EP1732542A2 - Use of metronidazole for preparing a pharmaceutical composition for treating a cutaneous vascularisation disorder - Google Patents
Use of metronidazole for preparing a pharmaceutical composition for treating a cutaneous vascularisation disorderInfo
- Publication number
- EP1732542A2 EP1732542A2 EP05729333A EP05729333A EP1732542A2 EP 1732542 A2 EP1732542 A2 EP 1732542A2 EP 05729333 A EP05729333 A EP 05729333A EP 05729333 A EP05729333 A EP 05729333A EP 1732542 A2 EP1732542 A2 EP 1732542A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- receptor
- use according
- metronidazole
- composition
- chosen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Definitions
- the present invention relates to the field of the treatment of disorders of the skin vascularization, and more particularly the treatment of disorders of the skin vascularization in rosacea.
- the invention aims to provide new pharmaceutical compositions, more particularly dermatological compositions, useful for the treatment of disorders of the cutaneous vascularization, and more particularly the treatment of disorders of the cutaneous vascularization in rosacea and comprising as active agent metronidazole .
- Rosacea is a common chronic and progressive inflammatory dermatosis linked to vascular relaxation. It mainly affects the central part of the face and is characterized by reddening of the face or hot flashes, facial er, papules, pustules, and telangiectasia. In severe cases, especially in humans, the soft tissue in the nose can swell and produce a bulbous swelling called rhinophyma.
- Rosacea usually occurs between the ages of 25 and 70, and is much more common in fair skinned people. It affects more particularly women, although this condition is generally more severe in men. Rosacea is chronic and persists for years with periods of exacerbation and remission.
- Rosacea was originally called "acne rosacea” because its papules (slight raised skin) and inflammatory pustules (scabs of pus) are very similar to those of acne vulgaris.
- the etiology of which is based on both abnormal keratinization, increased sebum production and bacterial inflammation, inflammation of rosacea is vascular in nature and poorly understood.
- the result of this facial vascular anomaly is a permanent edema of the dermis which could accompany increased colonization by Demodex folliculorum, a mite that is usually found in the follicles of the face.
- stage 2 erythematato-telangiectatic (around 30 years).
- the malar areas are diffusely red.
- the chin and the middle part of the forehead can be affected.
- stage 4 of rhinophyma (around 50 years or later). This late phase mainly affects men, unlike the other stages.
- the nose is increased by volume, diffusely red and the follicular orifices are dilated.
- the skin gradually thickens.
- Minor forms of rosacea can be treated with active ingredients such as anti-seborrheics and anti-infectives, for example benzoyl peroxide, retinoic acid.
- active ingredients such as anti-seborrheics and anti-infectives, for example benzoyl peroxide, retinoic acid.
- active ingredients such as anti-seborrheics and anti-infectives, for example benzoyl peroxide, retinoic acid.
- active ingredients such as anti-seborrheics and anti-infectives, for example benzoyl peroxide, retinoic acid.
- benzoyl peroxide for example benzoyl peroxide, retinoic acid.
- cyclins As for the most diffuse forms of the disease, they respond well to general antibiotic therapy with cyclins. However, these treatments have unpleasant side effects for the patient, such as irritation or intolerance.
- the work of the Applicant has made it possible to demonstrate the interaction of metronidazole with the receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, the galanin in the treatment of rosacea.
- Beta-adrenergic receptors are involved in the regulation of various physiological functions, such as metabolic activity, cardiac activity, respiration, central nervous system activity, blood pressure and vascular tone.
- the 5-HT2 receptors the 5-HT5 receptors belong to the family of serotonin (5-HT) receptors. All 5-HT receptors are coupled to G proteins, except 5HT3 which is an ion channel. Activation of 5-HT2 receptors stimulates the activity of phospholipase C.
- the transduction system of 5-HT5 receptors is positively associated with adenylate cyclase.
- the AT1 receptor is involved in the regulation of vasoconstriction by angiotensin II.
- angiotensin II increases the tone of the subcutaneous arteries.
- Galanine is a peptide of 29 amino acids found in the central nervous system. According to certain studies, galanine has a role in the modulation of the cutaneous vascular reaction and in inflammation (Pincelli, 1990, Br J dermatol, vol. 122, pages 745-750).
- 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 to derivatives capable of altering the DNA structure of these cells.
- the work of the Applicant has made it possible to demonstrate the involvement of beta-adrenergic receptors, of the AT1 receptor, of the 5-HT2 receptor, of the 5-HT5 receptor, and of the galanin receptor in disorders of the cutaneous vascularization.
- the Applicant has now demonstrated the advantageous properties of metronidazole on disorders of the skin vascularization and more particularly on disorders of the skin vascularization in rosacea.
- metronidazole resulted in an interaction with beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor. More specifically, it has been found that the use of metronidazole inhibits the binding of natural ligands to these receptors.
- the invention aims to offer a new method of treatment of a cutaneous vascular disorder consisting in administering to a subject suffering from disorders of the cutaneous vascularization, an effective amount of metronidazole, in which metronidazole is capable of interact with at least one receptor chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
- the invention relates more particularly to the use of metronidazole for the preparation of a pharmaceutical composition, intended for the treatment of a disorder of the cutaneous vascularization. More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least one receptor chosen from the group comprising beta-adrenergic receptors, the AT1 receptor , the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
- the invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least two receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, 5-HT5 receptor, and the galanin receptor.
- the invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least three receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, 5-HT5 receptor, and the galanin receptor.
- the invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least four receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, 5-HT5 receptor, and the galanin receptor.
- the invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least five receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, 5-HT5 receptor, and the galanin receptor.
- the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, said vascular disorder being a component of rosacea and the metronidazole of said composition being capable of '' interact with at least one receptor selected from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
- the invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, in which metronidazole is capable of interacting with at least two receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
- the invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, in which metronidazole is capable of interacting with at least three receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
- the invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, in which metronidazole is capable of interacting with at least four receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
- the invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition defined above, in which metronidazole is capable of interacting with at least five receptors chosen from the group comprising beta-adrenergic receptors, the receptor AT1, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
- the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition in which metronidazole inhibits the binding of at least one natural ligand to its receptor, said receptor being chosen from the group comprising receptors beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
- composition object of the present invention is a dermatological composition, for topical administration on the skin.
- treatment of disorders of the skin vascularization is meant according to the present invention, the treatment and / or prevention of such a disorder.
- rosacea treatment is understood to mean, according to the present invention, the treatment and / or prevention of rosacea, in one or more of the stages described above.
- the composition is intended for the treatment of the first stage of rosacea.
- the composition is intended for the treatment of the second stage of rosacea.
- the composition is intended for the treatment of the third stage of rosacea.
- the composition is intended for the treatment of the fourth stage of rosacea.
- the composition contains 0.0001 to 20% by weight of metronidazole, preferably from 0.1 to 2%, and more preferably of the order of 0.75 to 1% of expressed metronidazole as a percentage by weight relative to the total weight of the composition.
- the present invention relates, in addition to the use of metronidazole, the use of derivatives thereof.
- derivatives means compounds which are distinguished from metronidazole, by substitution, addition or deletion of one or more chemical groups and having substantially the same activity.
