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1. WO2019214838 - USE OF AN ALCOHOL-CONTAINING COMPOSITION FOR IMPROVING THE SKIN BARRIER FUNCTION

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USE OF AN ALCOHOL-CONTAINING COMPOSITION FOR IMPROVING THE SKIN BARRIER FUNCTION

Field of the invention

The present invention relates to alcohol-containing compositions for dermal application which compositions also contain urea, and more particularly the use of such compositions for improving the skin barrier function.

Background of the invention

Alcohol-based disinfectants and biocidal products are regularly used in healthcare and medical care, such as in hospitals and in clinics, to prevent spreading of nosocomial infec-tions and other disinfectant purposes. However, studies on nurses and other health care personnel show that frequent hand washing and disinfection lead to a high risk of develop-ing skin dryness, fissures and hand eczema. Alcohol-based disinfectants are also perceived by users to be damaging to the skin, which hamper their use. Water, detergents, antimicro-bial agents and low molecular weight alcohols are all known to cause dryness and be irri tants to the skin.

Already in the seventies, Scheuplein and Blank in J Invest Dermatol 60:286-296, 1973, found ethanol and methanol to alter the stratum corneum and influence its barrier function. In a recent study repeated application of alcohol to healthy skin was shown to cause irrita tion and dryness, where 25% of sites treated with ethanol 20 times per day dropped-out due to adverse reactions (Cartner et al in Effect on different alcohols on stratum corneum kallikrein 5 and phospholipase A2 together with epidermal keratinocytes and skin irrita tion, hit. J. Cosmet. Sci. 39,188-196, (2017)). The European Chemical Agency (ECHA) has set a realistic default value of 25 hand disinfections per working day of 8 hours per health-care worker (ECHA. Recommendation no. 1 of the BPC Ad hoc Working Group on Human Exposure. Hand disinfection - PT 1 harmonisation of exposure determinants for professional users. (Agreed at the Human Health Working Group II on 24 March 2014).

https://echa.europa.eu/documents/l0l62/2l6640l6/recom_l_hand_disinfection_ptl_en.pd f)

It is well accepted that the normal intact stratum comeum is the major rate-limiting barrier to molecular diffusion through the human skin.

It would be desirable to provide a composition which could be used as a disinfectant, hav-ing improved skin tolerability and which reduces skin sensitivity towards irritating agents.

Accordingly, it is an object of the invention to provide a composition which can be used as a disinfectant, having improved skin tolerability, and reducing skin sensitivity to e.g soaps.

Summary of the invention

The present inventor has surprisingly found that a combination of urea and alcohol when applied to the skin repeatedly may not only counteract the skin irritating effect of the alco-hol, but also improve the barrier function of the skin, also at concentrations of the alcohol which are generally considered in the art to be effective for disinfection, i.e. at concentra-tions of at least 50 % by volume. According to the present invention an alcohol-based composition containing urea can surprisingly be used for improving the barrier function of the skin and reducing its sensitivity to dryness and occurrence of eczema.

Thus, according to the invention the skin can be protected during repeated disinfection procedures, and during disinfecting conditions.

According to the inventive finding also other dermal compositions containing relatively high amounts of the alcohol, although less than required for biocidal effects of the alcohol, such as 30 % by weight, will improve the skin barrier function.

By virtue of improving the barrier function, the inventive use of an alcohol containing composition may thus reduce the risk of developing eczema, especially on the hands, dur ing disinfection routines in e.g. hospitals and clinics.

Also, by reducing or even killing off bacteria and yeast present on the skin, any skin-barrier impairing effect from the presence of such bacteria and yeast can be reduced or prevented by the inventive use. Accordingly, the skin barrier function may be improved also from this point of view according to the invention.

The inventive use of an alcohol containing composition can enhance the barrier function of skin, and hence render skin more resistant to irritants and allergens, e.g. to chemicals released from bacteria or fungi present on the skin, or to other damaging chemicals in con tact with the skin.

The inventive use can generally reduce the risk of developing eczema, especially on the hands, and during treatment of other skin disorders on other body surfaces.

