MXPA06009314A - Use of metronidazole for preparing a pharmaceutical composition for treating pathologies related to the b-type receptor of interleukin 8 and/or to a pacap type 1 receptor - Google Patents

Abstract

The invention relates to the use of metronidasole for preparing a pharmaceutical composition for treating pathologies involving at least one B-type receptor selected in a group containing an IL-8RB receptor and a PAC-1 receptor.

Description

USE OF METHRONIDAZOLE FOR THE TREATMENT OF PATHOLOGIES LINKED TO INTERLEUCINE 8 TYPE B RECEPTOR AND / OR WITH PACAP TYPE 1 RECEIVER DESCRIPTION OF THE INVENTION The present invention relates to the treatment of pathologies linked to the type B receptor of interleukin 8 and / or to the type 1 receptor of PACAP. The invention relates to providing novel pharmaceutical compositions, more particularly dermatological, and comprising metronidazole in the form of an active agent. Rosacea is a chronic and progressive common inflammatory dermatosis linked with vascular relaxation. It mainly affects the central part of the face and is characterized by redness of the face or heat flushes, facial erythema, papules, pustules and telangiectasia. In severe cases, particularly in man, the soft tissue of the nose can swell and produce a bulbous inflammation called rhinophyma. In general, rosacea occurs between the ages of 25 and 70 years, and is much more common in people with fair complexions. It affects more particularly women, although this condition is more serious in men. Rosacea is chronic and persists over the years with periods of exacerbation and REF. : 174437 remission. Rosacea has been called originally "acne rosacea" because its papules (slight over-elevations of the skin) and its inflammatory pustules (scabs of pus) closely resemble those of acne vulgaris. In opposition to acne vulgaris, whose etiology is based on both an abnormal keratinization, an exacerbation of sebum production and a bacterial inflammation, the inflammation of rosacea is vascular and poorly understood. It results from this facial vascular anomaly, a permanent edema of the dermis that could accompany an increased colonization by Demodex folliculorum, a mite that is usually found in the follicles of the face. According to different works, Demodex folliculorum would have an etiological role in rosacea (Erbagi et al., 1998, Int J Dermatol, vol.37, pages 421-425, Purcell et al., 1986, J Am Acad Dermatol, vol. 15, pages 1159-1162; Sibenge et al., 1992, J Am Acad Dermatol, vol.26, pages 590-593). It seems that Demodex folliculorum causes or aggravates inflammatory reactions, resulting in papules and pustules, blocking the pilo-sebaceous follicles of the face (Roihu et al., 1998, J Cutan Pathol, vol.25, pages 550-552). This parasite would also trigger a humoral immune response (Nunzi et al., 1980, Br J Dermatol, vol 103, pages 543-551, Manna et al., 1982, Br J Dermatol, vol 107, pages 203-208). The pathogenesis of rosacea is not well known. Numerous factors may be involved without strongly inducing this condition. For example, are psychological factors, gastrointestinal problems, environmental factors (exposure to the sun, temperature, humidity) and emotional (stress), food (alcohol, spices), hormonal, vascular, in addition to an infection by Helicobacter pylori.