- compositions of the invention comprise, in addition to metronidazole, at least one other therapeutic agent capable of increasing the effectiveness of the treatment.
- at least one other therapeutic agent capable of increasing the effectiveness of the treatment.
- antibiotics antibacterials, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergics, retinoids, anti-free radicals, antipruritics, keratolytics, antiseborrhoeics, antihistamines, sulfides, immunosuppressive or antiproliferative products.
- compositions of the invention may also comprise any additive usually used in the pharmaceutical, dermatological field, compatible with metronidazole. Mention may in particular be made of sequestrants, antioxidants, sun filters, preservatives, for example DL-alpha-tocopherol, fillers, electrolytes, humectants, dyes, bases or common acids, mineral or organic, fragrances, 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, penetrating agents , gelling agents.
- sequestrants for example DL-alpha-tocopherol
- fillers electrolytes, humectants, dyes, bases or common acids, mineral or organic, fragrances, 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, pe
- additives can be present in the composition in an amount of 0 to 20% by weight relative to the total weight of the composition.
- sequestering agents examples include ethylenediamine tetracetic acid (EDTA), as well as its derivatives or its salts, dihydroxyethylglycine, citric acid, tartaric acid, or mixtures thereof.
- EDTA ethylenediamine tetracetic acid
- preservatives examples include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea, parabens, or mixtures thereof.
- humectants examples include glycerin and sorbitol.
- compositions of the invention may contain one or more penetrating agents in preferential concentrations ranging from 0 to 20% and more preferably ranging from 0.6 to 3% by weight relative to the total weight of the composition.
- penetrating agents use is preferably made, without this list being limiting, of compounds such as propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol, ethoxydiglycol.
- the compositions according to the invention may also contain one or more surfactants in preferential concentrations ranging from 0 to 10% and more preferably ranging from 0.1 to 2%.
- compositions of the present invention may be in all the galenical forms normally used for topical application, in particular in the form of aqueous, hydroalcoholic or oily solutions, of lotion-type dispersions, of aqueous, anhydrous or lipophilic gels, of 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 vice versa (W / O), or of suspensions or emulsions of soft, semi-liquid or solid consistency of cream, gel or ointment type or microemulsions, micro-capsules, micro-particles or vesicular dispersions of ionic and / or non-ionic type.
- the creams can be formulated from a mixture of mineral oil, or a mixture of beeswax and water which instantly emulsifies, in which metronidazole is added, dissolved in a small amount of oil such as almond oil.
- Ointments can be formulated by mixing a solution of metronidazole in an oil such as almond oil in chiauffered paraffin, then allowing the mixture to cool.
- compositions according to the invention mention may be made of these islands comprising an active phase containing (expressed as a percentage by weight): - 0 to 90%, preferably 5 to 25%, in particular 10 to 20%, of water;
- aqueous phase comprising a gelling agent and water.
- the aqueous phase of a composition according to the invention in the form of an emulsion may comprise water, floral water such as blueberry water, or natural thermal or mineral water, for example chosen from Vittel water, Vichy basin water, Uriage water, Roche Pos ay water, Bourboule water, Enghien-les-Bains water, water of Saint Gervais-les-Bains, the water of Néris- les-Bains, water from Allevard-les-Bains, water from Digne, water from Maizines, water from Neyrac-les-Bains, water from Lons-le-Saunier, Eaux Bonnes , Rochefort water, Saint Christau water, Fumades water and Tercis-les-Bains water, Avene water or Aix les Bains water.
- Said aqueous phase may be present at a content of between 10 and 90% by weight relative to the total weight of the composition, preferably between 20 and 80% by weight.
- gelling agents of the polyacrylamide family such as the Sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 mixture sold under the name Simulgel 600 by the company Seppic, the polyacrylamide / isoparaffin C13-14 / laureth-7 like, for example, that 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 or 180 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexylisocyanate) (SMDI), at 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 Structure
- the 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 preferential concentrations ranging from 0.1 to 15% and, more preferably, ranging from 0.5 to 5%.
- the gels can preferably be prepared by dispersing or dissolving metronidazole in an appropriate ratio, in a gel of carbomer, poloxamer or cellulosic type.
- the AT1 receptor binding test was carried out according to the method described by
- the 5-HT 5A receptor binding test was carried out according to the method described by Ress et al, 1994, FEBS Lett, vol. 355, pages 242-246.
- the 5-HT ⁇ receptor binding test was carried out according to the method described by
- the galanin receptor binding test was carried out according to the method described by Sullivan et al, 1997, Biochem Biophys Res Comm, vol. 233, pages 823-828.
- the binding of metronidazole to each receptor was determined by competitive experiments.
- the receptor, recombinant human protein was incubated according to the times indicated in Table 1 below, with a single concentration of specific labeled ligand, in the presence of metronidazole at 10 ⁇ M. Bound radioactivity was measured by scintillation counting.
- 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.
- Metronidazole interacts and therefore inhibits binding to beta adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
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Abstract
The invention relates to the use of metronidazole for preparing a pharmaceutical composition for treating a cutaneous vascularisation disorder.
Description
UTILISATION DU METRONIDAZOLE POUR LA PREPARATION D'UNE COMPOSITION PHARMACEUTIQUE DESTINEE A TRAITER UN DESORDRE DE LA VASCULARISATION CUTANEE USE OF METRONIDAZOLE FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF SKIN VASCULARIZATION DISORDER
La présente invention concerne le domaine du traitement des désordres de la vascularisation cutanée, et plus particulièrement le traitement des désordres de la vascularisation cutanée dans la rosacée. L'invention vise à fournir de nouvelles compositions pharmaceutiques, plus particulièrement dermatologiques, utiles pour le traitement des désordres de la vascularisation cutanée, et plus particulièrement le traitement des désordres de la vascularisation cutanée dans la rosacée et comprenant à titre d'agent actif le metronidazole.The present invention relates to the field of the treatment of disorders of the skin vascularization, and more particularly the treatment of disorders of the skin vascularization in rosacea. The invention aims to provide new pharmaceutical compositions, more particularly dermatological compositions, useful for the treatment of disorders of the cutaneous vascularization, and more particularly the treatment of disorders of the cutaneous vascularization in rosacea and comprising as active agent metronidazole .
La rosacée est une dermatose inflammatoire commune chronique et progressive liée à une relaxation vasculaire. Elle affecte principalement la partie centrale du visage et se caractérise par le rougissement du visage ou les bouffées de chaleur, l'ér thème facial, les papules, les pustules, et la télangiectasie. Dans les cas graves, particulièrement chez l'homme, le tissu mou du nez peut enfler et produire un gonflement bulbeux appelé rhinophyma.Rosacea is a common chronic and progressive inflammatory dermatosis linked to vascular relaxation. It mainly affects the central part of the face and is characterized by reddening of the face or hot flashes, facial er, papules, pustules, and telangiectasia. In severe cases, especially in humans, the soft tissue in the nose can swell and produce a bulbous swelling called rhinophyma.
La rosacée survient généralement entre l'âge de 25 et 70 ans, et elle est beaucoup plus commune chez les gens au teint clair. Elle touche plus particulièrement les femmes, bien que cette affection soit généralement plus sévère chez l'homme. La rosacée est chronique et persiste des années avec des périodes d'exacerbation et de rémission.Rosacea usually occurs between the ages of 25 and 70, and is much more common in fair skinned people. It affects more particularly women, although this condition is generally more severe in men. Rosacea is chronic and persists for years with periods of exacerbation and remission.
