WO2014049300A1

WO2014049300A1 - Topical use of laropiprant for the treatment of rosacea

Info

Publication number: WO2014049300A1
Application number: PCT/FR2013/052324
Authority: WO
Inventors: Carine Rosignoli; Jérôme AUBERT; Jean-François Fournier
Original assignee: Galderma Research & Development
Priority date: 2012-09-28
Filing date: 2013-09-30
Publication date: 2014-04-03
Also published as: FR3000399B1; FR3000399A1

Abstract

The invention relates to a topical pharmaceutical composition, in particular a dermatological composition, comprising laropiprant, an ester or a pharmaceutically acceptable salt thereof, and to the use of same for the treatment of dermatological conditions, in particular rosacea.

Description

TOPICAL USE OF LAROPIPRANT FOR THE TREATMENT OF

ROSACEA

The invention relates to a topical pharmaceutical composition, especially dermatological, and its use for the prevention or treatment of skin conditions, including rosacea.

Rosacea is a chronic inflammatory dermatosis affecting mainly the middle part of the face and the eyelids of some adults. It is characterized by telangiectatic erythema, dry skin, papules and pustules.

Classically, rosacea develops in adults between the ages of 30 to 50 years; it affects women more frequently, although the condition is usually more severe in men. Rosacea is chronic and persists for years with periods of exacerbation and remission.

Rosacea, formerly known as "rosacea", is not a condition of the pilosebaceous follicle, such as juvenile acne, but a primarily vascular condition whose inflammatory stage is devoid of cysts and comedones characteristic of acne. vulgar.

The etiology of rosacea is still poorly understood, although many theories have been developed. The most common thesis is based on the characteristic presence of the parasite Demodex folliculorum in patients with rosacea. Other factors have been described as contributing to the development of rosacea, such as psychological factors, environmental (sun exposure, temperature, humidity), immunological, emotional (stress), food (alcohol, spices), hormonal, vascular , gastrointestinal disorders, or even infection with Helicobacter pillori.

Rosacea can be classified as follows:

- Type I: Erythematotelangiectatic rosacea, mainly characterized by persistent centrofacial erythema and episodic redness. Often this type is also characterized by swelling, rough patches and the appearance of red blood vessels as well as burning and stinging sensations.

- Type II: Papulopustular rosacea, characterized by persistent centrofacial erythema and the appearance of transient centrofacial papules or pustules, similar to those of acne. These symptoms are sometimes accompanied by burning and stinging sensations. This type usually follows type I or combines with it.

- Type II I: Phymatous rosacea marked by the thickening of the skin and the appearance of irregular nodules. Although the nose is often the most affected area; becoming very large and covered with blisters ("rhinophyma"), other localizations are also observed: chin, forehead, cheeks and ears This type usually follows type I and I I or combines with them.

- Type IV: Ocular rosacea. In this type of rosacea, red and irritated eyes can tear and look bloodshot. Symptoms may include the sensation of having a foreign body in the eye, excessive tearing, sensitivity to light, blurred vision, burning, dryness, prickliness, pruritus and alacromy. They can occur with or without rosacea. The occurrence can occur before, during or after the appearance of the cutaneous signs.

Classically, rosacea is treated orally or topically with antibiotics such as tetracyclines, erythromycin, clindamycin, but also with vitamin A, salicylic acid, antifungal agents, steroids, metronidazole (an antibacterial agent) or by isotretinoin in severe forms or by anti-infectives such as benzoyl peroxide or azelaic acid. Also known is the treatment of rosacea with ivermectin which targets the parasite Demodex folliculorum present on the skin of patients (US

5952372). New oral therapies are also being studied, particularly a phase 2 study (http://www.clinicaltrial.gov - A Study of Laropiprant (MK-0524) in Participants With Moderate to Severe Erythematotelangiectatic Rosacea (MK- 0524-155 AM1)).

These various treatments for rosacea have unpleasant side effects for the patient, such as irritation or intolerance. In addition, none of the existing treatments can effectively treat and / or prevent all symptoms associated with rosacea.

