WO2014049295A1 - Combination of laropiprant and doxycycline for the treatment of rosacea - Google Patents

Description

 COMBINATION OF LAROPIPRANT AND DOXYCYCLINE FOR THE TREATMENT OF ROSACEAE

The invention relates to a pharmaceutical composition, especially a dermatological composition, and to its use for the prevention or the treatment of affections of the skin, in particular rosacea.

Many inflammatory skin disorders often result in unsightly and painful skin rashes, acne, telangiectasia, and acne-like rashes, such as macules, nodules, and pustules that may ooze or crust.

 For example, 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 redness episodic or hot flashes ("flush"). Often this type is also characterized by edema, rough plaques and the appearance of dilated blood vessels (telangiectasia) 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 III: Phosphate 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 II 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.

 There is no known cure for many inflammatory skin disorders, including inflammatory skin disorders of the face, such as rosacea. Current treatments, which are directed at controlling rashes and redness, inflammation of the skin, are of limited effectiveness in many patients and, in general, can be used only for a limited time. Standard treatments exclude the potentiating elements of pathologies such as sun exposure, wind exposure, alcohol consumption, spicy foods, irritants, cleaning lotions, and cosmetics.

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. Among the tetracyclines, doxycycline, in particular, has been described for treating ocular rosacea and rosacea (see, for example, US 2003/229055).

 The treatment of rosacea with alpha-1 or alpha-2 adrenergic receptor agonists (US 2006/0171974, US 2005/0165079, US 2005/0020600) is also known. In particular, brimonidine has been shown to be useful in the treatment of rosacea and in particular erythema caused by rosacea, see, for example, US patent applications 2004/242588 (DeJovin et al.), US 2005/020600 Scherer), US 2009/061020 (Theobald et al.), Or telangiectases possibly caused by rosacea, see, for example, US patent application 2006/0264515.

 Unfortunately, the use of these drugs, for example antibiotics, can often cause side effects and can cause intolerance problems in many patients. 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 more effective treatment of rosacea which has fewer side effects, in particular a composition conferring greater tolerance of the active ingredients, while reducing their side effects.

 The Applicant proposes to combine doxycycline and laropiprant and thus provide a more effective treatment of dermatological conditions, including 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 may also make it possible to eliminate a rebound effect sometimes observed at the end of treatment. Moreover, the combination of the two components makes it possible to obtain a certain advantage in terms of efficacy and tolerance, thus making it possible either to increase the therapeutic effect for similar doses or to maintain the same therapeutic effect while reducing the doses. .

The subject of the invention is a pharmaceutical composition, especially a dermatological composition, characterized in that it comprises laropiprant, an ester or a pharmaceutically acceptable salt thereof, and doxycycline or a pharmaceutically acceptable salt thereof.

 The subject of the invention is preferably a pharmaceutical composition, especially a dermatological composition, 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.

 In a particular embodiment, the subject of the invention is a pharmaceutical composition, especially a dermatological composition, characterized in that the concentration of doxycycline or its pharmaceutically acceptable salt thereof is between 0.0001% and 5% by weight, relative to the total weight of the composition.

 Such a pharmaceutical composition is especially characterized in that it is intended for topical or oral administration.

 It is also contemplated a pharmaceutical composition, especially dermatological, characterized in that it comprises laropiprant, an ester or a pharmaceutically acceptable salt thereof, doxycycline or a pharmaceutically acceptable salt thereof and further comprising minus one additional active ingredient or 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, anti-angiogenic 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, propenetrating agents, emulsifiers, gelling agents, agents thickeners, buffering agents, lipophilic excipients, agents disintegrants, soluble agents, compressing agents and a mixture thereof.

 The invention also relates to a pharmaceutical composition, characterized in that it comprises laropiprant, an ester or a pharmaceutically acceptable salt thereof, and doxycycline or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a dermatological condition, more particularly related to inflammatory skin disorders or signs and / or symptoms associated therewith.

 As used herein, the term "inflammatory disorders or associated signs and / or symptoms" refers to any disease associated with skin, nails, mucous membranes or with signs and / or symptoms of redness, hot flashes, burning sensation, desquamation, acne (pimples, papules, pustules (especially in the absence of white and black dots)), telangiectasias, wounds, surface irritation or pain, itching and / or inflammation. The degree or severity of the disease or state of health may vary.

