WO2012114051A1

WO2012114051A1 - Cutaneous pharmaceutical compositions for the local treatment of canine atopic dermatitis

Info

Publication number: WO2012114051A1
Application number: PCT/FR2012/050392
Authority: WO
Inventors: Jean-Luc Pougnas; Laurie COURIERE; Vincent Beuvry; Olivier Broussaud
Original assignee: Physica Pharma Sas
Priority date: 2011-02-24
Filing date: 2012-02-24
Publication date: 2012-08-30
Also published as: FR2971941B1; EP2678024A1; FR2971941A1

Abstract

The invention relates to a topical pharmaceutical composition which can be administered by applying same to the skin, for the use thereof as a cutaneous veterinary drug for the local treatment of canine atopic dermatitis. The composition contains cyclosporin A as an active ingredient. In a particular embodiment, said composition contains sodium N-cocoyl alaninate.

Description

Pharmaceutical compositions dermal and for the local treatment of atopic canine dermatitis

The present invention relates to pharmaceutical compositions and more particularly to the use of ciclosporin A in a veterinary composition intended for the local treatment of canine atopic dermatitis, also called atopic dermatitis of dogs.

Canine atopic dermatitis (DAC) is a pruriginous, corticosensitive dermatitis, characterized by involvement of the limbs and the face, genetic predisposition and frequent sensitization to environmental factors. It presents the second cause of pruritus after flea infestations, characteristic of flea allergy dermatitis (DAPP), and may affect more than 50% of animals in predisposed breeds.

For a long time, the etiology and pathogenesis of atopic dermatitis (AD) was reduced to the observation of allergy to aeroallergens. If this aspect remains important, we now know that this disease is multifactorial. It is a dermatosis with particularly complex mechanisms, and incompletely known whether in veterinary or human allergology. It results from both intrinsic factors, especially genetic factors, specific to the animal, and extrinsic factors present in the environment, such as aeroallergens or trophallergens.

Canine atopic dermatitis predisposes to sensitization to flea salivary allergens and therefore allergic dermatitis to bites chips (DAPP). It has been shown that four-fifths of dogs with DAPP are atopic and that one-third of atopic dogs develop DAPP. Dogs with exclusive DAPP are rare and atopic dogs are four times more likely to develop DAPP than non-atopic dogs.

Atopic dermatitis also promotes the occurrence of staphylococcal or Malassezia sp. since their adhesion is facilitated on weathered skin. However, it must be distinguished from clinically related dermatoses, such as ectoparasitoses (sarcoptic mange, trombiculosis, demodicosis), allergic dermatitis (DAPP) and others.

The pathogenesis and origin of canine atopic dermatitis are very specific and complex. Numerous factors such as genetic predisposition, immune response abnormality, biochemical abnormality, skin barrier alteration, behavioral disorders, atopenes, fleas, infectious agents, and diet, can cross-mediate and influence the onset and progression of disease.

The treatment of canine atopic dermatitis is delicate and a complete and definitive cure is difficult to obtain. However, a well-controlled treatment can very effectively control the symptoms of canine atopic dermatitis.

It is essential to distinguish two aspects of the treatment of atopic dermatitis, that of thrust and that of the long course. The first aims to control pruritus and infections, the second aims to limit the frequency or severity of attacks of atopic dermatitis. Hygiene, with daily brushing and the use of emollient shampoos can limit the allergenic pressure on the skin surface. Similarly, the control of associated dermatoses including flea infestation and infectious complications, can limit the aggravation of canine atopic dermatitis.

These last two modes make it possible to avoid complications and it is necessary to put them in place before considering treatment of atopic dermatitis. It is also possible to use prediction diets and specific treatments that can lead to desensitization.

Several treatment options for atopic canine dermatitis are described below.

Antihistamines have 20 to 30% effectiveness. They are inexpensive but show varying results.

Essential fatty acids have about 25% efficiency. They allow the improvement of the state of the skin and the hairs but require high doses to obtain variable results and a slow efficiency.

Immunotherapy directly targets the cause of the disease. However, there are few data available on this point and the results obtained are also variable. This therapy requires a good monitoring of the animal and its effectiveness is observed only from 6-12 months.

Topicals such as sprays and shampoos have variable and temporary effectiveness. They reduce allergenic contact with the skin and reduce the itchiness of contact. They lead to temporary and variable local improvement, which is not necessarily practical for homeowners.

