KR20230139402A - A pharmaceutical cosmetic composition that treats inflammatory skin syndrome - Google Patents

Abstract

The present invention relates to a cosmetic composition for pharmaceutical use in the treatment of inflammatory skin syndrome, comprising a mixture consisting of at least one compound belonging to the 4-alkyl-cyclohexanol type and methyl sulfonyl methane, in combination with a carrier suitable for topical use. As such, it is useful in treating various inflammatory conditions such as rosacea. The composition may act as an agent that simultaneously inhibits the release of chemical mediators up-regulated in injection and their action in causing activation of TRPV receptors. The composition can alleviate the effects of ultraviolet irradiation on skin where the inflammatory process has already progressed, and in particular, can alleviate erythema caused by ultraviolet irradiation on skin where the inflammatory process has already progressed.

Description

A cosmetic composition for pharmaceutical use to treat inflammatory skin syndrome {A pharmaceutical cosmetic composition that treats inflammatory skin syndrome}

The present invention relates to a cosmetic composition for pharmaceutical use in the treatment of inflammatory skin syndrome, and more particularly, the invention is intended for external use, for the treatment of rosacea, more generally inflammatory skin syndrome, and ultraviolet irradiation. For the treatment of inflammatory skin syndrome, for application to intact or damaged skin or mucous membranes, to treat erythema caused by UV irradiation, more generally by ultraviolet irradiation on skin where the inflammatory process has already progressed. relates to cosmetic compositions for pharmaceutical use

A variety of inflammatory conditions of the skin are known, which generally result in overexpression of cytokines, angiokines and inflammatory chemical mediators, and involve specific activation of specific membrane receptors that can modify ion exchange.

Rosacea, one of these inflammatory conditions, is a chronic disease that occurs primarily on the face, including the cheeks, chin, nose, and forehead, and is usually characterized by recurrence and worsening, and is characterized by intermittent erythema, permanent erythema, telangiectasia, and erythema. It includes a series of symptoms such as edema, papules, pustules and ocular lesions.

Rosacea affects both women and men, and usually occurs in people over 30 years of age.

The exact disease classification of rosacea has not yet been established. The scientific committee of the "National Rosacea Society" in the United States defines rosacea into four subtypes.

Subtype-1 - Erythema Vasodilatory Rosacea:

It is characterized by intermittent or permanent erythema mainly in the central area of the face. Telangiectasia, or dilatation of small blood vessels, is common, but is not essential for diagnosing this subtype. Edema, droppings, roughness and burning, and itching may also be observed. A history of intermittent erythema is common in individuals suffering from erythema vasodilatory rosacea.

Subtype-2 - papulopustular rosacea:

This subtype is transient in nature and is characterized by persistent erythema with papules and pustules, usually, but not limited to, limited to the central area of the face. Although it can be confused with acne vulgaris in many ways, it does not cause comedones called blackheads. Rosacea and acne can occur at the same time. Subtype-2 is often associated with subtype-1.

Subtype-3 - phymatous rosacea:

This subtype of rosacea includes symptoms such as thickening of the skin, bumpy surface of the skin with nodular elements, and enlarged nose (dry nose), while non-rheumatic rosacea occurs in multiple areas such as the cheeks, forehead, chin, and ears. It can occur in

Additionally, subtype-3 often occurs together with subtypes-1 and 2 and is accompanied by persistent erythema and telangiectasia. Subtype-4 - Ocular Rosacea

If a subject exhibits any of the following symptoms: interpalpebral conjunctival hyperemia, burning, itching, dryness, light sensitivity, telangiectasia of the conjunctiva and eyelid margins, and periorbital erythema, ocular rosacea should be diagnosed. do. Individuals are often diagnosed with ocular rosacea when they present with symptoms of rosacea.

Early treatment for rosacea can essentially delay its progression. If rosacea is left untreated, it usually gets worse, reducing the chances of successful treatment.