La rosacée a originellement été appelée "acné rosacée" parce que ses papules (légères surélévations de la peau) et ses pustules inflammatoires (croûtes de pus) ressemblent beaucoup à celles de l'acné vulgaire. Contrairement à l'acné vulgaire, dont l'étiologie est fondée à la fois sur une kératinisation anormale, une augmentation de la production de sébum et une inflammation bactérienne, l'inflammation de la rosacée est de nature vasculaire et mal comprise. Il résulte de cette anomalie vasculaire faciale un oedème permanent du derme qui pourrait accompagner une colonisation accrue par Demodex folliculorum, acarien qu'on trouve habituellement dans les follicules du visage.
Selon différents travaux, Demodex fof/iculorum aurait un rôle étiologique dans la rosacée (Erbagi et al., 1998, Int J Dermatol, vol.37, pages 421-425; Purcell et al, 1986, J Am Acad Dermatol, vol.15, pages 1 159-1162; Sibenge et al., 1992, J Am Acad Dermatol, vol.26, pages 590-593). Il semble que Demodex folliculorum cause ou aggrave des réactions inflammatoires, se traduisant par des papules et des pustules, en bloquant les follicules pilo-sébacés du visage (Roihu et al., 1998, J Cutan Pathol, vol.25, pages 550-552). Ce parasite déclencherait par ailleurs une réponse immune humorale (Nunzi et al., 1980, Br J Dermatol, vol 103, pages 543-551 ; Manna et al., 1982, Br J Dermatol, vol 107, pages 203-208). La pathogenèse de la rosacée est mal connue. De nombreux facteurs peuvent être impliqués sans forcément induire cette affection. Ce sont par exemple des facteurs psychologiques, des troubles gastro-intestinaux, des facteurs environnementaux (exposition au soleil, température, humidité) et émotionnels (stress), alimentaires (alcool, épices), hormonaux, vasculaires, voire une infection par Helicohacter pilori.Rosacea was originally called "acne rosacea" because its papules (slight raised skin) and inflammatory pustules (scabs of pus) are very similar to those of acne vulgaris. Unlike acne vulgaris, the etiology of which is based on both abnormal keratinization, increased sebum production and bacterial inflammation, inflammation of rosacea is vascular in nature and poorly understood. The result of this facial vascular anomaly is a permanent edema of the dermis which could accompany increased colonization by Demodex folliculorum, a mite that is usually found in the follicles of the face. According to various studies, Demodex fof / iculorum has 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 1 159-1162; Sibenge et al., 1992, J Am Acad Dermatol, vol. 26, pages 590-593). It seems that Demodex folliculorum causes or worsens inflammatory reactions, resulting in papules and pustules, by blocking the pilosebaceous 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 poorly understood. Many factors can be involved without necessarily inducing this condition. These are for example psychological factors, gastrointestinal disorders, environmental factors (exposure to the sun, temperature, humidity) and emotional factors (stress), food (alcohol, spices), hormonal, vascular, even an infection with Helicohacter pillory.
La rosacée évolue en 4 stades, mais le passage par tous les stades n'est pas obligatoire :Rosacea develops in 4 stages, but passing through all stages is not compulsory:
- stade 1 des relaxations vasculaires (vers 20 ans). Les patients ont des poussées soudaines de rougeur paroxystique du visage et du cou, avec sensation de chaleur, mais sans signes systémiques. Après les crises, la peau du visage redevient normale. Ces « flushes » sont déclenchés par les changements de température (entraînant parfois une thermophobie), l'absorption de boissons chaudes ou d'alcool.- stage 1 of vascular relaxations (around 20 years). Patients have sudden onset of paroxysmal redness of the face and neck, with a feeling of warmth, but without systemic signs. After the attacks, the facial skin becomes normal again. These "flushes" are triggered by changes in temperature (sometimes leading to thermophobia), the absorption of hot drinks or alcohol.
- stade 2 érythémato-télangiectasique (vers 30 ans). Les zones malaires sont diffusément rouges. On y observe des capillaires dilatés constituant la classique couperose. A la différence du stade 1 , la rougeur est permanente. Outre les joues, le menton et la partie médiane du front peuvent être touchés.- stage 2 erythematato-telangiectatic (around 30 years). The malar areas are diffusely red. We observe dilated capillaries constituting the classic rosacea. Unlike stage 1, the redness is permanent. In addition to the cheeks, the chin and the middle part of the forehead can be affected.
- stade 3 des papulo-pustules (vers 40 ans). Sur un fond d'érythème se développent des papules et des pustules de quelques millimètres de diamètre, sans comédons associés. Cette dermatose peut être très étendue, parfois à la partie glabre du cuir chevelu chez l'homme, mais respecte le pourtour de la bouche et des yeux. Les patients se plaignent d'une peau sensible, avec intolérance subjective à la plupart des topiques et des cosmétiques gras.- stage 3 of papulo-pustules (around 40 years). On a background of erythema develop papules and pustules a few millimeters in diameter, without associated comedones. This dermatosis can be very widespread, sometimes to the glabrous part of the scalp in men, but respects the periphery of the mouth and the eyes. Patients complain of sensitive skin, with subjective intolerance to most oily topicals and cosmetics.
- stade 4 du rhinophyma (vers 50 ans ou plus tard). Cette phase tardive touche principalement les hommes, contrairement aux autres stades. Le nez est augmenté de
volume, diffusément rouge et les orifices folliculaires sont dilatés. La peau s'épaissit progressivement.- stage 4 of rhinophyma (around 50 years or later). This late phase mainly affects men, unlike the other stages. The nose is increased by volume, diffusely red and the follicular orifices are dilated. The skin gradually thickens.
Les formes mineures de la rosacée peuvent être traitées par des actifs tels que les anti-séborrhéiques et les anti-infectieux, par exemple le peroxyde de benzoyle, l'acide rétinoïque. Quant aux formes les plus diffuses de l'affection, elles répondent bien à une antibiothérapie générale par les cyclines. Cependant, ces traitements présentent des effets secondaires désagréables pour le patient tels des phénomènes d'irritation ou d'intolérance.Minor forms of rosacea can be treated with active ingredients such as anti-seborrheics and anti-infectives, for example benzoyl peroxide, retinoic acid. As for the most diffuse forms of the disease, they respond well to general antibiotic therapy with cyclins. However, these treatments have unpleasant side effects for the patient, such as irritation or intolerance.
De plus, en raison de l'aspect multi-factoriel de la rosacée, il existe de très nombreuses thérapies contre cette affection, mais on est encore à la recherche d'un traitement efficace et sans risque pour le patient.In addition, due to the multi-factor aspect of rosacea, there are many therapies against this condition, but we are still looking for an effective and safe treatment for the patient.
Les travaux de la Demanderesse ont permis de mettre en évidence l'interaction du metronidazole avec les récepteurs choisis dans le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, le récepteur de la galanine dans le traitement de la rosacée.The work of the Applicant has made it possible to demonstrate the interaction of metronidazole with the receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, the galanin in the treatment of rosacea.