Rosacea evolves in 4 stages, but passing through all stages is not mandatory: - stage 1 vascular relaxation (approximately 20 years). The patients have sudden growths of paroxysmal flushing of the face and neck, with a sensation of heat, but without systemic signs. After the crises, the skin of the face becomes normal. These "ruboraciones" are triggered by changes in temperature (sometimes leading to a thermophobia), the absorption of hot drinks or alcohol. - stage 2 erythemato-telangiectatic (around 30 years). The malar zones are diffusely reddened. Dilated capillaries are observed that constitute the classic mud. Unlike stage 1, the blush is permanent. In addition, the cheeks, the chin and the middle part of the forehead may be intruded. - stage 3 of papulo-pustules (around 40 years old). On a background of erythema develop papules and pustules of a few millimeters in diameter, without associated comedones. This dermatosis can be very extensive, sometimes in the hairless part of the scalp in men, but it respects the contour of the mouth and eyes. Patients complain of sensitive skin, with subjective intolerance to most topics and fatty cosmetics. - stage 4 of the rhinophyma (around 50 years or later). This late phase affects mainly men, contrary to the other stages. The nose increases in volume, diffusely red and dilated the follicular orifices. The skin becomes progressively thick. The minor forms of rosacea can be treated by active agents such as anti-seborrheic and anti-infective, for example benzoyl peroxide, retinoic acid. As for the more diffuse forms of affection, they correspond to a general antibiotic therapy by cyclins. However, these treatments have unpleasant side effects for the patient, such as irritation or intolerance. In addition, in relation to the multi-factorial aspect of rosacea, there are many therapies against this condition, but there is still the investigation of an effective treatment and without risk to the patient. The interleukin 8 receptors are receptors of seven transmembrane domains and are coupled to the G proteins. Two interleukin 8 receptors have been identified, called IL-8RA or CXCR1 and IL-8RB or CXCR2. The PACAP, "pituitary adenylate cyclase activation peptide", possesses 68% identity with the vasoactive intestinal peptide (VIP), one of the members of the secretin / glucagon / GHRH family. The PACAP displays pleiotropic effects throughout the body during development, but also in the adult. Participates in essential functions such as growth, endocrine and digestive activity, cardiovascular and respiratory control, immune responses and circadian rhythm. It is set and activated by multiple subtypes of receptors where some (type II) have the particularity of also fixing the VIP with the same high affinity. These receptors are widely distributed in the brain and peripheral tissues. Among the PACAP receptors, the type 1 receptor, PAC-1 (or PVR1) is known. PACAP and IL-8 have an implication in inflammation. Indeed, PACAP decreases the release of pro-inflammatory cytokines and inhibits the activation of neutrophils. Metronidazole, or (methyl-2-nitro-5-imidazolyl) -2-ethanol, is known in the prior art for its antibacterial, antiparasitic and antiprotozoal properties. It exerts a selective toxicity with respect to anaerobic microorganisms as well as hypoxic cells. At the level of the latter, metronidazole is reduced in derivatives capable of altering the DNA structure of these cells. The Applicant's work allowed to highlight the involvement of the type B receptor of interleukin 8 (IL-8RB) and the type 1 receptor of PACAP (PAC-1) in some pathologies and particularly in rosacea. The Applicant's work made it possible to demonstrate that the use of metronidazole would result in the modulation of the binding of natural ligands to the receptors chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor. As indicated above, the invention aims to offer a new method of treating pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor. This method of treatment consists in administering to a patient an effective amount of metronidazole in which metronidazole is capable of influencing the binding of a ligand on at least one receptor selected from the group comprising the IL-8RB receptor and the PAC-receptor. 1. Accordingly, the invention relates more particularly to the use of metronidazole for the preparation of a pharmaceutical composition for the treatment of pathologies involving at least one receptor selected from the group comprising the IL-8RB receptor and the PAC-1 receptor. . More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition intended to treat pathologies involving at least one receptor selected from the group comprising the IL-8RB receptor and the PAC-1 receptor, and wherein Metronidazole is able to modulate the interaction of the ligand with at least one receptor selected from the group comprising the IL-8RB receptor and the PAC-1 receptor. The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above and in which metronidazole modulates the binding of at least one natural ligand to its receptor, this receptor being chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor. More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, intended to treat a pathology involving at least one receptor selected from the group comprising the IL-8RB receptor and the receptor PAC-1. The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, intended to treat a pathology involving two receptors chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor, being this pathology rosacea. More particularly, the objective pharmaceutical composition of the present invention is a dermatological composition, for topical application on the skin. For the treatment of pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor, it is understood, according to the present invention, the treatment and / or prevention of such pathology . In particular, these pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor are rosacea, psoriasis, acute and chronic inflammations, autoimmune diseases and septic shock. More particularly, it will be about rosacea. By treatment of rosacea, it is understood according to the invention, the treatment and / or prevention of rosacea, with one or more of the stages described above. According to a first embodiment of the invention, the composition is intended for the treatment of the first stage of rosacea. According to a second embodiment of the invention, the composition is intended for the treatment of the second stage of rosacea. According to a third embodiment of the invention, the composition is intended for the treatment of the third stage of rosacea. According to a fourth embodiment of the invention, the composition is intended for the treatment of the