The Applicant asserts that although various therapeutic means are available to control inflammatory lesions such as papules and pustules, no means exist to control erythema, which must represent the early stages of the syndrome described above. I came to pay attention to this.

Furthermore, the Applicant believes that other aspects considered as aggravating factors are caused by ultraviolet irradiation, which measures the degree of erythema and the transition from intermittent to persistent erythema; It has been noted that actual rosacea can be considered photo-induced or at least photo-exacerbated dermatitis.

“Transient Receptor Potential cation channels of subfamily V number 1” (TrpV1), also known as capsaicin vanilloid receptor-1, is a protein encoded by the gene TRPV1 in humans.

During the inflammatory process, TRPV1 receptors are activated by various inflammatory chemical mediators such as cytokines, growth factors, prostaglandins, bradykinin, etc.

In particular, TRPV1, TRPV2, TRPV3, and TRPV4 were found to be activated in rosacea; Especially in the early stages of erythema vasodilatory rosacea, activation of TRPV1 receptors has been confirmed to be a representative feature of characteristic neurogenic-type inflammation.

Accordingly, the aim of the present invention is to inhibit inflammatory processes in the skin, which simultaneously results in increased production of inflammatory chemical mediators and up-regulation of TRPV membrane receptors.

Specifically, the aim of the present invention is to act to simultaneously interfere with both the release of chemical mediators that are up-regulated in injection and their action to cause activation of TRPV receptors.

Accordingly, in a first aspect, the present invention relates to a cosmetic and/or pharmaceutical composition as described in claim 1.

Specifically, the cosmetic and/or pharmaceutical composition of the present invention comprises a mixture consisting of methyl sulfonyl methane (also known as dimethyl sulfone) and one or more compounds belonging to the 4-alkyl cyclohexanol type, which composition is suitable for use in injections such as It is useful in treating a variety of inflammatory conditions.

In fact, the composition of the present invention is used, on the one hand, for its efficacy in interfering with the activation of TRPV receptors by inhibiting the release of inflammatory chemical mediators, and on the other hand, for interfering with the activation of the TRPV receptor itself, for example, It is used for its efficacy in significantly reducing the intensity of various uncomfortable sensations such as burning and itching.

In addition, the composition of the present invention is used for its ability to reduce the effect of ultraviolet irradiation on skin where an inflammatory process has already progressed, and in particular, for its efficacy in alleviating erythema caused by ultraviolet irradiation on skin where an inflammatory process has already progressed.

Preferably, the 4-alkyl cyclohexanol type includes 4-lower-alkyl cyclohexanol, wherein 4-cyclohexanol is methyl, ethyl, t-butyl, propyl means substituted with an alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms.

Therefore, preferably, the cosmetic and/or pharmaceutical composition of the invention comprises a mixture consisting of methyl sulfonyl methane and at least one compound belonging to the 4-lower-alkyl cyclohexanol type.

More preferably, the cosmetic and/or pharmaceutical composition of the present invention comprises a mixture consisting of methyl sulfonyl methane and 4-t-butyl-cyclohexanol.

This composition was found to have special and excellent efficacy in acting as an antagonist on the TRPV epithelial receptor, which is active in the erythematosus angiectasia syndrome of rosacea. In practice, this combination is useful for achieving two effects: overall improvement of skin conditions (e.g. obvious signs such as erythema) and relief of sensations such as burning, itching, stinging sensation, etc.

Moreover, surprisingly, the combination of methyl sulfonyl methane and 4-t-butyl-cyclohexanol prevents the presence of certain lesions, for example, rosacea in the papulopustular stage, in which certain inflammatory lesions such as papules and pustules are also present. It has been confirmed that it provides excellent results in treating inflammatory processes in the skin, which are characterized by These results are due to inhibition of TRPV receptors.

Preferably, the compositions of the invention comprise a carrier suitable for topical use.