By dermatological condition is meant in a nonlimiting manner dermatitis such as 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 the granuloma annularis. In one embodiment preferred, the pharmaceutical composition according to the invention is used to treat or prevent inflammatory skin dermatological disorders, such as rosacea.

 The invention further relates to the use of laropiprant or a pharmaceutically acceptable salt thereof in combination with doxycycline or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for prevention and / or treatment of a skin condition, preferably rosacea.

 More particularly, the dermatological condition is rosacea and more particularly rosacea of subtype 1,11 and IV.

 It is also contemplated that laropiprant, an ester or a pharmaceutically acceptable salt thereof, in combination with doxycycline or a pharmaceutically acceptable salt thereof, for simultaneous or sequential use in the treatment and / or prevention of a dermatological condition, more particularly related to inflammatory skin disorders or signs and / or symptoms associated therewith. This is preferably the treatment and / or prevention of rosacea. Even more preferably, the invention is directed to this combination for simultaneous or sequential use in the treatment and / or prevention of subtype 1.11 and IV rosacea.

 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 1.11 and IV subtype rosacea, said method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of laropiprant, an ester or a pharmaceutically acceptable salt thereof, and doxycycline or a salt thereof. pharmaceutically acceptable 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 1,11 and IV, said method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of laropiprant, an ester or a pharmaceutically acceptable salt thereof, and administering a pharmaceutical composition comprising a quantity therapeutically effective doxycycline or a pharmaceutically acceptable salt thereof.

 The administration of laropiprant, an ester or a pharmaceutically acceptable salt thereof, and doxycycline, or a pharmaceutically acceptable salt thereof, may be simultaneous or sequential.

 The invention further comprises a kit comprising a first container comprising a pharmaceutical composition comprising laropiprant, an ester or a pharmaceutically acceptable salt thereof; and a second container comprising a pharmaceutical composition comprising doxycycline or a pharmaceutically acceptable salt thereof.

 The invention and the advantages thereof will be better understood on reading the description of non-limiting embodiments which follow.

The present invention therefore relates to a pharmaceutical composition, especially dermatological, comprising laropiprant, an ester or a pharmaceutically acceptable salt thereof, and doxycycline or a pharmaceutically acceptable salt thereof.

By dermatological composition is preferably meant a pharmaceutical composition applied topically, orally or ocularly to the eye.

Laropiprant or MK0524 (MERCK & Co) is [(3R) -4- (4-chlorobenzyl) -7-fluoro-5- (methylsulfonyl) -1,2,3,4-tetrahydrocyclopenta [b] indol- 3-yl] acetic whose formula is represented 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 a drug in combination with nicotinic acid (or niacin) for the treatment of mixed or combined 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 blood vessels.

There, it binds to the DP1 receptor present at the level of 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.

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, in particular of subtype Ι, ΙΙ and IV.

. 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. The combined effect of laropiprant and brimonidine is very advantageous for the prevention and / or effective treatment of rosacea, particularly subtype Ι, ΙΙ and IV.

In the present context, doxycycline refers to alpha-6-deoxy-5-oxytetracycline or 1,4,4a, 5,5a, 6,1 1, 12a-octahydro-3,5,10,12,12a pentahydroxy-6-methyl-1,1,1-dioxo-2-naphthacene-carboxamide of formula:

 The various forms of this tetracycline described are especially doxycycline hydrochloride, doxycycline monohydrate and doxycycline hyclate. 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.

Also included in the invention is the administration of laropiprant or doxycycline prodrug. By "prodrug" is meant in the present invention a compound which is converted to the corresponding active, for example laropiprant and doxycycline, when administered in vivo, or which has the same activity on its own. In particular, derivatives may be mentioned hydrolysable, such as esters of the active compounds or 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.

 By way of non-limiting examples of such principles, mention may be made of medicaments used to treat the dermatological condition or the underlying disease which causes the skin disorder, antibiotics, antibacterial agents, antiviral agents, antiparasitic agents, antifungal agents, anesthetics, analgesics, antiallergics, retinoids, free antiradicals, antipruritics, keratolytics, antiseborrhoeic agents, antihistamines, sulfides, immunosuppressive or antiproliferative corticosteroids, intravenous immunoglobulins, anti-inflammatory agents, -angiogenic, anti-inflammatory and / or a mixture thereof.