Les récepteurs bêta-adrenergiques sont impliqués dans la régulation de diverses fonctions physiologiques, telles que l'activité métabolique, l'activité cardiaque, la respiration, l'activité du système nerveux central, la pression sanguine et le tonus vasculaire.Beta-adrenergic receptors are involved in the regulation of various physiological functions, such as metabolic activity, cardiac activity, respiration, central nervous system activity, blood pressure and vascular tone.
Les récepteurs 5-HT2, les récepteurs 5-HT5 appartiennent à la famille des récepteurs de la sérotonine (5-HT). L'ensemble des récepteurs de la 5-HT sont couplés aux protéines G, sauf la 5HT3 qui est un canal ionique. L'activation des récepteurs 5-HT2 stimule l'activité de la phospholipase C. Le système de transduction des récepteurs 5- HT5 est associé positivement à l'adénylate cyclase.The 5-HT2 receptors, the 5-HT5 receptors belong to the family of serotonin (5-HT) receptors. All 5-HT receptors are coupled to G proteins, except 5HT3 which is an ion channel. Activation of 5-HT2 receptors stimulates the activity of phospholipase C. The transduction system of 5-HT5 receptors is positively associated with adenylate cyclase.
Le récepteur AT1 est impliqué dans la régulation de la vasoconstriction par l'angiotensine II. Chez l'homme, l'angiotensine II augmente le tonus des artères subcutanées.
La galanine est un peptide de 29 acides aminés présent dans le système nerveux centrai. Selon certains travaux, la galanine aurait un rôle dans la modulation de la réaction vasculaire cutanée et dans l'inflammation (Pincelli, 1990, Br J dermatol, vol.122, pages 745-750).The AT1 receptor is involved in the regulation of vasoconstriction by angiotensin II. In humans, angiotensin II increases the tone of the subcutaneous arteries. Galanine is a peptide of 29 amino acids found in the central nervous system. According to certain studies, galanine has a role in the modulation of the cutaneous vascular reaction and in inflammation (Pincelli, 1990, Br J dermatol, vol. 122, pages 745-750).
Le metronidazole, ou (methyl-2-nitro-5-imidazolyl)-2-éthanol, est connu dans l'art antérieur pour ses propriétés antibactérienne, antiparasitaire et antiprotozoaire. Il exerce une toxicité sélective vis à vis des microorganismes anaérobies ainsi que des cellules hypoxiques, Au niveau de ces dernières, le metronidazole est réduit en dérivés capables d'altérer la structure ADN de ces cellules.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 to derivatives capable of altering the DNA structure of these cells.
Les travaux de la Demanderesse ont permis de mettre en évidence l'implication des récepteurs bêta-adrénergiques, du récepteur AT1 , du récepteur 5-HT2, du récepteur 5- HT5, et du récepteur de la galanine dans les désordres de la vascularisation cutanée.The work of the Applicant has made it possible to demonstrate the involvement of beta-adrenergic receptors, of the AT1 receptor, of the 5-HT2 receptor, of the 5-HT5 receptor, and of the galanin receptor in disorders of the cutaneous vascularization.
La Demanderesse a maintenant mis en évidence les propriétés intéressantes du metronidazole sur les désordres de la vascularisation cutanée et plus particulièrement sur les désordres de la vascularisation cutanée dans la rosacée.The Applicant has now demonstrated the advantageous properties of metronidazole on disorders of the skin vascularization and more particularly on disorders of the skin vascularization in rosacea.
II a été constaté de façon surprenante que l'utilisation du metronidazole avait pour conséquence une interaction avec les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine. De façon plus particulière, il a été constaté que l'utilisation du metronidazole inhibe la fixation des ligands naturels sur ces récepteurs.It was surprisingly found that the use of metronidazole resulted in an interaction with beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor. More specifically, it has been found that the use of metronidazole inhibits the binding of natural ligands to these receptors.
Comme indiqué précédemment, l'invention vise à offrir une nouvelle méthode de traitement d'un désordre vasculaire cutané consistant à administrer à un sujet, atteint de désordres de la vascularisation cutanée, une quantité efficace de metronidazole, dans laquelle le metronidazole est capable d'interagir avec au moins un récepteur choisi dans le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.As indicated previously, the invention aims to offer a new method of treatment of a cutaneous vascular disorder consisting in administering to a subject suffering from disorders of the cutaneous vascularization, an effective amount of metronidazole, in which metronidazole is capable of interact with at least one receptor chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
En conséquence l'invention se rapporte plus particulièrement à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique, destinée au traitement d'un désordre de la vascularisation cutanée.
Plus particulièrement, l'invention se rapporte à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique destinée au traitement d'un désordre vasculaire cutané, impliquant au moins un récepteur choisi le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5- HT5, et le récepteur de la galanine.Consequently, the invention relates more particularly to the use of metronidazole for the preparation of a pharmaceutical composition, intended for the treatment of a disorder of the cutaneous vascularization. More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least one receptor chosen from the group comprising beta-adrenergic receptors, the AT1 receptor , the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
L'invention se rapporte également à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique destinée au traitement d'un désordre vasculaire cutané, impliquant au moins deux récepteurs choisis le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5- HT5, et le récepteur de la galanine.The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least two receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, 5-HT5 receptor, and the galanin receptor.
L'invention se rapporte également à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique destinée au traitement d'un désordre vasculaire cutané, impliquant au moins trois récepteurs choisis le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5- HT5, et le récepteur de la galanine.The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least three receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, 5-HT5 receptor, and the galanin receptor.
L'invention se rapporte également à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique destinée au traitement d'un désordre vasculaire cutané, impliquant au moins quatre récepteurs choisis le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5- HT5, et le récepteur de la galanine.The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least four receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, 5-HT5 receptor, and the galanin receptor.
L'invention se rapporte également à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique destinée au traitement d'un désordre vasculaire cutané, impliquant au moins cinq récepteurs choisis le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5- HT5, et le récepteur de la galanine.The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, involving at least five receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, 5-HT5 receptor, and the galanin receptor.
Plus particulièrement, l'invention se rapporte à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique destinée au traitement d'un désordre vasculaire cutané, ledit désordre vasculaire étant une composante de la rosacée et le metronidazole de ladite composition étant capable d'interagir avec au moins un
récepteur choisi dans le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of a cutaneous vascular disorder, said vascular disorder being a component of rosacea and the metronidazole of said composition being capable of '' interact with at least one receptor selected from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
L'invention se rapporte également à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique telle que définie précédemment, dans laquelle le metronidazole est capable d'interagir avec au moins deux récepteurs choisis dans le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, in which metronidazole is capable of interacting with at least two receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
L'invention se rapporte également à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique telle que définie précédemment, dans laquelle le metronidazole est capable d'interagir avec au moins trois récepteurs choisis dans le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, in which metronidazole is capable of interacting with at least three receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
L'invention se rapporte également à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique telle que définie précédemment, dans laquelle le metronidazole est capable d'interagir avec au moins quatre récepteurs choisis dans le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, in which metronidazole is capable of interacting with at least four receptors chosen from the group comprising beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
L'invention se rapporte également à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique définie précédemment, dans laquelle le metronidazole est capable d'interagir avec au moins cinq récepteurs choisis dans le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition defined above, in which metronidazole is capable of interacting with at least five receptors chosen from the group comprising beta-adrenergic receptors, the receptor AT1, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
Plus particulièrement, l'invention se rapporte à l'utilisation du metronidazole pour la préparation d'une composition pharmaceutique dans laquelle le metronidazole inhibe la fixation d'au moins un ligand naturel sur son récepteur, ledit récepteur étant choisi dans le groupe comprenant les récepteurs bêta-adrénergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition in which metronidazole inhibits the binding of at least one natural ligand to its receptor, said receptor being chosen from the group comprising receptors beta-adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
La composition objet de la présente invention est une composition dermatologique, pour administration topique sur la peau.