Preferably, the composition of the present invention ranges from 0.05% to 90% by weight, more preferably from 0.5% to 15% by weight, and even more preferably from 2% to 7.5% by weight, based on the total weight of the mixture. methyl sulfonyl methane in a concentration of . Preferably, the composition of the present invention contains 0.05% to 90% by weight, more preferably 0.1% to 10.0% by weight, based on the total weight of the mixture. More preferably, it comprises compounds belonging to the 4-lower-alkyl cyclohexanol type, at a concentration ranging from 0.5% to 5% by weight.

Preferably, the composition of the present invention further comprises metronidazole. Preferably, the metronidazole ranges from 0.05% to 1% by weight, more preferably from 0.20% to 0.75% by weight, and even more preferably from 0.4% to 0.5% by weight, based on the total amount of the mixture. It exists in a concentration of

In this way, the compositions of the invention are particularly advantageous when intended to treat inflammatory conditions of the skin, characterized by erythema and actual lesions such as papules and pustules.

Preferably, the composition of the present invention also includes other ingredients typically found in cosmetic and/or pharmaceutical compositions, such as surfactants, emulsifiers, emollients, preservatives, solvents, etc.

Preferably, the composition according to the invention has the form of a cream, unguent, ointment, gel, milk, lotion or other typical forms used in cosmetics and/or pharmaceuticals.

More preferably, the composition according to the invention is in the form of a soft, non-greasy cream suitable for all types of skin.

In a second aspect, the invention relates to the above-described composition for use as a medicament according to claim 8.

In fact, the applicant of the present invention has surprisingly found that the above-mentioned cosmetic and/or pharmaceutical compositions can be used as agents that simultaneously interfere with both the release of chemical mediators that are up-regulated in injection and their action in causing the activation of TRPV receptors. I found out.

In a third aspect, the invention relates to the above-described composition for use as described in claim 9.

In fact, the applicant of the present invention has surprisingly found that the above-mentioned cosmetic and/or pharmaceutical compositions can be used to alleviate the effect of ultraviolet irradiation on skin where inflammatory processes have already developed.

In a fourth aspect, the invention relates to the above-described composition for use as described in claim 10. In fact, the applicant of the present invention has surprisingly found that the above-mentioned cosmetic and/or pharmaceutical compositions are used to prevent inflammatory processes from already progressing.

It was discovered that it could be used to relieve erythema caused by ultraviolet irradiation on the skin.

The composition should be used on the skin by spreading it evenly and repeating this action even several times daily. Other features and advantages of the present invention are intended to be illustrative and not limiting, but rather to describe preferred, non-limiting embodiments.

It will become clearer by considering the detailed explanation of Hyeon-ye below.

Activity of methyl sulfonyl methane.

Regarding the release of TNFα from human keratinocytes induced by contact with sodium lauryl sulfate (SLS), inhibition of release was achieved using methyl sulfonyl methane (MSM), which was found to have the activity of inhibiting the release of TNFα. The inhibition of release achieved using the known compound hydrocortisone was compared. In this comparison, after 24 hours under the same treatment conditions, the reduction in TNFα release achieved with MSM was 12.33%, whereas the reduction achieved with hydrocoratisone was only 5.25%. That is, the experiments performed showed that MSM, even when TNFα was overexpressed by ultraviolet irradiation, led to the release of TNFα (this cytokine is expressed by keratinocytes in inflammatory processes in the skin), and the overall It has been shown to be able to alleviate the severity of erythema. These results suggest that methyl sulfonyl methane can lead to under-expression of the above-mentioned proteins, even in acute inflammation (exposure to SLS, immediate assessment), suggesting that methyl sulfonyl methane has high potential in controlling inflammatory processes in the skin. It shows that you have sex. Additionally, it should be noted that TNFα can activate the TRPV receptor, and therefore, reduced production thereof may prevent it from exerting its agonist effect on the receptor itself.

Activity of 4-alkyl cyclohexanol. Molecules of this type can act as antagonists of TRPV receptors and, therefore, exert various ameliorative effects on various inflammatory processes.