Steroids are very effective in dogs. They cause quick relief but often cause many side effects. Moreover, their effectiveness decreases over time.

Until recently, the most effective treatment was based on the administration of oral corticosteroids.

However, in view of the possible side effects of these, administration of ciclosporin A has now become a possible alternative and the use of ciclosporin A orally as an alternative to corticosteroids for the treatment of atopic dermatitis canine is more and more used.

At present, in the veterinary field, the only drug with marketing authorization is ATOPICA®, marketed by the Swiss company Novartis Animal Health. This ciclosporin A drug is administered orally at a dose of 5 mg / kg once daily until satisfactory clinical improvement is achieved.

From a chemical point of view, ciclosporin A is a macromolecular cyclic peptide compound composed of 11 amino acids. This molecule has a broad spectrum of useful pharmacological activities including immunosuppressive and anti-inflammatory activity. Cyclosporine A is highly lipophilic and hydrophobic which makes it poorly soluble in water. Much work has been done to increase the uptake of ciclosporin after oral administration, which is the primary route of administration for transplant rejection in transplant patients. Thus, a series of patents, issued from a priority GB 2 257 359 dating from 1991, including 2 initial patent applications FR 2 678 169 and EP 539319 gave rise to two divisional applications having the same priority, FR 2,685,706 and EP 953630. These initial patents FR 2,678,169 and EP 539319 disclose ciclosporin pharmaceutical compositions using a vehicle comprising 1,2-propylene glycol, a mixture of mono-, di- and triglycerides and a hydrophilic surfactant. . These patents specify that this composition is in microemulsion form and makes it possible to increase the bioavailability of ciclosporin A during oral administration. Another series of patents, FR 2 685 706 and EP 953630 more particularly describes compositions comprising a trans-esterification product of corn oil and glycerol in order to improve the stability of the composition, to increase its bioavailability during oral administration and to reduce variability in intra- and inter-individual bioavailability.

Thus, the aforementioned patents describe compositions based on solvents and surfactants. The components of the hydrophilic phase are essentially the products marketed under the tradenames Transcutol® (2- (2-ethoxyethoxy) ethanol) and Glycofurol® as well as 1,2-propyleneglycol. The preferred components for the lipophilic phase are medium chain fatty acid triglycerides marketed under the trade names Miglyol® (caprylic / capric triglyceride), Captex® (propylene glycol dicaprate), Myritol® (caprylic / capric triglyceride), Capmul® ( Glyceryl caprilate), Neobee® (caprylic / capric triglyceride) and Mazol® (glycerol ester). Suitable surfactants are in particular the reaction products of ethylene glycol with natural or hydrogenated vegetable oils such as those sold under the trade names Cremophor® RH40 (Polyoxyl 40 Hydrogenated Castor Oil) and Nikkol® (PEG 40 Castor Oil Hydrogenated). It will be appreciated by those skilled in the art that the inventions described above specifically target the improvement of the oral solubility of ciclosporin.

Moreover, patent FR 2,636,534 issued from a British priority of 1989 also describes ciclosporin compositions in microemulsion form for oral administration for the treatment of atopic dermatitis. Topical application is discussed with an in-vivo preclinical skin allergic contact dermatitis reduction test in guinea pigs. However, the use of these compositions in the dog as part of a local treatment of atopic dermatitis (and not allergic contact dermatitis) is in no way mentioned, nor suggested.

Those skilled in the art find that all the patents described above are focused on improving the oral bioavailability of ciclosporin, this being explained by the fact that the first indication of this therapeutic agent concerns the prevention of transplant rejection. in humans. In order to improve the comfort of the transplanted subjects, those skilled in the art have therefore sought first and foremost to improve the bioavailability of ciclosporin following oral administration, with a view to avoiding the use of injection injections. ciclosporin which are often painful and poorly tolerated by patients. Sandimmun® marketed by the Swiss company Novartis is an injectable form based ciclosporin A (50 mg / ml) indicated during organ transplantation. The product is administered by infusion at 3 to 5 mg / kg per day immediately after transplantation for 2 weeks before switching to higher doses. low. Its administration must be followed closely to detect any side effects at the earliest.

Thus, several compositions comprising ciclosporin A in organic solutions based on solvents and intended for oral use have been developed and described in the aforementioned patents.