Par traitement des désordres de la vascularisation cutanée, on entend selon la présente invention, le traitement et/ou la prévention d'un tel désordre.The composition object of the present invention is a dermatological composition, for topical administration on the skin. By treatment of disorders of the skin vascularization is meant according to the present invention, the treatment and / or prevention of such a disorder.
Par traitement de la rosacée, on entend selon la présente invention, le traitement et/ou la prévention de la rosacée, à l'un ou plusieurs des stades décrits précédemment.The term “rosacea treatment” is understood to mean, according to the present invention, the treatment and / or prevention of rosacea, in one or more of the stages described above.
Suivant un premier mode de mise en œuvre de l'invention, la composition est destinée au traitement du premier stade de la rosacée.According to a first embodiment of the invention, the composition is intended for the treatment of the first stage of rosacea.
Suivant un deuxième mode de mise en oeuvre de l'invention, la composition est destinée au traitement du deuxième stade de la rosacée.According to a second embodiment of the invention, the composition is intended for the treatment of the second stage of rosacea.
Suivant un troisième mode de mise en oeuvre de l'invention, la composition est destinée au traitement du troisième stade de la rosacée.According to a third embodiment of the invention, the composition is intended for the treatment of the third stage of rosacea.
Suivant un quatrième mode de mise en oeuvre de l'invention, la composition est destinée au traitement du quatrième stade de la rosacée.According to a fourth embodiment of the invention, the composition is intended for the treatment of the fourth stage of rosacea.
Suivant un mode préférentiel de mise en oeuvre, la composition contient 0,0001 à 20% en poids de metronidazole, de préférence de 0,1 à 2%, et plus préférentiellement de l'ordre de 0,75 à 1% de metronidazole exprimé en pourcentage en poids par rapport au poids total de la composition.According to a preferred embodiment, the composition contains 0.0001 to 20% by weight of metronidazole, preferably from 0.1 to 2%, and more preferably of the order of 0.75 to 1% of expressed metronidazole as a percentage by weight relative to the total weight of the composition.
Bien entendu la présente invention concerne, outre l'utilisation du metronidazole, l'utilisation de dérivés de celui-ci. On entend par dérivés des composés qui se distinguent du metronidazole, par substitution, addition ou suppression d'un ou plusieurs groupements chimiques et présentant sensiblement la même activité.Of course the present invention relates, in addition to the use of metronidazole, the use of derivatives thereof. The term derivatives means compounds which are distinguished from metronidazole, by substitution, addition or deletion of one or more chemical groups and having substantially the same activity.
Avantageusement, les compositions de l'invention comprennent outre le metronidazole au moins un autre agent thérapeutique susceptible d'augmenter l'efficacité du traitement. A titre d'exemples non limitatifs de tels agents, on peut citer des antibiotiques, des antibactériens, des antiviraux, des antiparasitaires, des antifongiques, des anesthésiques, des analgésiques, des antiallergiques, des rétinoïdes, des anti-radicaux libres, des antiprurigineux, des kératolytiques, des
antiséborrhéiques, des anti-histaminiques, des sulfures, des produits immunosuppresseurs ou antiprolifératifs.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. By way of nonlimiting examples of such agents, mention may be made of antibiotics, antibacterials, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergics, retinoids, anti-free radicals, antipruritics, keratolytics, antiseborrhoeics, antihistamines, sulfides, immunosuppressive or antiproliferative products.
Les compositions de l'invention peuvent comprendre en outre tout additif usuellement utilisé dans le domaine pharmaceutique, dermatologique, compatible avec le metronidazole. On peut citer notamment des séquestrants, des antioxydants, des filtres solaires, des conservateurs, par exemple la DL-alpha-tocophérol, des charges, des électrolytes, des humectants, des colorants, de bases ou d'acides usuels, minéraux ou organiques, des parfums, des huiles essentielles, des actifs cosmétiques, des hydratants, des vitamines, des acides gras essentiels, des sphingolipides, des composés autobronzants tels que la DHA, des agents apaisants et protecteurs de la peau tels que l'allantoïne, des agents propénétrants, des gélifiants. Bien entendu l'homme du métier veillera à choisir ce ou ces éventuels composés complémentaires, et/ou leur quantité, de manière telle, que les propriétés avantageuses de la composition selon l'invention ne soient pas, ou substantiellement pas, altérées.The compositions of the invention may also comprise any additive usually used in the pharmaceutical, dermatological field, compatible with metronidazole. Mention may in particular be made of sequestrants, antioxidants, sun filters, preservatives, for example DL-alpha-tocopherol, fillers, electrolytes, humectants, dyes, bases or common acids, mineral or organic, fragrances, 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, penetrating agents , gelling agents. 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, altered.
Ces additifs peuvent être présents dans la composition à raison de 0 à 20 % en poids par rapport au poids total de la composition.These additives can be present in the composition in an amount of 0 to 20% by weight relative to the total weight of the composition.
On peut citer comme exemples d'agents séquestrants, l'acide ethylenediamine tétracétique (EDTA), ainsi que ses dérivés ou ses sels, la dihydroxyethylglycine, l'acide citrique, l'acide tartrique, ou leurs mélanges.Examples of sequestering agents that may be mentioned include ethylenediamine tetracetic acid (EDTA), as well as its derivatives or its salts, dihydroxyethylglycine, citric acid, tartaric acid, or mixtures thereof.
On peut citer comme exemples de conservateurs le chlorure de benzalkonium, le phénoxyéthanol, l'alcool benzylique, la diazolidinylurée, les parabens, ou leurs mélanges.Examples of preservatives that may be mentioned include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea, parabens, or mixtures thereof.
On peut citer comme exemples d'agents humectants, la glycérine et le sorbitol.Examples of humectants that may be mentioned include glycerin and sorbitol.
Les compositions de l'invention peuvent contenir un ou plusieurs agents propénétrants dans des concentrations préférentielles allant de 0 à 20 % et plus préférentiellement allant de 0,6 à 3% en poids par rapport au poids total de la composition. Parmi les agents propénétrants, on utilise préférentiellement, sans que cette liste soit limitative, des composés tels que le propylène glycol, le dipropylène glycol, le propylène glycol dipélargonate, le lauroglycol, l'éthoxydiglycol.