Taking into account the above, there is therefore a need for a topical treatment of rosacea which would avoid too much systemic exposure such as exposures observed during oral administrations, while maintaining an effective level of activity. The Applicant proposes to use laropiprant topically, preferably at a dose of between 0.0001% and 5%, relative to the total weight of the composition, and thus to provide a more effective treatment of diseases, especially dermatological, and especially rosacea, with potentially fewer side effects regardless of the duration of application. In particular, such a pharmaceutical composition makes it possible to appreciably reduce the duration of the treatment and to obtain a greater reduction in the symptoms of rosacea. This pharmaceutical composition can make it possible to maintain the same therapeutic effect while reducing the doses.

Laropiprant or MK0524 (MERCK & Co) is [(3R) -4- (4-chlorobenzyl) -7-fluoro-5- (methylsulfonyl) -1,2,3,4-tetrahydrocyclopenta [b] indol- 3-yl] acetic formula is shown below:

Laropiprant has mainly been described to date for oral use. Pharmacokinetic studies show that laropiprant is highly bound to plasma proteins in the body (Karanam et al, Drug Metab Dispos 2007 Jul, 35 (7): 1,196-202). Laropiprant is now marketed in combination with nicotinic acid (or niacin) for the treatment of mixed or combination dyslipidemia, or primary hypercholesterolaemia (Tredaptive® or Cordaptive®). The combination of nicotinic acid delayed release with laropiprant will inhibit the mechanism responsible for flushing, a result of intense local skin vasodilation, observed in most patients treated with nicotinic acid. Various genetic and pharmacological studies in animal models have demonstrated the mechanism of action underlying this local vasodilatation (Cheng et al, PNAS 2006, Apr 25; 103 (17): 6682-7). In the Langerhans cells of the epidermis (cutaneous immunomodulatory cells), nicotinic acid binds to its specific receptor, activating a G protein dependent signaling pathway leading to the appearance of D ₂ prostaglandins (PGD ₂ ). Two prostaglandin PGD ₂ receptors are known today: the type 1 receptor, or DP1, and the type 2 receptor, called DP2, sometimes called CRTH2. The PGD ₂ thus released by the Langerhans cells then diffuses into the dermis to reach the thermal arterioles. There, it binds to the DP1 receiver of arteriolar smooth muscle cells thus producing vasodilatation, and thus the skin flush and the hot flash sensation that accompanies it. Laropiprant, a potent, reversible and selective antagonist of DP1 receptors (Sturino et al., 2007, J Med Chem Feb. 22; 50 (4): 794-806), has been shown to be effective in reducing vasomotor symptoms induced by nicotinic acid.

Without being bound by theory, the applicant believes that the efficacy of laropiprant in the prevention and / or treatment of rosacea could be explained by the involvement of PGD ₂ in the flush and / or erythema of rosacea, subtype I or II. Indeed, it appears that the synthesis of PGD ₂ is increased in the skin of patients suffering from rosacea, in particular type I or II. This phenomenon could be regulated by laropiprant. This laropirant effect is very advantageous for the prevention and / or treatment of rosacea, in particular of subtype I or II.

Similarly, as described in the following references, many other skin conditions can be treated or prevented such as pruritus (J Invest Dermatol 2010 Oct; 130 (10): 2448-56 Induction of prostaglandin D2 Kaur S), melanoma (J Immunol 2008 Jan 15; 180 (2): 783-92.) Prostaglandin D2 inhibits the production of IFN-gamma by invariant NK T cells: consequences in the control of B16 melanoma, Torres D), atopic dermatitis or disorders of the cutaneous barrier (Eur J Pharmacol 2007 Feb 5, 556 (1-3): 207-14, Epub 2006 Nov 3. Effects of TS-022, a newly developed prostanoid DP1 receptor agonist, on experimental pruritus, cutaneous barrier disruptions and atopic dermatitis in mice, Arai I), cutaneous allergies (J Immunol 2004 Mar 15; 172 (6): 3822-9 Activation of the D Prostanoid Receptor 1 Regulates Immune and Skin Allergy Responses; Ang eli V), skin disorders associated with epidermal proliferations (Mol Carcinog. 2001 Jun; 31 (2): 90-100. Deregulated expression of DP1 induces epidermal proliferation and enhances skin carcinogenesis; Wang D), the disorders may also include actinic keratosis, psoriasis and disorders related to healing The plaintiff thus surprisingly found that the topical administration of a pharmaceutical composition, especially dermatological, characterized in that the concentration in laropiprant, its ester or its pharmaceutically acceptable salt, is between 0.0001% and 5%, preferably between 0.003% and 3% and more preferably between 0.01% and 3% by weight relative to the total weight of the composition , by weight, relative to the total weight of the composition is capable of treating or preventing rosacea. The invention relates to the use of laropiprant or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition, and especially a dermatological composition, intended for the prevention and / or treatment of a condition of the disease. skin, preferably for the prevention and / or treatment of rosacea, and in particular rosacea of subtype I or I I.