Although these inventions have made it possible to use ciclosporin A orally by improving its bioavailability, they do not, however, make it possible to offer a therapeutic of choice for the treatment of cutaneous conditions such as atopic dermatitis of dogs (also called atopic canine dermatitis). Indeed, the compositions disclosed in the patents mentioned above contain significant amounts of solvents and surfactants which can induce local irritation and significant side effects which are likely to aggravate skin lesions present in clinical cases of atopic dermatitis such as pruritus, erythema, excoriation, lichenification and hypermelanosis.

Thus, the said inventions were developed with the aim of improving the oral bioavailability of ciclosporin A and thus enabling a greater action by the systemic route. However, it is also known to those skilled in the art that ciclosporin A has numerous general side effects which are notably related to the systemic resorption thereof, the most marked side effect being a very significant renal toxicity. which requires strict biological monitoring of the treatment. Consequently, if the compositions described above actually make it possible to improve the Oral bioavailability of ciclosporin A, they also have the disadvantage of exposing patients to a general toxicity of the product.

However, the use of a therapy that respects the cutaneous balance and limits the systemic resorption of ciclosporin A after local application is particularly important in the eyes of the applicant for the treatment of dermatological conditions such as atopic dermatitis of the dog, particularly because this condition particularly weakens the skin of the animal by causing pruritus and appearance of redness on various body locations. The most frequently affected areas are located on the face and / or fingers and / or large folds. Over time, pigmentation and thickening of the skin may appear as diffuse or local erythema and itching may be more or less severe. Subsequently, in the absence of treatment, the lesions become more extensive and secondary to pruritus with the appearance of alopecia, lichenification, excoriations and hypermelanosis. The adhesion of infectious agent being facilitated on damaged skin, atopic dermatitis favors the appearance of staphylococcal infections or Malassezia sp .. The pyodermites are accompanied by papules, pustules, erythema, lichenification and squamosis. They can be localized to interdigital spaces, external auditory ducts, lips, fold of the face and inguinal region, or generalized. In addition, canine atopic dermatitis predisposes to sensitization to flea salivary allergens and therefore to allergic dermatitis flea bite (DAPP) which also causes a weakening of the skin, with a location of very different lesions.

As mentioned previously, ciclosporin A is highly lipophilic and hydrophobic which makes it poorly soluble in water. Because of its structure and physicochemical properties, ciclosporin A not penetrate the skin (Stratum corneum). Therefore, it was generally accepted that it was not possible to administer ciclosporin A topically, mainly because this molecule had a very low solubility in water which did not allow for to obtain a sufficient concentration in active.

Surprisingly, and against all the existing prejudices, the Applicant has succeeded in developing topical compositions based on ciclosporin A allowing a safe treatment by the local route of atopic dermatitis lesions in dogs.

An object of the present invention is therefore a topically administrable, skin-administering pharmaceutical composition comprising ciclosporin A for use as a veterinary medicament administrable by cutaneous application in the local treatment of canine atopic dermatitis.

In other words, the invention relates to the use of said pharmaceutical composition for preparing a topical veterinary drug, administrable cutaneously, to treat canine atopic dermatitis.

Preferably, said composition is an aqueous composition.

Another object of the present invention relates to a method for treating canine atopic dermatitis, by administering to a dog affected by this pathology a composition according to the invention comprising ciclosporin A topically (cutaneous application).

More specifically, in the course of her research, the Applicant has surprisingly discovered that compositions dermal-acting pharmaceutical compositions comprising ciclosporin A and at least one salt of a condensation product of glycine or alanine with at least one fatty acid included in the coconut oil were of interest. particularly to solve the problems developed while ensuring stability compatible with a pharmaceutical (veterinary) use of the product.

For the purposes of the present invention, the term "pharmaceutical composition with local action" is intended to mean a composition intended to act locally on the skin (topical action).

Preferably, said composition is an aqueous pharmaceutical composition, ie wherein the water is at least 20% by weight of the excipient.

"Cutaneous application" means an application of the therapeutic agent to all or part of the skin of a patient.