Avantageusement, les compositions selon l'invention peuvent contenir également un ou plusieurs agents tensioactifs dans des concentrations préférentielles allant de 0 à 10 % et plus préférentiellement allant de 0,1 à 2 %.The compositions of the invention may contain one or more penetrating agents in preferential concentrations ranging from 0 to 20% and more preferably ranging from 0.6 to 3% by weight relative to the total weight of the composition. Among the penetrating agents, use is preferably made, without this list being limiting, of compounds such as propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol, ethoxydiglycol. Advantageously, the compositions according to the invention may also contain one or more surfactants in preferential concentrations ranging from 0 to 10% and more preferably ranging from 0.1 to 2%.
Les compositions de la présente invention peuvent se présenter sous toutes les formes galéniques normalement utilisées pour une application topique, notamment sous forme de solutions aqueuses, hydroalcooliques ou huileuses, de dispersions du type lotion, de gels aqueux, anhydres ou lipophiles, d'émulsions de consistance liquide ou semi- liquide du type lait, obtenues par dispersion d'une phase grasse clans une phase aqueuse (H/E) ou inversement (E/H), ou de suspensions ou émulsions de consistance molle, semi-liquide ou solide du type crème, gel ou pommade ou encore de micro- émulsions, de micro-capsules, de micro-particules ou de dispersions vésiculaires de type ionique et/ou non ionique. De préférence les crèmes peuvent être formulées à partir d'un mélange d'huile minérale, ou d'un mélange de cire d'abeille et d'eau qui s'émulsifie instantanément, dans lequel on additionne metronidazole, dissout dans une petite quantité d'huile telle que l'huile d'amande. Les pommades peuvent être formulées en mélangeant une solution d e metronidazole dans une huile telle que l'huile d'amande dans de la paraffine chiauffée, puis en laissant refroidir le mélange.The compositions of the present invention may be in all the galenical forms normally used for topical application, in particular in the form of aqueous, hydroalcoholic or oily solutions, of lotion-type dispersions, of aqueous, anhydrous or lipophilic gels, of 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 vice versa (W / O), or of suspensions or emulsions of soft, semi-liquid or solid consistency of cream, gel or ointment type or microemulsions, 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 and water which instantly emulsifies, in which metronidazole is added, dissolved in a small amount of oil such as almond oil. Ointments can be formulated by mixing a solution of metronidazole in an oil such as almond oil in chiauffered paraffin, then allowing the mixture to cool.
A titre d'exemples de compositions selon l'invention, on peut citer ce Iles comprenant une phase active contenant (exprimé en pourcentage en poids) : - 0 à 90 %, préférentiellement 5 à 25 %, notamment 10 à 20 %, d'eau ;As examples of compositions according to the invention, mention may be made of these islands comprising an active phase containing (expressed as a percentage by weight): - 0 to 90%, preferably 5 to 25%, in particular 10 to 20%, of water;
- 0 à 10 %, préférentiellement 0 à 2 %, notamment 0 à 0,5 %, de tensio actif ;- 0 to 10%, preferably 0 to 2%, especially 0 to 0.5%, of surfactant;
- 0 à 20 %, préférentiellement 0 à 10 %, notamment 2 à 5 %, de propénétrant ;- 0 to 20%, preferably 0 to 10%, in particular 2 to 5%, of propenetrant;
- 0,0001 à 20% préférentiellement 0,1 à 2%, de metronidazole ; et une phase aqueuse comprenant un gélifiant et de l'eau.- 0.0001 to 20%, preferably 0.1 to 2%, of metronidazole; and an aqueous phase comprising a gelling agent and water.
La phase aqueuse d'une composition selon l'invention se présentant sous la forme d'une émulsion peut comprendre de l'eau, une eau florale telle que l'eau de bleuet, ou une eau thermale ou minérale naturelle, par exemple choisie parmi l'eau de Vittel, les eaux du bassin de Vichy, l'eau d'Uriage, l'eau de la Roche Pos ay, l'eau de la Bourboule, l'eau d'Enghien-les-Bains, l'eau de Saint Gervais-les-Bains , l'eau de Néris-
les-Bains, l'eau d'Allevard-les-Bains, l'eau de Digne, l'eau de Maizières, l'eau de Neyrac-les-Bains, l'eau de Lons-le-Saunier, les Eaux Bonnes, l'eau de Rochefort, l'eau de Saint Christau, l'eau des Fumades et l'eau de Tercis-les-bains, l'eau d'Avène ou l'eau d'Aix les Bains. Ladite phase aqueuse peut être présente à une teneur comprise entre 10 et 90 % en poids par rapport au poids total de la composition, de préférence comprise entre 20 et 80 % en poids.The aqueous phase of a composition according to the invention in the form of an emulsion may comprise water, floral water such as blueberry water, or natural thermal or mineral water, for example chosen from Vittel water, Vichy basin water, Uriage water, Roche Pos ay water, Bourboule water, Enghien-les-Bains water, water of Saint Gervais-les-Bains, the water of Néris- les-Bains, water from Allevard-les-Bains, water from Digne, water from Maizières, water from Neyrac-les-Bains, water from Lons-le-Saunier, Eaux Bonnes , Rochefort water, Saint Christau water, Fumades water and Tercis-les-Bains water, Avene water or Aix les Bains water. Said aqueous phase may be present at a content of between 10 and 90% by weight relative to the total weight of the composition, preferably between 20 and 80% by weight.
A titre d'exemples non limitatifs, on peut citer les gélifiants de la famille des polyacrylamides tels que le mélange Sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 vendu sous le nom Simulgel 600 par la société Seppic, le mélange polyacrylamide / isoparaffine C13-14 / laureth-7 comme, par exemple, celui vendu sous le nom de Sepigel 305 par la société Seppic, la famille des polymères acryliques couplés à des chaînes hydrophobes tel que le PEG- 150/decyl/SMDI copolymère vendu sous le nom de Aculyn 44 (polycondensat comprenant au moins comme éléments, un polyéthylèneglycol à 150 ou 180 moles d'oxyde d'éthylène, de l'alcool décylique et du méthylène bis(4-cyclohexylisocyanate) (SMDI), à 35% en poids dans un mélange de propylèneglycol (39%) et d'eau (26%)), la famille des amidons modifiés tels que l'amidon de pomme de terre modifié vendu sous le nom de Structure Solanace ou bien leurs mélanges.By way of nonlimiting examples, there may be mentioned gelling agents of the polyacrylamide family such as the Sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 mixture sold under the name Simulgel 600 by the company Seppic, the polyacrylamide / isoparaffin C13-14 / laureth-7 like, for example, that 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 or 180 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexylisocyanate) (SMDI), at 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 Structure Solanace or their mixtures.
Les gélifiants préférés sont issus de la famille des polyacrylamides tel que le Simulgel 600 ou le Sepigel 305 ou leurs mélanges.The preferred gelling agents come from the family of polyacrylamides such as Simulgel 600 or Sepigel 305 or their mixtures.
Le gélifiant tel que décrit ci-dessus peut être utilisé aux concentrations préférentielles allant de 0,1 à 15 % et, plus préférentiellement, allant de 0,5 à 5 %. Les gels peuvent être préparés de préférence en dispersant ou en dissolvant le metronidazole dans un rapport approprié, dans un gel de type carbomère, poloxamère ou cellulosique.The gelling agent as described above can be used at preferential concentrations ranging from 0.1 to 15% and, more preferably, ranging from 0.5 to 5%. The gels can preferably be prepared by dispersing or dissolving metronidazole in an appropriate ratio, in a gel of carbomer, poloxamer or cellulosic type.