In one embodiment, the term "treatment" or "treating" refers to an improvement, prophylaxis, or reversal of a disease or disorder, or at least one discernible symptom thereof. . In another embodiment, "treatment" or "treating" means an improvement, prophylaxis, or reversal of at least one measurable physical parameter associated with the disease or disorder being treated, which is not necessarily discernible. at or by the subject treated. In another additional embodiment, "treatment" or "treating" refers to the inhibition or slowing down of the progression of a disease or disorder, physically, for example, the stabilization of a discernible symptom, physiologically, for example , the stabilization of a physical parameter, or both. In another embodiment, "treatment" or "treating" means delaying the onset of a disease or disorder.

In some embodiments, compounds of interest are administered as a preventive measure. In the present context, "prevention" or "prevention" means a reduction in the risk of acquiring a specified disease or disorder.

For the purposes of the present invention, the term "patient" means any mammal, and more particularly human beings, men or women. Dermatological conditions are particularly understood to mean skin and eye disorders. As a non-limiting example, rosacea and even more preferably rosacea of subtype I and II may be mentioned.

The actually administered amount of laropiprant or a pharmaceutically acceptable salt thereof and optionally other active ingredients or additives to be used according to the invention depends on the desired therapeutic or cosmetic effect, and can therefore vary in a large extent. Those skilled in the art, in particular the physician can easily, on the basis of his general knowledge determine the appropriate amounts. Thus, and according to a preferred embodiment, the pharmaceutical composition (s) are (are) administered once or twice a day. Preferably, the treatment may have a duration ranging from 1 week to 3 months, preferably from 2 weeks to 1 month. In the compositions according to the invention, the dose The daily dose of laropiprant or a pharmaceutically acceptable salt thereof is 1 mg to 1 g, preferably 10 mg to 500 mg, more preferably 50 mg to 150 mg.

The courses can be renewed in cycle with or without rest period.

In a particular embodiment, the subject of the invention is the use of a topical composition, especially a dermatological composition, characterized in that the pharmaceutical concentration of laropiprant or its pharmaceutically acceptable salt thereof is between 0.001 and 5. or 6% by weight, preferably between 0.003 and 5 or 6% by weight, preferably from 0.003 to 3%, relative to the total weight of the composition.

In a more particular embodiment, the subject of the invention is the use of a topical composition, in particular a dermatological composition, characterized in that the laropiprant pharmaceutical concentration or its pharmaceutically acceptable salt thereof is between 0.01. and 3% by weight, based on the total weight of the composition.

In a particularly preferred manner, the composition comprises laropiprant present in a concentration of between 0.5% and 3% by weight, relative to the total weight of the composition comprising it.

It is also contemplated a pharmaceutical composition, especially dermatological, characterized in that it comprises laropiprant, an ester or a pharmaceutically acceptable salt thereof and further comprising at least one additional active ingredient or an additive.

The additional active ingredient is preferably selected from the group comprising antibiotics, antibacterial agents, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergics, retinoids, anti-free radicals, antipruritic drugs, keratolytics, antiseborrhoeics, antihistamines, sulfides, immunosuppressive or antiproliferative products, corticosteroids, intravenous immunoglobulins, antiangiogenic agents, anti-inflammatories and / or a mixture thereof. The additive is preferably selected from the group consisting of normal, mineral or organic sequestering, chelating agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, dyes, bases or acids, perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, soothing and protective agents for the skin, penetrating agents, emulsifiers, gelling agents and a mixture of these.

The invention also relates to a topical pharmaceutical composition, characterized in that it comprises laropiprant, an ester or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a dermatological condition , preferably rosacea.