If it is known to those skilled in the art that certain N-acyl amino acids may be used in "anti-aging" cosmetic compositions, cf. PCT applications WO 2010/026325 and WO 2010/023390, which disclose regulatory properties of these compounds with respect to certain cells of the skin in order to obtain the desired cosmetic effects, whereas the state of the art does not disclose, nor suggest, the use of a condensation product between a given amino acid and at least one fatty acid included in the coconut oil in order to increase the aqueous solubility of poorly soluble therapeutic agents in water, while respecting the previously developed issues. The international application WO 02/076506 discloses dispersed systems for pharmaceutical use comprising at least one active principle, at least one lipoamino acid consisting of the combination of a fatty acid and an amino acid as intestinal absorption promoters or pulmonary, depending on whether the dispersed system is respectively in a dosage form suitable for oral administration or in a dosage form suitable for administration to the lungs.

In addition, these dispersed systems are systemically acting and in no case locally acting (see WO 02/076506, page 3, lines 21-24 and Example 4, the latter relating to a transdermal dispersed system, that is, ie a dispersed system allowing to cross the skin and spread it throughout the body for therapeutic purposes).

In addition, Examples 1 to 8 relate to dispersed systems including surfactants (such as PEG30

polyhydroxystearate) and solvents (such as propylene glycol or its derivatives), as well as lipophilic compounds (such as soybean oil or oleic acid), and this in significant proportions (on average, the total of these compounds exceeds 50% of the weight of the composition). However, the use of such compounds in such proportions can not be compatible with administration by cutaneous application because of the anticipated adverse effects of inflammatory or allergic nature that they induce such as redness, irritation, edema, etc.. Thereby ; the use of such systems can not be envisaged for a local action by dermal application.

The international application WO 03/055528, also in the name of the Applicant, is limited to describing, in general,

ion complexes derived directly from the combination of a acylamino acid and a biologically active molecule for better absorption and systemic effect. This application

International does not disclose a composition in any way

topical pharmaceutical, administrable by cutaneous application, within the meaning of the present invention. This document is therefore also part of the technological background.

Preferably, the pharmaceutical composition according to the invention is a composition (preferably aqueous) comprising: at least one salt of a condensation product of an amino acid of general formula (I)

NH ₂ -CH-COOH

R

(I)

and at least one fatty acid included in the coconut oil; in which R represents a hydrogen atom (R = H) or a methyl group (R = CH3).

The condensation product of an amino acid of general formula (I) with at least one fatty acid included in coconut oil can be defined as an N-Acyl amino acid (in this case N-Acyl glycine or N -Acyl alanine), that is to say a product resulting from the condensation of the amine function carried by the aforementioned amino acid (respectively glycine or alanine) with the carboxylic acid function carried by one or more of the fatty acids included in coconut oil. The condensation product of an amino acid of general formula (I) with coconut oil, that is to say with all the fatty acids constituting coconut oil in their respective proportion, can be defined as a N-cocoyl amino acid (in this case N-cocoyl glycine or N-cocoyl alanine).

The coconut oil generally contains a mixture of fatty acids whose length of the carbon chain can be between 6 and 18 carbon atoms (mixture of fatty acids in Ce - Cis).

The invention therefore also relates to any topical pharmaceutical composition, administrable by cutaneous application, comprising at least one N-acyl component Ce-Cis amino acid, the "acyl" part consisting of a fatty chain present in coconut oil. . By way of example, the naturally occurring fatty acids in coconut oil are generally caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, coconut palmitoleic acid, stearic acid, oleic acid, linoleic acid and linolenic acid. Preferably, the acyl part will exclusively consist of the fatty chain of lauric, myristic, caprylic or capric acid.

According to a particularly preferred embodiment of the invention, the above-mentioned condensation product (also referred to as N-acyl amino acid) is N-cocoyl alanine which consists of the mixture, in particular, of N-lauroyl alanine, N-myristoyl alanine, N -capryl alanine and N-capryloyl alanine according to the proportions of fatty acid derivatives

usually in coconut oil. Without being limited by theory, it appears that the mixture of different N-acyl alanine constituting N-Cocoyl Alanine in the proportions of fatty acid derivatives usually found in coconut oil makes it possible to obtain pharmaceutical compositions (Veterinary) according to the present invention having excellent properties in terms of solubilization of the active and stability.

According to a particular embodiment, the above-mentioned condensation product is N-Lauroyl Alanine.

Preferably, the composition according to the invention comprises an aqueous vehicle representing 20% or more of the weight of the excipient of said composition, preferably more than 60% of the weight of the excipient and advantageously more than 75% by weight. of the excipient of said composition.