In a first aspect the invention relates to the use of a composition containing: 30-96 % by weight of an alcohol selected from the group consisting of ethanol, isopropanol, and n-propanol, or a combination thereof; 0.5-20 % by weight of urea, and water for improving the skin barrier function in a mammal by dermal application of the composition to the skin.

In a preferred embodiment the composition used according to the invention additionally contains a hydrolysable carboxylic ester. The ester serves to prevent formation of ammo nia which may result from urea hydrolysis during storage of the urea-containing composi tion. By using a hydrolysable ester, the addition of a carboxylic acid for preventing for mation of ammonia may be avoided. Thereby any possible stinging which may otherwise result from the presence of such added carboxylic acid can be avoided.

The composition is preferably used in the form of a gel, especially a gel which collapses when applied on the skin, such as a carbomer type of gel.

When the composition used according to the invention is in the form of a gel which col lapses on the skin, the hydrolysable carboxylic ester may also serve the purpose of stabi lising the gel during storage.

The carboxylic ester may also improve the transparency of the gel.

The inventive use of the alcohol containing composition may be biocidal, cosmetic, veter inary or medical.

Accordingly, in a medical aspect the present invention relates to a composition containing: 30-96 % by weight of an alcohol selected from the group consisting of ethanol, isopropa nol, and n-propanol, or a combination thereof; 0.5-20 % by weight of urea, and water, for use in improving the barrier function of the skin by repeated application of the composi tion to a desired area of the skin.

The inventive composition may be used for treating atopic dermatitis (AD), for avoiding eczema, for prophylactic treatment of the skin for subsequent exposure of the skin to irri tating substances, or for prolonging the period of time until relapse of eczema. Treatment and prevention of eczema may also be related to the change of skin microflora, where it is known that certain microorganisms may increase sensitivity to eczema (e.g. head and neck dermatitis). The inventive composition can also be used for treatment of other skin disor ders characterized by microorganisms, such as dandruff, which usually involves the yeast Malassezia furfur but also bacteria such as Propionobacterium and Staphylococcus. Fur thermore, other superficial skin infections by Malassezia furfur known as Pityriasis versi color can be treated successfully. The inventive composition could also be used for pre venting asthma, as will be explained below.

The same approach is applicable on animal skin where the biocidal properties of the in vention in combination with the barrier-improving properties decrease skin susceptibility to damaging microorganisms.

In yet an aspect the invention relates to a method of improving the barrier function of the skin in a mammal, comprising the step of applying repeatedly a composition containing: 30-96 % by weight of an alcohol selected from the group consisting of ethanol, isopropa nol, and n-propanol, or a combination thereof; 0.5-20 % by weight of urea, and, water, to a desired area of the skin of the mammal in which area the barrier function of the skin is to be improved.

According to the invention the composition is preferably applied repeatedly during a day, i.e. preferably at least twice daily.

In yet another aspect the invention relates to the use of a composition containing: 30-96 % by weight of an alcohol selected from the group consisting of ethanol, isopropanol, and n-propanol, or a combination thereof; 0.5-20 % by weight of urea, and water for disinfection of skin of a mammal, wherein the barrier function of the skin is improved when the com position is applied repeatedly to the skin.

The term“collapse” as used in connection with gel herein, is intended to refer to the de sired property of a gel of being capable of being transformed into a liquid upon application to the skin. Collapse thus entails a marked loss of viscosity and essential loss of the gel form and is mediated by salts present on the skin.

As used herein the term“biocidal” is intended to comprise disinfectant, antiseptic, antibac terial, antimicrobial, antifungal etc.

To some extent such properties will be obtained from the alcohol present in the composi tion, especially disinfectant properties, and especially at concentrations above 50 % by volume, such as at 50% by weight of the composition. In instances or applications of the invention where additional such properties are desired, the composition could be comple mented accordingly with conventionally used additives, such as disinfectant agents, anti septic agents, antibacterial agents, antimicrobial agents, anti-fungal agents.