The invention also relates to the topical use of laropiprant or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and / or treatment of a skin condition such as dermatitis, contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, eczema, phytodermatitis, radiodermatitis, stasis dermatitis, psoriasis, chronic lichen simplex, scleroderma, ulcers and erosions resulting from trauma, burns, bullous disorders or ischemia of the skin or mucous membranes; different forms of ichthyosis, epidermolysis bullosa, hypertrophic scars, keloids; cutaneous changes in intrinsic aging, photoaging; vascular tumors such as angiomas; the formation of frictional blisters caused by mechanical shearing of the skin and cutaneous atrophy resulting from the topical use of corticosteroids, inflammation of the mucous membranes, such as cheilitis, chapped lips, nasal irritation, inflammation of the mucous membranes and vulvo -vaginite; disorders of hair follicles and sebaceous glands, such as acne; rosacea and rhinophyma, erythema, rash, skin tumors, bruising, perioral dermatitis, and folliculitis barbae and inflammatory reactions, such as drug eruptions, erythema multiforme, erythema nodosum , and ring granuloma

The invention further relates to the topical use of laropiprant or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and / or treatment of a skin condition, preferably rosacea. More particularly, the dermatological condition is rosacea and more particularly rosacea of subtype I and I I. The present invention also relates to a method for the treatment and / or prevention of dermatological conditions, more particularly to the treatment and / or prevention of rosacea, and more particularly for the treatment and / or prevention of rosacea of subtype I or II, said method comprising the topical administration of a pharmaceutical composition comprising a therapeutically effective amount of laropiprant, an ester or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method for the treatment and / or prevention of dermatological conditions, more particularly for the treatment and / or prevention of rosacea, and more particularly for the treatment and / or prevention rosacea of subtype I or II, said method comprising administering a topical pharmaceutical composition comprising a therapeutically effective amount of laropiprant, an ester or a pharmaceutically acceptable salt thereof.

The term "pharmaceutically acceptable salt (s)" as used herein refers to the salts of a compound of interest, preferably for topical use in mammals, and which possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds. The pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, hydrochloride, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate salts. , bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e., 1, 1 '- methylene -bis- (2-hydroxy-3-naphthoate)). Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review of pharmaceutically acceptable salts, see Berge et al. (J Pharm Sci 1977 Jan; 66 (1): 1-19). The compositions of the invention further comprise a pharmaceutically or cosmetically acceptable vehicle, i.e. a vehicle adapted for use in contact with human cells, without toxicity, intolerance, irritation, undue allergic response and the like, and proportionate to a reasonable benefit / risk ratio.

It is also included in the invention, the administration of laropiprant prodrug form. By "prodrug" is meant in the present invention a compound which is converted to the corresponding active ingredient, for example laropiprant, when administered in vivo, or which has the same activity on its own. In particular, mention may be made of hydrolysable derivatives, such as the esters of the active compounds or the compounds in which the amino groups and / or alcohols are protected by one or more protective groups well known to those skilled in the art. The compositions of the invention may further comprise at least one other active ingredient capable of increasing the effectiveness of the treatment. By active ingredient is meant any agent, therapeutic or otherwise, capable of preventing and controlling rosacea. Examples of preservatives that may be mentioned include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea, parabens or mixtures thereof.

As humectants, mention may in particular be made of glycerine and sorbitol.

As chelating agents, mention may be made, for example, of ethylenediaminetetraacetic acid (EDTA), as well as its derivatives or its salts, dihydroxyethylglycine, citric acid, tartaric acid or their mixtures.

As propenetrating agents, mention may in particular be made of propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol and ethoxydiglycol.

As fats which may be used in the invention, mention may be made in a nonlimiting manner of oils, and in particular mineral oils (liquid petroleum jelly), oils of vegetable origin (avocado oil, soya oil), animal origin (lanolin), synthetic oils (perhydrosqualene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers). It is also possible to use fatty alcohols such as cetyl alcohol, fatty acids, waxes and gums, in particular silicone gums, as fatty substances. As emulsifiers and coemulsifiers that can be used in the invention, mention may be made, for example, of fatty acid and polyethylene glycol esters such as PEG-100 stearate, PEG-50 stearate and PEG-40 stearate; fatty acid esters of polyol such as glyceryl stearate, sorbitan tristearate and oxyethylenated sorbitan stearates available under the trade names Tween

20 or Tween 60, for example; and their mixtures.