Said condensation product is used in a salified form. This salified form is soluble in water and can easily be obtained using an organic amine base such as monoethylamine, diethylamine or an inorganic base such as sodium hydroxide or hydroxide of potassium.

It is important to note that this (soluble) salt of said condensation product is not complexed with ciclosporin A.

In addition, one of the major advantages associated with the compositions

According to the invention, the latter are stable and do not precipitate when placed under usual stability conditions.

In a particularly advantageous manner, the composition according to the invention does not comprise irritating agents, such as surfactants and organic solvents or cosolvents, which represents a significant advantage insofar as the skin of the dog to be treated is , in good standing general, particularly sensitive and already has inflammations and / or irritations.

According to a particularly preferred embodiment, R represents a methyl group (R = CH 3) in the general formula (I). In other words, the amino acid of general formula (I) is alanine, this particular derivative allowing, surprisingly, to obtain compositions which have excellent skin tolerance as well as sufficient stability. This allows to consider the use of these compositions for the cutaneous application of one or more drugs.

As indicated in Example 2 (see below), a stability study demonstrated that the cocoyl alanine salt pharmaceutical composition of Example 1 was able to administer a drug topically. for cutaneous applications, in particular for cutaneous applications aimed at treating canine atopic dermatitis (DAC).

As a comparative example, compositions according to Example 1 were prepared using a different amino acid: valine. The

The compositions of Example 1 were therefore prepared using cocoyl valine in the form of sodium salt. The compositions obtained revealed significant instability (see Example 3 infra), rendering their use as a medicament, and in particular as a veterinary medicinal product, unsuitable.

The process for obtaining the composition according to the invention comprises the following steps: at. Introduction of a volume of water representing between 50% and 90%, and preferably close to 75%, of the total weight of the water of the composition obtained in fine in a container equipped with a stirrer;

b. Adding a desired amount of said salt from the product of

condensation until complete solubilization with slight heating of the solution if necessary;

vs. Addition of the therapeutic agent with moderate agitation at a suitable temperature generally between 25 ° C and 50 ° C;

d. Cooling of the solution formed with stirring;

e. Addition of a desired amount of water to obtain a

duly dosed solution in therapeutic agent

By "light heating" is meant heating at a temperature between 30 ° C and 70 ° C.

Preferably, the salt of the condensation product is added in an amount of between 1% and 25% of the final weight of the product,

preferably in an amount of between 5% and 15% of the final weight of the product, preferably in an amount equivalent to about 10% of the final weight of the product and wherein the therapeutic agent is added in an amount of between 1% and 10% the final weight of the product, preferably in an amount between 4% and 8% of the final weight of the product, preferably in an amount equivalent to about 5% of the final weight of the product.

According to the invention it is also possible to prepare a solution of cocoyl sodium alaninate from the mixture with stirring of a solution of sodium hydroxide and cocoyl alanine in suitable amounts.

The examples below will make it possible to better understand the present invention. However, these examples are for illustrative purposes only and should in no way be construed as limiting the scope of the invention in any way.

Example 1 Preparation of a Formula Containing More than 70% of Aqueous Phase

The process for obtaining this composition is as follows:

A solution of N-Cocoyl Alaninate is prepared in a volume of water representing 90% of the total amount of water until complete solubilization. The pH of this solution is then adjusted to a pH of about 7.8 while the heating is stopped. Once the solution is clear, ciclosporin A is added and the final volume adjustment is done with water. A clear and colorless final solution is thus obtained with a pH in the region of 7.8.

Example 2: stability of the composition A stability study according to pharmaceutical standards was conducted on the composition described in Example No. 1 to verify that it can be compatible with use as a drug.

The protocol used was to place the samples obtained in Example No. 1 under the conditions of temperature and residual humidity recommended by the European Pharmacopoeia (25 ° C / 60% Residual Moisture) for a period of 12 months.

It is important to note that the product is placed in bottles equipped with dosing pumps to deliver a precise dose of product, this packaging being adapted to the pharmaceutical use of the product and its application on the skin.

The results are recorded in the table below.

The results presented above show that no change in the appearance of the product and no appearance of precipitate occurs during a period of 12 months following the manufacture of the product on samples placed under the conditions indicated above. The product can therefore be used as a medicine and distributed in a suitable packaging such as a bottle provided with a dosing pump to ensure reproducible delivery of the dose to be administered.