fourth stage of rosacea. According to a preferred embodiment, the composition contains 0.0001 to 20% metronidazole, preferably 0.1 to 2% of metronidazole and more preferably of the order of 0.75 to 1% metronidazole expressed by weight relative to the total weight of the composition. Of course, the present invention relates, in addition to the use of metronidazole, to the use of derivatives thereof. Derivatives of compounds that are distinguished from metronidazole are understood as being by substitution, addition or deletion of one or more chemical groups and which exhibit substantially the same activity. Advantageously, the compositions of the invention comprise in addition to metronidazole, at least one other therapeutic agent capable of increasing the effectiveness of the treatment. As non-limiting examples of these agents, antibiotics, antibacterials, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergics, retinoids, anti-free radicals, anti-pruritic, keratolytic, anti-seborrheic, anti-histaminic can be cited. , sulfides, immunosuppressive or antiproliferative products. The compositions of the invention may further comprise any additive commonly used in the pharmaceutical, dermatological domain, compatible with metronidazole. Mention may be made in particular of sequestrants, antioxidants, sunscreens, preservatives, for example DL-alpha-tocopherol, fillers, electrolytes, humectants, colorants, bases or customary, mineral or organic acids, perfumes, essential oils, cosmetic actives, moisturizers, vitamins. , essential fatty acids, sphingolipids, self-tanning compounds such as DHA, thickening agents and skin protectants such as allantoin, pro-penetrants, gelling agents. Of course, the skilled person will know how to choose this or these possible complementary compounds, and / or their amount, in such a way that the advantageous properties of the composition according to the invention are not, or are not substantially altered. These additives may be present in the composition in a proportion of 0 to 20% by weight relative to the total weight of the composition. Examples which may be mentioned are sequestering agents, ethylenediamine tetraacetic acid (EDTA), as well as their derivatives or their salts, dihydroxyethylglycine, citric acid, tartaric acid or their mixtures. Mention may be made, as examples of preservatives, of benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea, parabens or their mixtures. Examples of wetting agents are glycerin and sorbitol. The compositions of the invention may contain one or more propenetrating agents in preferential concentrations ranging from 0 to 20% and more preferably ranging from 0.6 to 3% by weight, based on the total weight of the composition. Among the propenetrating agents, compounds such as propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol, ethoxydiglycol, are preferably used without this list being limiting. Advantageously, the compositions according to the invention can also contain one or more surfactants in concentrations preferably ranging from 0 to 10% and more preferably ranging from 0.1 to 2%. The compositions of the present invention may be present in all galenic forms normally used for topical application, in particular in the form of aqueous, hydroalcoholic or oily solutions, lotion-type dispersions, aqueous gels, anhydrides or lipophilic, emulsions of consistency liquid or semi-liquid of the milky type, obtained by dispersing a fatty phase in an aqueous phase (H / E) or vice versa (E / H) or of suspensions or emulsions of a soft, semi-liquid or solid consistency of the cream type , gel or ointment or even micro-emulsions, micro-capsules, micro-particles or vesicular dispersions of ionic and / or non-ionic type. Preferably, the creams can be formulated from a mixture of mineral oil, or a mixture of beeswax or water that is instantly emulsified, in which metronidazole is added, dissolved in a small amount of oil, such as almond oil. The ointments can be formulated by mixing a solution of metronidazole in an oil, such as almond oil in hot paraffin, then allowing the mixture to cool. As examples of the compositions according to the invention, mention may be made of those comprising an active phase containing (expressed as a percentage by weight): 0 to 90%, preferably 5 to 25%, particularly 10 to 20% , of water; - 0 to 10%, preferably 0 to 2%, particularly 0 to 0.5%, of surfactant; - 0 to 20%, preferably 0 to 10%, particularly 2 to 5%, of propenetrant; - 0.0001 to 20%, preferably 0.1 to 2%, of metronidazole; and an aqueous phase comprising a gelling agent and water. The aqueous phase of a composition according to the invention which is presented in the form of an emulsion may comprise water, a floral water, such as cranberry water or a thermal water or natural mineral, for example chosen from the water of Vittel, Vichy bathing water, Uriage water, Roche Posay water, Bourboule water, Enghien-les-Bains water, Saint Gervais-les-Bains water, Neris water -les-Bains, the water of Allevard-les-Bains, the water of Digne, the water of Maiziéres, the water of Neyrac-les-Bains, the water of Lons-le-Saunier, the Eaux Bonnes (good waters), the water of Rochefort, the water of Saint Christau, the water of Fumades and the water of Tercis-les-bains, the water of Avene (oats) or the water of Aix les Bains. This aqueous phase can be present in an amount comprised between 10 and 90% by weight relative to the total weight of the composition, preferably comprised between 20 and 80% by weight. By way of non-limiting examples, mention may be made of gelling agents of the polyacrylamide family, such as the mixture of the copolymer sodium acryloyldimethyltaurate / isohexadecane / polysorbate 80 sold under the name Simulgel 600 by the company Seppic, the polyacrylamide / isoparaffin mixture Cl3-14 / laureth-7 as, for example, sold under the name of 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 with 150 to 180 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexyl isocyanate) (SMDI), at 35% by weight in one mixture of propylene glycol (30%) and water (26%)), the family of modified starches such as modified potato starch sold under the name of Structure Solanace or mixtures thereof. Preferred gelling agents come from the family of polyacrylamides such as Simulgel 600 or Sepigel 305 or their mixtures. The gelling agent as described above can be used at the preferred concentrations ranging from 0.1 to 15% and, more preferably, ranging from 0.5 to 5%. The gels can be preferably prepared by dispersing or dissolving the metronidazole in an appropriate ratio, in a carbomer, poloxamer or cellulose type gel. Other advantages and features of the invention will appear from the examples below with respect to the inventive activity of metronidazole.