As gelling agents, by way of non-limiting examples, mention may be made of the family of polyacrylamides, such as the mixture Sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 sold under the name Simulgel ™ 600 by the company

Seppic ™, the polyacrylamide / isoparaffin C13-14 / laureth-7 mixture, for example that sold under the name Sepigel 305 ™ by the company Seppic ™, the family of acrylic polymers coupled to hydrophobic chains such as PEG- 150 / decyl / SMDI copolymer sold under the name Aculyn 44 ™ (polycondensate comprising at least one element, a polyethylene glycol containing 150 or 180 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexyl isocyanate)) (SMDI), 35% by weight in a mixture of propylene glycol (39%) and water (26%)), the family of modified starches such as modified potato starch sold under the name Solanace Structure ™ or their mixtures.

The preferred gelling agents come from the family of polyacrylamides such as

Simulgel 600 ™ or Sepigel 305 ™ or mixtures thereof.

These active ingredients and / or additives may be present in the composition in a proportion of 0.001 to 10% by weight relative to the total weight of the composition.

Administration may be topical, ocular, intraocular, intravenous, parenteral, subcutaneous, epicutaneous, intradermal, transdermal, intramuscular, enteral, oral, rectal, intranasal, sublingual, oral, intra-respiratory or inhalation. nasal.

Among these routes of administration, the topical route and the ocular route are particularly preferred. The eyedrops are particularly adapted to the ocular route. The topical administrable composition is more particularly intended for the treatment of skin and mucous membranes. By topical application is meant the application or spreading of the composition according to the invention to the surface of the skin or mucosa. The compositions of the present invention may be in any of the galenical forms normally used for topical application, especially in the form of solutions, lotions, gels, ointments, emulsions of liquid or semi-liquid consistency of the milk type. , obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O), or of powders, impregnated buffers, sprays, suspensions or emulsions of soft, semi-liquid or solid consistency cream, ointment or microemulsions, micro-capsules, microparticles or vesicular dispersions of ionic and / or nonionic type. It may also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release. These compositions are prepared according to the usual methods.

Advantageously, the composition comprises an ointment, a cream, a lotion or a gel.

If the pharmaceutical composition, in addition to laropiprant or a pharmaceutically acceptable salt thereof, comprises other active ingredients, they may be in the same composition to be administered at the same time, or in different compositions to be administered simultaneously. but separately, sequentially; before or after administration of laropiprant or a pharmaceutically acceptable salt thereof and brimonidine or a pharmaceutically acceptable salt thereof.

The compositions according to the invention are useful for the treatment and / or prevention of rosacea, in particular of subtype I or II.

Throughout this text, unless otherwise specified, it is understood that when concentration ranges are given, they include the upper and lower limits of said range.

Hereinafter the list of examples characterizing, in a surprising and non-limiting manner, the topical efficacy of laropiprant on both the DP1 receptor and in-vivo models of rosacea and inflammation.

Legend of figures

Figure 1 is a table reporting the evaluation of the effect of topical laropiprant on mouse ear edema. Figure 2 is a graph showing the dose-dependent inhibition of mouse ear edema by topically applied laropiprant (at t = 1h after application). Ind = Indomethacin. Lar = laropiprant.

Figure 3 is a graph showing the inhibition of mouse ear edema by topically applied laropiprant over time. AA = 4% arachidonic acid. Ind = Indomethacin.

Figure 4 is a graph showing the time course of BW245C-induced vasodilation after topical application of laropiprant compared to Shionogi S-5751 /

Figure 5 is a graph that shows the dose-dependent effect of laropiprant on the BW245C-induced vasodilatation model.

Figure 6 is a graph that shows the dose-dependent effect of laropiprant on the resiniferatoxin-induced vasodilatation (RTX) model.

Examples:

Example 1 - Evaluation of the anti-inflammatory activity of laropiprant after a single topical administration in a model of arachidonic acid-induced BALB / c mouse ear edema

Experimental Protocol: Inducer of Edema: Arachidonic Acid Was Dissolved in 4% THF / Methanol

Treatment: The compounds tested were dissolved in a solution of arachidonic acid (AA) at the final concentration of 20 μΙ of the test compound. These compounds were applied on the inner side of the right ear.

Assessment method: The thickness of the ear was measured at T = 0; T + 1 h; T + 2h and T + 4h.