In the skin, TRPV receptors are located on keratinocytes and sebaceous gland cells, and their activation triggers biochemical processes that lead to the perception of unpleasant sensations such as burning and itching.

4-Alkyl cyclohexanol is an antagonist of TRPV receptors and is therefore a useful tool for counteracting sensations arising from inflammatory processes.

In other words, compositions based on methyl sulfonyl methane and 4-alkyl cyclohexanol derivatives are groundbreaking in controlling inflammatory processes and the sensations they cause.

The composition has been shown to be effective in controlling the clinical picture of inflammatory processes, such as rosacea, where apparent damage is aggravated by sensations that may even be accompanied by pain.

Examples of Compositions of the Invention

Composition 1. Topical pharmaceutical emulsion based on methyl sulfonyl methane and 4-t-butyl-cyclohexanol, comprising the following ingredients:

2% by weight of Steareth 2, 3% by weight of Steareth 21, 10% by weight of Ppg-15 stearyl ether, 5% by weight of stearic acid, 0.01% by weight of (BHT) and 2.50% by weight of 4-t-butyl-cyclohexanol. The resulting mixture (phase A) was heated to 80°C. To this phase A, an appropriate amount of water and a preservative are added, heated to 75°C, and finally, the resulting mixture, B, consisting of 5% by weight of methyl sulfonyl methane and 5% by weight of ethyl alcohol, is heated to 40°C. The phases were added to give composition 1.

Composition 2. Topical emulsion based on dimethyl sulfone, 4-t-butyl-cyclohexanol and metronidazole, comprising the following ingredients:

Composition 2 was prepared in a similar manner to Composition 1, except that phase B further included 0.25% by weight of metronidazole.

clinical evaluation

Afterwards, several clinical evaluations were performed to confirm the efficacy of the combination of methyl sulfonyl methane and 4-t-butyl-cyclohexanol in suppressing erythema and enhancing skin moisturization. In this regard, it should be shown that inhibition of TRPV receptor activation results in increased differentiation capacity of the epithelium and ultimately a substantial improvement in barrier function resulting in increased surface moisturization.

First evaluation. The first clinical evaluation was performed by repeated and continuous application of the above-described composition 1 of the present invention for 30 days to 12 mixed gender individuals suffering from rosacea. This type of evaluation, intended to demonstrate the efficacy of a product for rosacea, requires at least 90 days of treatment, so the 30-day period described above is quite short.

Table 1 below shows skin moisture values, expressed in arbitrary units of the moisture meter, obtained from 12 subjects treated and untreated with Composition 1 of the present invention.

It is clearly confirmed that patients treated with composition 1 of the present invention comprising a combination of methyl sulfonyl methane and 4-t-butyl-cyclohexanol have a significant increase in skin moisturization.

Second evaluation. To demonstrate the erythema reducing efficacy of Composition 1 of the present invention in rosacea patients, a secondary evaluation was then performed using reflectance spectrophotometry in 12 subjects.

Table 2 below shows the erythema scores, expressed in arbitrary units, obtained from 12 subjects treated and untreated with Composition 1 of the present invention. The clinical results show that in the treatment of rosacea, two compounds, viz. , appears to be the result of a surprising synergistic mechanism triggered by methyl sulfonyl methane and 4-t-butyl-cyclohexanol.

Thus, the combination of methyl sulfonyl methane and 4-t-butyl-cyclohexanol inhibits the overall picture of various inflammatory processes, such as rosacea, that can occur on the skin, characterized by erythema and unpleasant sensations such as itching and burning. It appears to be very beneficial.

Accordingly, the mechanism by which the above combination works is a synchronized two-fold mechanism, on the one hand, it inhibits the release of inflammatory chemical mediator (TNFα) due to the action of methylsulfonine methane, thereby interfering with the activation of TRPV receptors, On the other hand, due to the antagonistic action of 4-t-butyl-cyclohexanol, it significantly relieves the severity of sensations such as pruritus, burning and even pain, which are common features in the general clinical picture of inflammatory processes.