Example 1 - Activity of metronidazole. 1) Protocol: The PAC-1 receptor binding test was performed following the protocol described by Cauvin et al., 1991, Regul Peptides, vol. 35, pages 161-173. The IL-8RB receptor binding test was performed following the protocol described by White et al., 1998, J Biol Chem, vol. 273, pages 10095-10098. 2) Experimental conditions: The binding of metronidazole on each receptor was determined by the competition experiences. The receptor, recombinant human protein, was incubated according to the time indicated in Table 1 below, with a single concentration of labeled specific ligand, in the presence of 10 μM metronidazole. The bound radioactivity was measured by scintillation counting.

Table 1 3) Expression analysis of the results: The specific binding of the ligand to the receptor is defined as the difference between the total binding and the non-specific binding determined in the presence of an excess of unlabeled ligand. The results are expressed in percentage of controlled specific binding and percentage of inhibition of the specific controlled binding obtained in the presence of metronidazole (Table 2).

Table 2 In this way, metronidazole induces the binding of the ligand to its IL-8RB receptor and the PAC-1 receptor. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (12)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor.
2. 2. Use according to claim 1, wherein the metronidazole modulates the binding of at least one natural ligand to its receptor, the receptor of the group comprising the IL-8RB receptor and the PAC-1 receptor being chosen.
3. 3. Use according to claim 1 or 2, wherein the pathology involving at least one receptor selected from the group comprising the IL-8RB receptor and the PAC-1 receptor is rosacea.
4. 4. Use according to any of claims 1 to 3, wherein the pharmaceutical composition is a dermatological composition for topical application.
5. 5. Use according to any of claims 1 to 4, wherein the composition is intended for the treatment of at least one stage of rosacea.
6. 6. Use according to any of claims 1 to 5, wherein the composition is intended for the treatment of the first stage of rosacea.
7. 7. Use according to any of claims 1 to 6, wherein the composition is intended for the treatment of the second stage of rosacea.
8. 8. Use according to any of claims 1 to 7, wherein the composition is intended for the treatment of the third stage of rosacea.
9. 9. Use according to any of claims 1 to 8, wherein the composition is intended for the treatment of the fourth stage of rosacea.
10. 10. Use according to any of claims 1 to 9, wherein the composition contains in the order of 0.0001 to 20% metronidazole, preferably 0.1 to 2% metronidazole and more preferably in the order of 0.75 to 1% by weight of metronidazole.
11. 11. Use according to any of claims 1 to 10, wherein the composition further contains an active agent selected from the group of antibiotics, antibacterial, antiviral, antiparasitic, antifungal, anesthetic, analgesic, anti-allergic, retinoid, anti- free radicals, anti-pruritic, keratolytic, anti-seborrheic, anti-histamine, sulfide, immunosuppressant or antiproliferative products.
12. 12. Use according to any of claims 1 to 11, wherein the composition contains an additive selected from the group of sequestrants, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, colorants, bases or usual acids, minerals or organic, perfumes, essential oils, cosmetic actives, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, thickening agents and skin protectants, pro-penetrants, gelling agents or a mixture of these.