Groups: (compound / dose) Identification

Group 1: THF / Methanol I to 5

Group 2: Arachidonic acid 4% (AA) 6 to 10

Group 3: AA + Indomethacin at 5% I I to 15

Group 4: AA + LAROPIPRANT at 0.1% 16 to 20

Group 5: AA + LAROPIPRANT at 0.3% 21 to 25

Group 6: AA + LAROPIPRANT at 1% 26 to 30 Group 7: AA + LAROPIPRANT at 2.5% 31 to 35

Group 8: AA + LAROPIPRANT at 5% 36 to 40

The results presented in FIG. 1 show for each measurement time (0, 1 h, 2 h and 4 h) the edema (mean) size values and the inhibition percentage after application of indomethacin (Group 3) and the laropiprant (groups 4-8). For the inhibition data, a statistical t-test is performed to qualitatively compare the inhibitions obtained for group 2 (scored ***) with those obtained for the other groups (denoted NS = not comparable, *, ** and *** ). A result of *** obtained with one of the groups 4 to 8 means that there is no significant statistical difference with the reference group 2. A result of * or ** obtained with one of the groups 4 to 8 means that there is a significant (**) or very significant (*) difference with the reference inhibition group 2.

Conclusions: (see Figures 1, 2 and 3) 1 hour after the application of topical arachidonic acid 4%, an increase in the thickness of the ear of 85% was induced.

Indomethacin 5%, used as a positive control, inhibits AA induced ear edema by 96%. Laropiprant concentrations of 0.1%, 0.3%, 1%, 2.5% and 5% respectively inhibit edema by 27%, 59%, 64%, 86% and 89% respectively. Laropiprant 0.3%, shows a strong dose-dependent anti-inflammatory relationship on AA-induced ear edema.

Example 2 Evaluation of the Activity of Different DP1 Antagonists (Laropiprant, Shionogi S-5751) Used as Pretreatment, on Cutaneous Vasodilatation Induced by a Single Topical Application of BW245C in Mice

SKH1.

Rationale: Compounds derived from arachidonic acid have important roles in the inflammatory response where they can act as vasodilators.

Evaluation method: The PI M3 Doppler laser is used to measure skin perfusion on the backs of mice. One measurement was taken every 2 minutes for 46 minutes. Each mouse was his own witness. Results: (Cf Figure 4) The aim of this study was to evaluate the activity of the different reference DP1 antagonists, such as Laropiprant and the compound Shionogi S- 5751, on cutaneous vasodilation induced by BW245C after single topical application on SKH 1 mice.

The level of vasodilation achieved with topical application of the 3% DP1 BW245C agonist and the repeatability of the response was improved with the new protocol.

Laropiprant and S-5751, both at a concentration of 3% in acetone, applied for the first time for 30 minutes and a second time 2 minutes before application of the inducer, significantly inhibited vasodilatation cutaneous

(AUC of the relative area of vasodilation: -69%, ^*** p <0.001 for Laropiprant and -46%, ^** p <0.01 for S-5751).

Example 3 Evaluation of the dose-dependent activity of Laropiprant, used as a pre-treatment, on cutaneous vasodilatation induced by a single topical application of BW245C in the SKH1 mouse model.

rational:

In this study, we evaluated the dose-dependent effect of Laropiprant, a DP1-R1 reference antagonist, in a specific DP1-R murine model.

Evaluation method:

The Doppler laser PIM3 makes it possible to measure the dermal perfusion on the back of the mice every 2 minutes and 2 for 46 minutes. Each mouse was his own witness.

Results (Figure 5)

The aim of the study was to evaluate the dose-dependent effect of Laropiprant, a DP1-R1 reference antagonist, in a specific DP1-R murine model. A previous study (see Example 2 and Figure 2) has already validated the antagonistic effect of laropiprant

3% in this model. Laropiprant was used at doses ranging from 0.1 to 3% in acetone, topically on the back of SKH1 mice before application of the 3% inducer. Laropiprant induced a dose-dependent inhibition of vasodilatation-dependent DP1 R (relative area of vasodilation, ^*** p <0.001) with the best inhibition found with the lower part of the dose (0.1%). Example 4 Evaluation of the dose-dependent activity of Laropiprant, used as a pre-treatment, on cutaneous vasodilatation induced by a single topical application of RTX in the SKH1 mouse model.