In another evaluation, the present inventors also evaluated the activity against erythema induced by irradiating ultraviolet rays at a dose twice the MED (minimum erythema dose). This test was performed on healthy subjects and evaluated by reflectance spectrophotometry. When Composition 1 of the present invention was used as a treatment, erythema caused by ultraviolet irradiation was reduced by more than 60%.

Third evaluation. Thereafter, in order to confirm the erythema alleviating efficacy of Composition 2 of the present invention in patients suffering from papulopustular stage of rosacea, the third clinical evaluation was performed as follows using the same method as the second evaluation described above.

This evaluation is still ongoing and preliminary experimental results show that, after several days of treatment, in patients administered Composition 2 of the invention comprising a combination of methyl sulfonyl methane, 4-t-butyl-cyclohexanol and metronidazole, inflammation, In particular, it has already been confirmed that inflammatory lesions such as erythema, specifically papules and consistency, and subjective unpleasant symptoms such as tingling, burning and itching have been significantly improved.

Numerous modifications and variations of the preferred embodiments will be readily apparent to those skilled in the art, without departing from the scope of the present invention. Accordingly, the present invention is not limited to the stated preferred embodiments, which are shown by way of merely illustrative and non-limiting example, but is defined by the appended claims.

Claims (8)

As a cosmetic and/or pharmaceutical composition,
A mixture consisting of at least one compound belonging to the 4-alkyl-cyclohexanol type and methyl sulfonyl methane, wherein the at least one compound belonging to the 4-alkyl-cyclohexanol type is 4-t-butyl-cyclohexanol. Characterized by
is a cosmetic and/or pharmaceutical composition. According to paragraph 1,
Based on the total amount of the mixture, comprising the methyl sulfonyl methane at a concentration of 0.05% by weight - 90% by weight, and the 4-t-butyl-cyclohexanol at a concentration of 0.05% by weight - 90% by weight. A cosmetic and/or pharmaceutical composition characterized in that. According to claim 1 or 2,
A cosmetic and/or pharmaceutical composition comprising the methyl sulfonyl methane at a concentration of 0.5% by weight to 15% by weight based on the total amount of the mixture. According to any one of claims 1 to 3,
A cosmetic and/or pharmaceutical composition comprising the 4-t-butyl-cyclohexanol at a concentration of 0.1% by weight to 10.0% by weight based on the total amount of the mixture. The cosmetic and/or pharmaceutical composition according to any one of claims 1 to 4, further comprising metronidazole. A mixture consisting of at least one compound belonging to the 4-alkyl-cyclohexanol type and methyl sulfonyl methane, wherein the at least one compound belonging to the 4-alkyl-cyclohexanol type is 4-t-butyl-cyclohexanol. ,
For use as a medicament for the treatment of inflammatory conditions of the skin characterized by up-regulation of chemical mediators of inflammation due to rosacea and up-regulation of TRPV membrane receptors.
Cosmetic and/or pharmaceutical compositions. A mixture consisting of at least one compound belonging to the 4-alkyl-cyclohexanol type and methyl sulfonyl methane, wherein the at least one compound belonging to the 4-alkyl-cyclohexanol type is 4-t-butyl-cyclohexanol. ,
Cosmetic and/or pharmaceutical composition for mitigating the effects of ultraviolet irradiation on skin where inflammatory processes have already developed. A mixture consisting of at least one compound belonging to the 4-alkyl-cyclohexanol type and methyl sulfonyl methane, wherein the at least one compound belonging to the 4-alkyl-cyclohexanol type is 4-t-butyl-cyclohexanol. ,
Cosmetic and/or pharmaceutical composition for alleviating erythema caused by ultraviolet irradiation on skin where an inflammatory process has already progressed.