D'autres avantages et caractéristiques de l'invention apparaîtront des exemples ci- après concernant l'activité du metronidazole.Other advantages and characteristics of the invention will appear from the examples below concerning the activity of metronidazole.
Exemple 1 : Activité du metronidazoleExample 1: Activity of metronidazole
1) Protocole :
Le test de liaison aux récepteurs bêta-1 et bêta-2 adrénergiques a été réalisé suivant la méthode décrite par Smith et Teiler 1999, Cardiovasc Drug Ther, vol.13, pages 123-1) Protocol: The beta-1 and beta-2 adrenergic receptor binding test was carried out according to the method described by Smith and Teiler 1999, Cardiovasc Drug Ther, vol.13, pages 123-
126.126.
Le test de liaison au récepteur AT1 a été réalisé suivant la méthode décrite parThe AT1 receptor binding test was carried out according to the method described by
Bergsma et al, 1992, Biochem Biophys Res Comm, vol.183, pages 989-995.Bergsma et al, 1992, Biochem Biophys Res Comm, vol. 183, pages 989-995.
Le test de liaison au récepteur 5-HT5A a été réalisé suivant la méthode décrite par Ress et al, 1994, FEBS Lett, vol.355, pages 242-246.The 5-HT 5A receptor binding test was carried out according to the method described by Ress et al, 1994, FEBS Lett, vol. 355, pages 242-246.
Le test de liaison au récepteur 5-HT^ a été réalisé suivant la méthode décrite parThe 5-HT ^ receptor binding test was carried out according to the method described by
Bonhauss et al, 1995, Brit J Pharmacol, vol.1155, pages 622-628.Bonhauss et al, 1995, Brit J Pharmacol, vol. 1155, pages 622-628.
Le test de liaison au récepteur de la galanine a été réalisé suivant la méthode décrite par Sullivan et al, 1997, Biochem Biophys Res Comm, vol.233, pages 823-828.The galanin receptor binding test was carried out according to the method described by Sullivan et al, 1997, Biochem Biophys Res Comm, vol. 233, pages 823-828.
2) Conditions expérimentales :2) Experimental conditions:
La liaison de metronidazole sur chaque récepteur a été déterminée par des expériences de compétition. Le récepteur, protéine humaine recombina nte, a été incubé selon des temps indiqués dans le tableau 1 ci-dessous, avec ι_ιne simple concentration de ligand spécifique marqué, en présence du metronidazole à 10 μM. La radioactivité liée a été mesurée par comptage de la scintillation.The binding of metronidazole to each receptor was determined by competitive experiments. The receptor, recombinant human protein, was incubated according to the times indicated in Table 1 below, with a single concentration of specific labeled ligand, in the presence of metronidazole at 10 μM. Bound radioactivity was measured by scintillation counting.
Tableau 1Table 1
3) Analyse et expression des résultats : 3) Analysis and expression of results:
La liaison spécifique du ligand au récepteur est définie comme la différence entre la liaison totale et la liaison non spécifique déterminée en présence d'un excès de ligand non marqué.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.
Les résultats sont exprimés en pourcentage de liaison spécifique contrôle et en pourcentage d'inhibition de la liaison spécifique contrôle obtenue en présence du metronidazole (tableau 2).The results are expressed in percentage of specific control binding and in percentage of inhibition of specific control binding obtained in the presence of metronidazole (Table 2).
Le metronidazole interagit et donc inhibe la liaison aux récepteurs bêta adrénergiques, au récepteur AT1 , au récepteur 5-HT2, au récepteur 5-HT5, et au récepteur de la galanine.
Metronidazole interacts and therefore inhibits binding to beta adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
Claims
REVENDICATIONS
1) Utilisation du metronidazole pour la préparation d'une composition pharmaceutique destinée à traiter un désordre de la vascularisation cutanée.1) Use of metronidazole for the preparation of a pharmaceutical composition intended for treating a disorder of the cutaneous vascularization.
2) Utilisation selon la revendication 1 , caractérisée en ce que ledit désordre vasculaire cutané implique au moins un récepteur choisi dans le groupe comprenant les récepteurs bêta adrenergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5- HT5, et le récepteur de la galanine.2) Use according to claim 1, characterized in that said cutaneous vascular disorder involves at least one receptor chosen from the group comprising beta adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the receptor galanin.
3) Utilisation selon la revendication 1 ou 2, caractérisée en ce que ledit désordre vasculaire cutané implique au moins deux récepteurs choisis dans le groupe comprenant les récepteurs bêta adrenergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.3) Use according to claim 1 or 2, characterized in that said cutaneous vascular disorder involves at least two receptors chosen from the group comprising beta adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
4) Utilisation selon l'une quelconque des revendications 1 à 3, caractérisée en ce que ledit désordre vasculaire cutané implique au moins trois récepteurs choisis dans le groupe comprenant les récepteurs bêta adrenergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.4) Use according to any one of claims 1 to 3, characterized in that said cutaneous vascular disorder involves at least three receptors chosen from the group comprising beta adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the receptor 5 -HT5, and the galanin receptor.
5) Utilisation du selon l'une quelconque des revendications 1 à 4, caractérisée en ce que ledit désordre vasculaire cutané implique au moins quatre récepteurs choisis dans le groupe comprenant les récepteurs bêta adrenergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.5) Use of according to any one of claims 1 to 4, characterized in that said cutaneous vascular disorder involves at least four receptors chosen from the group comprising beta adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the receptor 5-HT5, and the galanin receptor.
6) Utilisation du metronidazole selon l'une quelconque des revendications 1 à 5, caractérisée en ce que ledit désordre vasculaire cutané implique au moins cinq récepteurs choisis dans le groupe comprenant les récepteurs bêta adrenergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.6) Use of metronidazole according to any one of claims 1 to 5, characterized in that said cutaneous vascular disorder involves at least five receptors chosen from the group comprising beta adrenergic receptors, the AT1 receptor, the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
7) Utilisation selon la revendication 1 , caractérisée en ce que ledit désordre vasculaire est une composante de la rosacée et en ce que le metronidazole est capable d'interagir avec au moins un récepteur choisi dans le groupe comprenant les récepteurs bêta adrenergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5- HT5, et le récepteur de la galanine.
8) Utilisation selon l'une quelconque des revendications 1 à 7, caractérisée en ce que le metronidazole inhibe la fixation d'au moins un ligand naturel sur son récepteur, ledit récepteur étant choisi dans le groupe comprenant les récepteurs bêta adrenergiques, le récepteur AT1 , le récepteur 5-HT2, le récepteur 5-HT5, et le récepteur de la galanine.7) Use according to claim 1, characterized in that said vascular disorder is a component of rosacea and in that metronidazole is capable of interacting with at least one receptor chosen from the group comprising beta adrenergic receptors, the AT1 receptor , the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor. 8) Use according to any one of claims 1 to 7, characterized in that metronidazole inhibits the binding of at least one natural ligand to its receptor, said receptor being chosen from the group comprising beta adrenergic receptors, the AT1 receptor , the 5-HT2 receptor, the 5-HT5 receptor, and the galanin receptor.