Example 3 Comparative Study with Cocoyl Valinate Sodium

As a comparative example, there is prepared a composition defined as follows which contains a condensation derivative of coconut oil with valine:

Ciclosporin A 3g

Cocoyl Sodium Valinate 15g

Demineralized water qs 100 mL (about 82g)

The process for preparing the solution is that described in Example 1.

The final pH of the composition defined above is close to 7.

The formed composition is translucent immediately after manufacture but is not stable over time. Thus, a stability study revealed that the solution formed shows white precipitates after two months of stability and a corresponding decrease in the titre of the

ciclosporin revealing instability and inability to use as a veterinary medicinal product.

Example 4: efficacy study in dogs with atopic dermatitis

The present invention has been used in the context of a treatment trial for atopic dermatitis in dogs. The product of Example 1 was applied daily to dogs with canine atopic dermatitis.

Efficacy was assessed 28 days after the first administration using a LICAD and PICAD score system.

LICAD is a scoring system that has been set up to evaluate erythema, excoriation and lichenification.

PICAD is another scoring system for the assessment of pruritus.

Four animals were treated and observed for 28 days.

The results are recorded in the tables below.

The results presented above show that all the clinical cases studied showed an improvement of the clinical signs (erythema, excoriation, lichenification and pruritus) after 28 days of daily skin treatment.

The effectiveness of the composition described in Example 1 was demonstrated in this preliminary test for the treatment of canine atopic dermatitis after daily topical application for 28 days.

In addition, no local or general significant side effects are observed during treatment.

The composition described according to the invention may comprise, as excipients (in addition to water), various ingredients which may especially promote the application of the product, enhance its effectiveness, improve stability, facilitate dispensing or dosage, limit or on the contrary, depending on the case, facilitate evaporation. By way of illustration (this list being in no way limiting or exhaustive) mention may be made of viscosity or texturing agents such as polymers of natural origin (for example derived from cellulose) or synthetic polymers (for example acrylic polymers) intended for prolonged contact with the skin, pH-stabilizing agents such as inorganic or organic acid salts and their conjugate bases, agents

skin-moisturizing agents such as urea, humectants or emollients such as glycerin, antimicrobial preservatives such as benzoic acid or sorbic acid derivatives and their salts, agents to prevent the product of a possible oxidation such as sulfites and their derivatives, agents to reduce or otherwise promote the evaporation of the product after its application such as volatile compounds, as well as agents to ensure a protective role of the skin such as fat derivatives, etc. Moreover, the composition according to the invention can in particular be applied using a suitable multi-dose delivery system such as a bottle provided with a metering pump in order to deliver a reproducible dose of said product.

Another presentation may consist of a single-dose packaging optionally having an applicator tip.

Alternatively, the composition may also be administered from a system that can be applied to the skin over a prolonged period such as a patch to provide extended residence time at the application site.

Claims

claims

1. A topically administrable, cutaneous administrable pharmaceutical composition comprising ciclosporin A for use as a veterinary drug for topical application in the topical treatment of canine atopic dermatitis.

2. Pharmaceutical composition according to claim 1, said composition being an aqueous composition.

3. The pharmaceutical composition according to claim 1 or 2, said composition comprising: at least one salt of a condensation product of an amino acid of general formula (I)

NH _r CH-COOH

R

(I)

and at least one fatty acid included in the coconut oil; in which R represents a hydrogen atom or a methyl group.

The pharmaceutical composition of claim 3 wherein R is methyl.

5. Composition according to one of claims 1 to 4, said composition comprising an aqueous vehicle representing 20% or more of the weight of the excipient of said composition, preferably more than 60% of the weight of the excipient and advantageously more than 75% of the weight of the excipient of said composition.

6. Composition according to one of claims 1 to 5, wherein the salt of said condensation product is an organic or inorganic cation salt.

The composition of claim 6, wherein the salt of said condensation product is an inorganic cation salt, preferably a sodium salt.

8. Composition according to one of claims 1 to 7, said composition does not comprise irritants, such as surfactants and organic solvents or cosolvents.

9. Composition according to one of claims 1 to 8, said

composition being administrable via an applicator device selected from multi-dose delivery devices such as a bottle provided with a metering pump, the single-dose delivery devices,

preferably having an applicator tip, and devices for prolonged application to the skin such as a patch.