The compositions of the invention may furthermore comprise any additive or adjuvant conventionally used in the pharmaceutical, dermatological or cosmetic field, compatible with laropiprant and doxycycline in the presence.

Mention may in particular be made of sequestering agents, chelants of antioxidants, sunscreens, preservatives, for example DL-alpha-tocopherol, fillers, electrolytes, humectants, dyes, bases or acids which are usual, mineral or perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA, soothing and protective agents for the skin such as allantoin, propenetrating agents, emulsifiers, gelling agents, thickeners, buffering agents, lipophilic excipients, disintegrating agents, soluble agents, compressing agents or a mixture thereof. Of course, those skilled in the art will take care to choose this or these optional additional compounds, and / or their quantity, in such a way that the Advantageous properties of the composition according to the invention are not, or not substantially, impaired.

 As preservatives, there may be mentioned, for example, quaternary ammoniums such as benzalkonium chloride; phenoxyethanol; benzyl alcohol; diazolidinylurea; parabens, such as methylparaben, propylparaben or butylparaben; benzoic acid and its sodium or potassium salts such as sodium benzoate; sorbic acid and its sodium or potassium salts such as potassium sorbate; mercurial derivatives such as phenylmercury salts (acetate, borate or nitrate) or thiomersal; or their mixtures.

 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 the PEG-150 / decyl / SMDI copolymer sold under the name of Aculyn 44 ™ (polycondensate comprising at least as elements, a polyethylene glycol containing 150 or 180 moles of ethylene oxide, decyl alcohol and methylene bis (4 cyclohexylisocyanate) (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 mixtures thereof.

 The preferred gelling agents are derived from the family of polyacrylamides such as Simulgel 600 ™ or Sepigel 305 ™ or mixtures thereof.

According to one embodiment, and in particular for an oral administration, the composition comprises one or more thickening agents, making it possible to obtain an adequate viscosity, selected from the group consisting of polysaccharides, cellulose derivatives and carboxyvinyl polymers of Carbopol ^® type. These polymers include, but are not limited to, Carbopol ^® 934P, Carbopol ^® 71 G, carbopol ^® 971 P and Carbopol ^® 974P.

 The composition may comprise one or more thickening agents selected from cellulose derivatives. Cellulose derivatives useful as thickeners include, but are not limited to, methylcellulose, ethylcellulose, ethylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose and hydroxyalkylcelluloses such as hydroxyethylcellulose, hydroxymethylcellulose hydroxypropylcellulose and hydroxypropyl methylcellulose, and a combination thereof.

The composition may comprise one or more thickeners selected from polysaccharides. Polysaccharides which may be used as thickening agents include, but are not limited to, xanthan gum, gum tragacanth, carrageenans such as λ-carrageenan, κ-carrageenan or ι-carrageenan, galactomannans such as carob seeds, guar seed meal or tara seed meal, gellan gum, gum arabic, karaya gum, pectins, starch and its derivatives obtained by esterification or etherification, and tamarind, and a combination of these. The composition may also comprise, as thickeners, a mixture of one or more cellulose derivatives and one or more polysaccharides.

 The composition according to the invention may further comprise at least one disintegrating agent such as sodium carboxymethyl starch, crosslinked sodium carboxymethylcellulose or crosslinked polyvinylpyrrolidone, and more advantageously crosslinked polyvinylpyrrolidone.

 The composition according to the invention may further comprise at least one soluble agent of the polyol (or sugar-alcohol) type. A polyol (or sugar alcohol) is a hydrogenated form of sugar in which the carbonyl group (i.e., aldehyde or ketone) has been reduced to a primary or secondary hydroxyl group. In particular, the diluent soluble agent is selected from the group comprising mannitol, xylitol, sorbitol, maltitol and their mixture. Said soluble agent is used in the form of granules, powders or a mixture of granules and powders.

 Finally, the technical implementation of the tablets may also lead to the introduction of compression agents:

 lubricating agents such as magnesium stearate, stearic acid, glycerol monostearate, polyoxyethylene glycols having a molecular weight of 400 to 7,000,000, hydrogenated castor oil, glycerol behenate, mono- glycerides, bi-or trisubstituted, sodium stearyl fumarate;

 flow agents, such as colloidal silica or any other silica, for example the product marketed by Degussa under the trademark Aerosil;

 binders such as starch, buffers, absorbents, diluents such as lactose and any other pharmaceutically acceptable additive.