Such additives could also be used in cosmetic, veterinary, or medical use of the composi-tion, when such additional properties of the composition are desired.

Brief description of attached drawings

FIG. 1 shows transepidermal water loss (TEWL) in areas treated with a simple ethanol-urea gel of Example 1 as a percentage in relation to untreated control skin, N=l2.

FIG 2 shows skin irritation in sodium lauryl sulphate exposed area in areas previously treated with the simple ethanol urea-gel of Example 1 in relation to untreated control area, N=l2.

FIG. 3 shows transepidermal water loss (TEWL) in areas treated with the more complex ethanol-urea gel of Example 2 in relation to untreated control skin, N=8.

FIG. 4 shows skin irritation in sodium lauryl sulphate exposed area in areas previously treated with the more complex ethanol urea-gel of Example 2 in relation to untreated con trol area, N=7.

Detailed description of the invention and preferred embodiments thereof

According to the present invention, alcohol-containing compositions can surprisingly be used for improving the barrier function of the skin, measured either as reduced transepi-dermal water loss (TEWL), or, as a reduced sensitivity of the skin, e.g. to a known soap irritant.

Stated differently, it seems that the presence of urea in the inventive composition allows for simultaneous exposure of the skin to irritating substances, and hence skin-damaging alcohols can be used in the composition for killing off bacteria on the skin, while at the same time the risk of any possible damage to the skin by such treatment is being reduced.

By virtue of the inventive use the skin will also be rendered more tolerable to subsequent exposure of the skin to an irritant.

SE 511 551 discloses that repeated application of a urea containing composition to the skin can build up a protection against the skin irritation that would otherwise arise upon contact of the skin with an irritating substance, such as a surfactant solution. The invention disclosed therein thus generally relates to the use of a urea containing composition for prophylactic treatment of normal skin in order to prevent irritation.

It has now surprisingly been found that a similar effect will be obtained also when urea is combined with a substantial amount of an irritating agent such as an alcohol, such as e.g. 70 % by weight of ethanol, upon repeated application of the combination to the skin.

AD is considered a primary disorder related to SC barrier failure with elevated transepi-dermal water loss (TEWL) linked to mutations in the filaggrin gene. Another common feature of AD is colonization by Staphylococcus aureus , where the antimicrobial barrier function is compromised. In the art, defect barrier function in AD has been suggested to have consequences not only for the development of eczema but also to other conditions such as asthma. The skin barrier itself has been suggested a likely contributor to the devel-opment of contact sensitization, as irritant contact dermatitis is reported to often precede allergic contact dermatitis with onset at lower ages, i.e. shows a similar temporal relation ship clinically as with eczema and asthma. Also ichthyosis may be linked to the filaggrin gene. These findings emphasise the need for treatments which maintain a healthy barrier function and prevent deterioration of the skin. Hence the inventive composition could be used for treating or preventing dermatitis, AD, and ichthyosis, and also for preventing asthma.

In the art, the alcohols used in alcohol-based disinfectants are typically ethanol, isopropa-nol, and n-propanol, or a combination thereof. For disinfectant purposes the alcohol con tent is typically between 60 % and 90 % by volume. Once alcohol concentrations drop below 50% by volume, usefulness for disinfection drops sharply without the addition of other biocidal agents. For disinfection preferred alcohol concentrations in the art are with in 60-80 % by volume. Many institutions use 70 % by volume alcohol blends as standard.

Dermal compositions having a high content of alcohols, although lower than for an effec tive disinfection action from the alcohol, such as down to 30 % alcohol by weight, may be desirable for other antimicrobial purposes, such as in deodorants. The present invention could be used to reduce the irritability of the alcohol in such products too.

It is believed that the inventive use serves to make the skin more tight, i.e. less permeable. Therefore, the irritability of the skin to other skin irritating substances could also be re-duced by the inventive use of the alcohol containing compositions. Accordingly, in some embodiments the alcohol containing composition used according to the invention could include other irritating substances in the formulation in addition to the alcohol, such as e.g. denaturants (e.g. methyl ethyl ketone), quaternary compounds (e.g. benzalkonium chlo-ride, chlorhexidine), and fragrances.