Summary:

The animal model of neurogenic skin inflammation was induced by a single topical application of resiniferatoxin (RTX), 0.03% on the back of a SKH 1 mouse. RTX is an extremely potent capsaicin analogue and exposure causes the release of neuropeptides RTX. Most of these neuropeptides have vasodilatory properties and a component of RTX induced by neurogenic inflammation is cutaneous vasodilatation. In the current RTX model, the objective assessment of cutaneous vasodilation was evaluated by Doppler laser perfusion imaging. The increase in cutaneous blood flow caused by the application of RTX to the skin is largely hindered by a TRPV1 receptor antagonist, AMG9810 at 3% (relative area of vasodilatation, AUC decreased by 23% and ^* p <0.05 for kinetics). Laropiprant was evaluated in this model at 0.3% and 3%. Laropirant used at a dose of 3% inhibited the vasodilation induced by the topical application of RTX 0.03% on the backs of SKH1 mice.

Measurement of RTX-induced vasodilatation

A skin area of 1.8 x 1.5 cm on the back of the mouse is divided into two regions of interest. One region is treated with the vehicle, the other with resiniferatoxin (RTX) at a concentration of 0.03%. The compounds to be tested are applied 4 minutes before the single topical application of resiniferatoxin (RTX) on a skin region. The other region was used for vehicle applications. Each mouse is its own witness. Cutaneous blood perfusion is evaluated every 2 minutes on the back of the mouse with a Doppler laser perfusion imaging PIM3 (Perimed, France). Before treatment, analyzes are performed and blood infusion change measurements are made for 20 minutes.

Conclusions: Figure 6 has been analyzed. The yield of two parameters, the erythematous surface and the infusion blood intensity ratio, is calculated as a relative area of vasodilation (mm ² ).

For each mouse, the value of the control area is subtracted from the value of the treated area. The results are expressed as mean ± standard deviation (SEM). The statistical analysis performed is based on a repeated analysis of variance (P) of the surface relative vasodilation. This analysis made it possible to compare the group effect on the kinetics of vasodilatation.

Claims

1) A topical pharmaceutical composition containing laropiprant, an ester or a pharmaceutically acceptable salt thereof.

2) Composition according to claim 1, characterized in that the concentration of laropiprant, its ester or its pharmaceutically acceptable salt is between 0.0001% and 5% by weight, relative to the total weight of the composition. 3) Composition according to claim 2, characterized in that the concentration of laropiprant or its pharmaceutically acceptable salt thereof is between 0.003 and 3% by weight, relative to the total weight of the composition.

4) Composition according to one of claims 1 to 3, which is in the form of an ointment, a cream, a lotion or a gel.

5) Composition according to one of claims 1 to 4, for use in the treatment and / or prevention of a dermatological condition. 6) composition for use according to claim 5, wherein Γ dermatological condition is selected from dermatitis, contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, eczema, phytodermatitis , radiodermatitis, stasis dermatitis, psoriasis, chronic lichen simplex, scleroderma, ulcers and erosions resulting from trauma, burns, bullous disorders or ischemia of the skin or mucous membranes; different forms of ichthyosis, epidermolysis bullosa, hypertrophic scars, keloids; cutaneous changes in intrinsic aging, photoaging; vascular tumors such as angiomas; the formation of frictional blisters caused by mechanical shearing of the skin and cutaneous atrophy resulting from the topical use of corticosteroids, inflammation of the mucous membranes, such as cheilitis, chapped lips, nasal irritation, inflammation of the mucous membranes and vulvo - vaginitis; disorders of hair follicles and sebaceous glands, such as acne; rosacea and rhinophyma, erythema, rash, skin tumors, bruising, perioral dermatitis, and folliculitis barbae and inflammatory reactions, such as drug eruptions, erythema multiforme, erythema nodosum , and the granuloma annularis. 7) Composition for use according to claim 6, wherein the dermatological condition of rosacea.

The composition for use according to claim 7, wherein the dermatological condition is a rosacea of subtype I or II.

9) Composition according to any one of the preceding claims, characterized in that the composition also contains at least one active ingredient, preferably selected from the group comprising antibiotics, antibacterial agents, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergics, retinoids, anti-free radicals, antipruritic, keratolytic, antiseborrhoeic, antihistamines, sulfides, immunosuppressive or antiproliferative products, corticosteroids, intravenous immunoglobulins, -angiogenic, anti-inflammatory and a mixture thereof.

10) Composition according to any one of the preceding claims, characterized in that the composition also contains at least one additive, preferably selected from the group comprising sequestering agents, chelating agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, dyes, bases or usual acids, mineral or organic, perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds , soothing and skin-protecting agents, propenetrating agents, emulsifiers, gelling agents and a mixture thereof.