These active ingredients and / or additives may be present in the composition in a proportion of 0.0001 to 10% by weight relative to the total weight of the composition. The concentration of these active ingredients and / or additives in the composition may vary according to the nature of said active ingredients and / or additives and according to the intended mode of administration.

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

 Among these routes of administration, the oral route, the topical route and the ocular route are particularly preferred. The eye drops 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 oral administration, especially in the form of tablets, capsules, pills, powder or any form for solid oral preparation or in any form of oral preparation. . The pharmaceutical composition generally comprises a physiologically acceptable medium, for example for the preparation of tablets or capsules or for an oral preparation such as the vehicles used in a completely conventional manner.

The composition according to the present invention may be in the form of a conventional (monolayer) or multilayer tablet, in particular of 2 or 3 layers. When the pharmaceutical composition is controlled release or sustained release, the composition may be a multilayer tablet, a layer may have a specific duration of disintegration different from another layer. The composition may also be in the form of conventional capsules (containing powder) or comprising microgranules or sachets comprising powder for an oral preparation or granules.

The pharmaceutical compositions according to the present invention are of acceptable size for conventional oral administration. Thus, compositions having a weight of less than 800 mg, preferably less than 500 mg, and more particularly less than 400 mg (for example compositions weighing 150 mg, 200 mg or 250 mg) are preferred. It is also envisaged, for a topical application, compositions 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 powders, impregnated buffers, sprays, suspensions or emulsions of soft, semi-liquid or solid consistency of the cream, ointment or micro-type. emulsions, microcapsules, 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, for oral administration, the composition comprises a tablet, a capsule, a pill, granules or is in the form of a powder. For topical administration, the composition is advantageously in the form of an ointment, a cream, a lotion or a gel.

If the pharmaceutical composition, in addition to laropiprant or a pharmaceutically acceptable salt thereof and doxycycline 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 doxycycline 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 1,11 and IV.

The invention also relates to the use of laropiprant or a pharmaceutically acceptable salt thereof and doxycycline or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition, and in particular dermatological intended for the prevention and / or treatment of a skin condition, preferably for the prevention and / or treatment of rosacea, and in particular rosacea of subtype 1.11 and IV.

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 1.11 and IV may be mentioned.

The actually administered amount of laropiprant or a pharmaceutically acceptable salt thereof and doxycycline or a pharmaceutically acceptable salt thereof and optionally other active ingredients or additives to be used according to the invention depends on the therapeutic or cosmetic effect sought, and can therefore vary to 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 composition (s) pharmaceutical (s) are administered 1 to 2 times / day. Preferably, the treatment may have a duration ranging from 1 week to 6 months, renewable, and preferably from 2 weeks to 4 months.

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

 In the compositions according to the invention, 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. mg. In one embodiment, laropiprant, an ester or a pharmaceutically acceptable salt thereof, is present in the composition at a concentration of between 0.0001% and 5% by weight, based on the total weight of the composition. comprising, preferably between 0.001% and 3% by weight, relative to the total weight of the composition. When a composition comprises more than one of these compounds, their total concentration is included in the aforementioned amounts.

In the compositions according to the invention, the daily dose of doxycycline or a pharmaceutically acceptable salt thereof is 20 mg to 200 mg, preferably 50 mg to 100 mg, more preferably 30 to 40 mg . In one embodiment, the doxycycline or a pharmaceutically acceptable salt thereof is present in the composition at a concentration of between 0.0001 and 5% by weight based on the total weight of the composition, preferably between 0.001 and 3. % by weight relative to the total weight of the composition. When a composition comprises more than one of these compounds, their total concentration is included in the aforementioned amounts.

In a particularly preferred manner, the composition comprises laropiprant present at a concentration of between 0.001% and 3% by weight, relative to the total weight of the composition comprising it, and doxycycline present at a concentration of between 0.001 and 3% by weight. weight relative to the total weight of the composition.

