 15 10.00 04 Tocopheryl acetate 1.00 05 Jojoba oil 2.00 06 Butyloxytoluene 0.01 07 Ascorbyl palmitate 0.10 08 Ethyl pyruvate 5.00 Phase B 09 Propylene glycol 2.00 10 Lactic acid 10.00 eleven Demineralized water 10.00 Phase C 12 Dimethyl sulfone 10.00 13 Metronidazole 2.00 fourteen Disodium EDTU 0,07 fifteen Glycerol 5.00 16 Phenoxyethanol 1.00 17 Methylparaben 0.10 eighteen Ethylparaben 0.10 19 Propylparaben 0.10 twenty Demineralized water Up to 100

Method of preparation: phase A) is heated to 75 ° C; phase C) is heated to + 75 ° C; combine phase A) with phase C) with constant stirring until the solution is homogenized; cooled to + 45 ° C; then combined with phase B) with constant stirring and cooling to 25 ° C.

Claims (1)

A composition for dermal use, having a photoprotective and anti-erythema effect, containing a solar filter and dimethyl sulfone, where the amount of dimethyl sulfone is from 0.5 to 50 wt.% And the amount of the solar filter is from 1 to 20 wt.%, Where the specified solar filter is selected from PABA , Homosalate, Camphor, benzalkonium, methosulfate, benzophenone-3, phenylbenzimidazolesulfonic acid, butyl methoxybenzoylmethane, terephthalylidendicamphorsulfonic acid, benzylidene camphorsulfonic acid, octocrylene, octyl methoxycinnamate, polyacrylamides methylbenzylidene, PEG-25 RABA, octyl salicylate, octyldimethyl RABA, isoamyl p-methoxy cinnamate, benzophenone-4, 3-benzylidene camphors, 4-methylbenzylidene camphors, isopropylbenzyl salicylate, octyl triazones.

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