According to the invention a generally preferred range of alcohol is 50 to 96 % by weight, such as 50 to 90 % by weight, more preferably 60-90 % by weight, typically 60-80 % by weight, such as e.g. 65-75 % by weight. The composition can suitably be formulated so as to exhibit an amount of about 70 % by weight of alcohol, which is slightly above the standard concentration of 70 % by volume as conventionally used in alcohol-based disin fectants. For purposes of comparison, it can be noted that for a mixture of ethanol and wa ter an ethanol content of 60.0 % by weight corresponds to 67.7 % by volume of ethanol, 80.0 % by weight corresponds to 85.4 % by volume, and 70.0 % by weight corresponds to 76.9 % by volume at 20°C. Ethanol is a preferred alcohol for use in the inventive compo sitions, and it is generally preferred that ethanol constitutes the major part of the alcohol-content, preferably at least 85 % by weight, and more preferably at least 90 % by weight of the alcohol content. Preferably, any other primary alcohols present in the composition, in addition to the ethanol, such as any of propanols, and butanols, are merely used for de naturing the ethanol, as may be required under national regulations. When alcohol is used at lower concentrations, such as lower than 50 % by weight, if desired, the disinfecting effect could be enhanced by addition of a biocidal agent such as e.g. chlorhexidine.

Urea is contained in an amount of from 0.5-20 % by weight in the inventive composition, preferably 1.5-20, more preferred 2-20, and especially preferred 3-10 % by weight, such as e.g. 5 % by weight. The lower limit of 0.5% by weight is believed to be suitable for a composition which is applied very frequent during a day.

Accordingly, when formulated as a disinfectant for frequent use during a day, a lower amount of urea may be preferred, such as from 0.5 % by weight, or from 1 % by weight, up to 5 % by weight, e.g. up to 4, or up 3 % by weight.

In a preferred embodiment the inventive composition contains a hydrolysable carboxylic ester. Hydrolysable esters that can be used in the invention are in general those listed in US 4 488 989, and more preferably propyl lactate, butyl acetate, ethyl acetate, ethyl lac-tate, ethyl citrate, ethyl glycolate, menthyl lactate, pyroglutamic acid ethyl ester, or a mix ture thereof. Generally preferred esters are the lactates, and an especially preferred ester is ethyl lactate. During hydrolysis the hydrolysable ester will form the corresponding car boxylic acid and alcohol. The carboxylic acid formed will lower the pH and neutralise the ammonia being liberated by the slow hydrolysis of urea. The amount of hydrolysable car boxylic ester should be selected so as to be effective for neutralising the ammonia formed. The amount required for this purpose is generally within a ratio by weight of ester to urea of 1 :5 to 1 :25, depending on the specific ester and the molecular weight thereof.

It is also conceived that methyl salicylate could be included in certain embodiments of the inventive composition.

In a preferred embodiment a gel is formed from the composition used according to the invention, more preferably a gel which collapses on the skin. Examples of such gels which collapse on the skin after application thereof are known in the art, and can for example be formed from crosslinked electrolyte-sensitive hydrogels, such as polyacrylic acid (car-bomer), or ammonium acryloyldimethyltaurate/VP copolymer. The collapse of the gel is typically mediated by the action of salt present on the skin. Such gels are consequently sensitive to the presence of salt in the composition, accordingly the amount of salt in the composition should be kept sufficiently low, so as to not break the gel form. The inventive gel may for example be essentially transparent.

In a preferred embodiment the inventive composition used contains an effective amount of ammonium acryloyldimethyltaurate/VP copolymer forming a gel. In a more preferred em bodiment the inventive composition used contains an effective amount of one or more

carbomers for forming a gel. In order for a collapsible carbomer gel to be formed a num ber of requirements have to be fulfilled. Accordingly, the content of salts in the composi-tion must be very low, and the pH should be above about 4, preferably at least 4.5, and more preferably at least 5. A lower pH and/or higher amounts of salts will prevent the car bomer molecules from forming a suitable transparent gel. A generally preferred range of pH is a value from 5-7, e.g. 5-6.