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. The invention further relates to laropiprant, an ester or a pharmaceutically acceptable salt thereof, in combination with doxycycline or a pharmaceutically acceptable salt thereof, for simultaneous or sequential use in the treatment and / or prevention a dermatological condition, preferably rosacea, more preferably rosacea of subtype 1,11 and IV.

By "sequential" is meant a time-separated application of laropiprant or a pharmaceutically acceptable salt thereof and doxycycline or a pharmaceutically acceptable salt thereof. The user can therefore successively apply laropiprant, an ester or a pharmaceutically acceptable salt thereof, and doxycycline or a pharmaceutically acceptable salt thereof, after a few seconds or after several hours in the same day, especially in an interval ranging from 1 hour to 3 days. According to one alternative, laropiprant, an ester or a pharmaceutically acceptable salt thereof is first administered, and secondly doxycycline or a pharmaceutically acceptable salt thereof. According to another alternative, doxycycline or a pharmaceutically acceptable salt thereof is first administered and secondly laropiprant, an ester or a pharmaceutically acceptable salt thereof.

Laropiprant, an ester or a pharmaceutically acceptable salt thereof, and doxycycline or a pharmaceutically acceptable salt thereof may be administered by the same route of administration or by two separate routes.

 In one embodiment, the administration of laropiprant or a pharmaceutically acceptable salt thereof may be performed sequentially or concurrently with the administration of doxycycline or a pharmaceutically acceptable salt thereof.

 Preferably, both compounds are administered topically and / or orally.

The compositions of laropiprant, an ester or a pharmaceutically acceptable salt thereof, and doxycycline or a pharmaceutically acceptable salt may be packaged separately in two separate containers.

 In one embodiment, the invention comprises a kit comprising,

a first container comprising a pharmaceutical composition comprising laropiprant, an ester or a pharmaceutically acceptable salt thereof;

 a second container comprising a pharmaceutical composition comprising doxycycline or a pharmaceutically acceptable salt thereof.

 Such containers may be in various forms. It may be in particular tubes or flasks.

 According to one embodiment, the two containers are independent of one another.

 According to a particular embodiment, the two compositions are packaged in a unitary device, said containers forming compartments integral with one another.

Claims

1) A pharmaceutical composition, especially dermatological, characterized in that it comprises laropiprant, an ester or a pharmaceutically acceptable salt thereof, and doxycycline 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 1, characterized in that the concentration of doxycycline or its pharmaceutically acceptable salt thereof is between 0.0001 and 5% by weight, relative to the total weight of the composition. 4) Composition according to any one of the preceding claims, characterized in that it is intended for topical or oral administration. 5) Composition according to any one of the preceding claims, characterized in that it further 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. 6) Composition according to any one of the preceding claims, characterized in that it further contains at least one additive, preferably selected from the group comprising sequestering agents, chelating agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, the usual dyes, bases or acids, mineral or organic, perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, soothing and protective agents of the skin, propenetrating agents, emulsifiers, gelling agents, thickeners, buffering agents, lipophilic excipients, disintegrating agents, soluble agents, compressing agents and a mixture thereof. 7) Composition according to any one of claims 1 to 6, for use in the treatment and / or prevention of a dermatological condition such as dermatitis, contact dermatitis, atopic dermatitis, seborrheic dermatitis, dermatitis nummular, 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, redness, skin tumors, ecchymoses, perioral dermatitis, and folliculitis barbae and inflammatory reactions, such as drug eruptions, erythema multiforme, erythema nodosum , and the granuloma annularis. 8) Composition according to claim 7, for use in the treatment and / or prevention of rosacea, preferably rosacea of subtype I, II and IV. 9) Laropiprant, an ester or a pharmaceutically acceptable salt thereof, in combination with doxycycline or a pharmaceutically acceptable salt of the latter, for simultaneous or sequential use in the treatment and / or prevention of a dermatological condition, preferably rosacea. 10) Laropiprant, an ester or a pharmaceutically acceptable salt thereof, in combination with doxycycline or a pharmaceutically acceptable salt thereof according to claim 9, for simultaneous or sequential use in the treatment and / or prevention rosacea of subtype I or II. 1 1) Kit comprising,  a first container comprising a pharmaceutical composition comprising laropiprant, an ester or a pharmaceutically acceptable salt thereof;  a second container comprising a pharmaceutical composition comprising doxycycline or a pharmaceutically acceptable salt thereof