The hydrolysable ester can be used for stabilising a pH-sensitive gel against undesired increase in the pH value due to the formation of ammonia from hydrolysis of urea. Thus, by means of the hydrolysable ester, an improved stability of a carbomer gel can be ob tained.

In the prior art, a buffer, such as those made of lactic acid or citric acid, is typically used for controlling the pH value of dermal compositions containing urea. By virtue of the presence of a hydrolysable ester, the addition of a buffer, which may typically be provided in the form of a salt, is not required for stabilising the pH in the inventive urea-containing composition. Such buffer salt may otherwise prevent a gel from being formed.

In the prior art, a carboxylic acid may typically be used for controlling the pH value of a dermal composition. By virtue of the hydrolysis of the carboxylic ester used in the present invention, said ester will provide a reservoir of carboxylic acid, and will provide for pro longed sustained release thereof to the composition. Accordingly, a carboxylic acid does not have to be added as such to the composition for lowering the pH of the composition used according to the invention. Thus, salt formation associated with the presence of a substantive amount of added carboxylic acid can be avoided, and also stinging from an added carboxylic acid can be prevented. Preferably, an acid, such as a carboxylic acid, is not added to the inventive composition.

Presence of added acids and buffers in the inventive composition will render the formation of an attractive gel more difficult. Accordingly, when a gel is desired, acids and buffers are preferably not added to the composition used according to the invention.

The inventive composition can be provided for veterinary use, or for human use. For ex-ample, the composition could be used on animals, such as domestic animals or cattle, e.g. dogs, cats, and cows, especially dogs.

For a prolonged or sustained antimicrobial effect, such as an antifungal effect, the in ventive composition may contain an antimicrobial agent that will be deposited on the skin upon application of the composition to the skin. Examples of such antimicrobial agents are quaternary compounds (e.g. cetrimide, benzalkonium chloride), phenols, halogen releasing agents (e.g. iodine and chlorine compounds), aldehydes (e.g. formaldehyde), heavy met als.

Propanediol can also be included in the inventive composition as a humectant, solvent and for antimicrobial purposes, e.g. for antifungal purposes.

In certain embodiments the inventive composition may contain an antifungal agent, such as e.g. piroctone olamine. Piroctone olamine is believed to be especially useful when the composition is targeting dandruff, e.g. on hairy areas such as the scalp and animals.

As known in the art, the acidic carbomer polymer must be neutralised in order to achieve maximum viscosity, and thus to form a gel. The present inventor has found that piroctone olamine can be used to neutralize the acidic carbomer polymer, and for adjusting the pH of the inventive compositions. It is conceived that the alcohol containing composition can also be used on other areas of the skin of the human body where an antimicrobial effect or disinfection is desired, such as for treating bacteria or fungi in facial skin, such in the T-zone, or in the head and neck area.

Niacinamide could be used in the inventive composition to further improve the skin condi tion.

The inventive composition used according to the invention can preferably be formulated as an antimicrobial composition for use in repeated disinfection procedures of human skin, especially hands, on hospitals.

Other types of gels can also be used, such as gels which are not sensitive to salts, such as for example based on cellulosic ether polymers, e.g. hydroxymethyl, hydroxyethyl, and hydroxypropyl cellulose, and carboxymethylcellulose (CMC). However such other gels will generally exhibit less favourable cosmetic properties, and tend to be perceived as sticky on the skin.

The composition used according to the invention is believed to generally improve the re-sistance of the skin, i.e. to irritating substances in bacteria, and in fungi, as well as to de-tergents etc.

Accordingly, when formulated so as to be disinfectant, the inventive composition will be able to kill off bacteria, fungi/yeasts and virus present on the treated skin, and to make the treated skin more resistant to irritant substances released from such microorganisms.

The inventive composition can be applied to a desired portion of the skin, for improving the barrier function in said portion of the skin. The composition is preferably applied in the form of a gel, especially a collapsible gel. The number of applications of an inventive formulation per day is determined by the desired effects from the formulation, where higher frequencies allow lower concentration of urea, and once daily application require higher concentration of urea to obtain similar daily dosage.

According to the invention the composition is preferably used on hands and forearms of the human body, especially when the composition contains 50 % by weight or more of alcohol.

The inventive composition could be provided in a dispenser, e.g. a hand wash or a gel, or as a disposable article, such as a swab, wipe, or rub which is impregnated or soaked with the inventive composition.

The compositions of the alcohol gels with urea should preferably not contain non-volatile compounds (e.g. lipids, oils, carbohydrates) which dilute and counteract the effects of urea and potentially act as nutrients to deleterious microorganisms on the skin.

During the testing, wherein the inventive compositions were applied twice daily, it was noted that the inventive effect may not be discernible until after a number of days of re peated applications of the inventive composition. Accordingly, it may take over a week until the inventive effect is obtained. It is believed that the time until the inventive effect is obtained will be reduced with increasing number of daily applications.

Example

Healthy skin was treated with a simple alcoholic gel with urea, a complex alcoholic gel with urea, or a plain ethanol gel (placebo/control without urea) twice daily for 18 days on one of the volar forearms (randomized), where the other arm served as untreated control. At inclusion and after 8 and 18 days skin barrier function is measured as transepidermal water loss (TEWL). All percentages of the compositions are given by weight unless oth erwise indicated. About 0.4 g was applied to the skin at each time (i.e. 0.8 g per day), to a surface area of about 50-70 cm2.

Example 1 (according to the invention)

The simple alcoholic gel formulation contained 5% urea, 70% ethanol, 0.8 % carbomer and water to 100%, and pH was adjusted to 5-6 using piroctone olamine.

The results from treatment with the above simple gel twice daily shows TEWL in the treated arm to be significantly lower than in the contralateral arm after 18 days. The results are set forth in FIG.1.

In addition, skin susceptibility to the soap sodium lauryl sulphate (SLS, an irritating sur factant) was significantly reduced after treatment with the gel, measured as barrier damage

(increased TEWL) and erythema (redness using a colorimeter) after exposure of the skin to SLS in aluminium chamber attached to the skin for 24 hours, as shown in FIG. 2.

Also visual grading of erythema showed the ethanol-urea treated skin to be less irritated after the soap exposure than the untreated control skin, as can be seen from Table 1 below.

Example 2 (according to the invention)

The complex alcohol gel contained 5 % urea, 70% ethanol, 0.8 % carbomer, 1 % niacina-mide, 4 % propanediol and water, adjusted to pH 5-6.

Also this more complex gel reduced TEWL and made the skin more tolerant to the soap exposure. The results are set forth in FIG. 3.

Example 3 (comparative)

The plain placebo gel contained 70% ethanol, 0.8 % carbomer, and water, pH was adjust-ed to 5-6. This gel was tested on 2 healthy individuals in the same randomised study as the other gels of Examples 1 and 2. The results showed increased TEWL and increased sensi tivity to the soap, supporting the findings that alcohol damages the skin and the improve ment noted from the treatment with ethanol-urea gels were attributed to urea and not the excipients in the gel.

In Table 1 below, visual evaluation of the degree of irritation in the skin exposed to 1% sodium lauryl sulphate after treatment with the simple ethanol-urea gel of Example 1, the more complex urea gel of Example 2, and a comparative plain ethanol-gel is given. The table gives the number of subjects with the defined scores in treated skin and untreated control skin (within parenthesis) and the percent of the summed scores in the treated area compared to the untreated. The p-value denotes the significance level between the gel and the untreated control.

The above-described treatment with the alcohol-gels with urea of the invention in Exam ples 1 and 2 did not show any evidence of drying effects of the skin, measured as skin capacitance (Corneometer 825) at the end of the treatment (i.e. non-statistical significant difference between urea-treated gel and Control skin; p=0.52, and between complex urea- gel and Control skin; p=0.31).

Table 1