9) Utilisation selon l'une quelconque des revendications 1 à 8, caractérisée en ce que ladite composition pharmaceutique est une composition dermatologique pour application topique.9) Use according to any one of claims 1 to 8, characterized in that said pharmaceutical composition is a dermatological composition for topical application.
10) Utilisation selon l'une quelconque des revendications 1 à 9, caractérisée en ce que la composition est destinée au traitement d'au moins un stade de la rosacée.10) Use according to any one of claims 1 to 9, characterized in that the composition is intended for the treatment of at least one stage of rosacea.
11) Utilisation selon l'une quelconque des revendications 1 à 10, caractérisée en ce que la composition est destinée au traitement du premier stade de la rosacée.11) Use according to any one of claims 1 to 10, characterized in that the composition is intended for the treatment of the first stage of rosacea.
12) Utilisation selon l'une quelconque des revendications 1 à 11 , caractérisée en ce que la composition est destinée au traitement du deuxième stade de la rosacée.12) Use according to any one of claims 1 to 11, characterized in that the composition is intended for the treatment of the second stage of rosacea.
13) Utilisation selon l'une quelconque des revendications 1 à 12, caractérisée en ce que la composition est destinée au traitement du troisième stade de la rosacée.13) Use according to any one of claims 1 to 12, characterized in that the composition is intended for the treatment of the third stage of rosacea.
14) Utilisation selon l'une quelconque des revendications 1 à 13, caractérisée en ce que la composition est destinée au traitement du quatrième stade de la rosacée.14) Use according to any one of claims 1 to 13, characterized in that the composition is intended for the treatment of the fourth stage of rosacea.
15) Utilisation selon l'une quelconque des revendications 1 à 14, caractérisée en ce que ladite composition contient de 0,0001 à 20% en poids, de préférence de 0,1 à 2%, et plus préférentiellement de l'ordre de 0,75 à 1 % en poids de metronidazole.15) Use according to any one of claims 1 to 14, characterized in that said composition contains from 0.0001 to 20% by weight, preferably from 0.1 to 2%, and more preferably of the order of 0 , 75 to 1% by weight of metronidazole.
16) Utilisation selon l'une quelconque des revendications 1 à 15, caractérisée en ce que ladite composition contient en outre un autre agent actif choisi dans le groupe des antibiotiques, des antibactériens, des antiviraux, des antiparasitaires, des antifongiques, des anesthésiques, des analgésiques, des antiallergiques, des rétinoïdes, des anti-radicaux libres, des antiprurigineux, des kératolytiques, des
antiséborrhéiques, des anti-histaminiques, des sulfures, des produits immunosuppresseurs ou antiprolifératifs.16) Use according to any one of claims 1 to 15, characterized in that said composition additionally contains another active agent chosen from the group of antibiotics, antibacterials, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergics, retinoids, anti-free radicals, antipruritics, keratolytics, antiseborrhoeics, antihistamines, sulfides, immunosuppressive or antiproliferative products.
17) Utilisation selon l'une quelconque des revendications 1 à 16, caractérisée en ce que la composition contient un additif choisi dans le groupe des séquestrants, des antioxydants, des filtres solaires, des conservateurs, des charges, des électrolytes, des humectants, des colorants, de bases ou d'acides usuels, minéraux ou organiques, des parfums, des huiles essentielles, des actifs cosmétiques, des hydratants, des vitamines, des acides gras essentiels, des sphingolipides, des composés auto bronzants, des agents apaisants et protecteurs de la peau, des agents propénétrants, des gélifiants ou un mélange de ceux-ci.
17) Use according to any one of claims 1 to 16, characterized in that the composition contains an additive chosen from the group of sequestrants, antioxidants, sun filters, preservatives, fillers, electrolytes, humectants, dyes, bases or common acids, mineral or organic, perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, soothing and protective agents. the skin, penetrating agents, gelling agents or a mixture thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0401720A FR2866568B1 (en) | 2004-02-20 | 2004-02-20 | USE OF THE METRONIDAZOLE FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION FOR TREATING A DISORDER OF SKIN VASCULARIZATION |
| PCT/FR2005/000369 WO2005089749A2 (en) | 2004-02-20 | 2005-02-17 | Use of metronidazole for preparing a pharmaceutical composition for treating a cutaneous vascularisation disorder |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1732542A2 true EP1732542A2 (en) | 2006-12-20 |
Family
ID=34833945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP05729333A Withdrawn EP1732542A2 (en) | 2004-02-20 | 2005-02-17 | Use of metronidazole for preparing a pharmaceutical composition for treating a cutaneous vascularisation disorder |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20070238772A1 (en) |
| EP (1) | EP1732542A2 (en) |
| JP (1) | JP2007523132A (en) |
| KR (1) | KR20060124708A (en) |
| CN (1) | CN1921850A (en) |
| AU (1) | AU2005224122A1 (en) |
| BR (1) | BRPI0506557A (en) |
| CA (1) | CA2554637A1 (en) |
| FR (1) | FR2866568B1 (en) |
| RU (1) | RU2006133535A (en) |
| WO (1) | WO2005089749A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2750636C (en) * | 2009-01-23 | 2017-07-25 | Jr Chem, Llc | Rosacea treatments and kits for performing them |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4837378A (en) * | 1986-01-15 | 1989-06-06 | Curatek Pharmaceuticals, Inc. | Topical metronidazole formulations and therapeutic uses thereof |
| CA2161737C (en) * | 1995-10-30 | 1998-10-20 | Richard J. Mackay | Metronidazole gel |
| GB9626513D0 (en) * | 1996-12-20 | 1997-02-05 | Bioglan Ireland R & D Ltd | A pharmaceutical composition |
| DE602004004399T2 (en) * | 2003-06-18 | 2007-06-21 | Galderma S.A., Cham | GREEN-COLORED TOPICAL PHARMACEUTICAL COMPOSITION BASED ON METRONIDAZOLE |
-
2004
- 2004-02-20 FR FR0401720A patent/FR2866568B1/en not_active Expired - Fee Related
-
2005
- 2005-02-17 RU RU2006133535/15A patent/RU2006133535A/en unknown
- 2005-02-17 CN CNA2005800055709A patent/CN1921850A/en active Pending
- 2005-02-17 CA CA002554637A patent/CA2554637A1/en not_active Abandoned
- 2005-02-17 AU AU2005224122A patent/AU2005224122A1/en not_active Abandoned
- 2005-02-17 KR KR1020067016589A patent/KR20060124708A/en not_active Application Discontinuation
- 2005-02-17 EP EP05729333A patent/EP1732542A2/en not_active Withdrawn
- 2005-02-17 WO PCT/FR2005/000369 patent/WO2005089749A2/en not_active Application Discontinuation
- 2005-02-17 US US10/590,074 patent/US20070238772A1/en not_active Abandoned
- 2005-02-17 JP JP2006553617A patent/JP2007523132A/en active Pending
- 2005-02-17 BR BRPI0506557-7A patent/BRPI0506557A/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2005089749A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2005224122A1 (en) | 2005-09-29 |
| FR2866568B1 (en) | 2007-08-24 |
| KR20060124708A (en) | 2006-12-05 |
| RU2006133535A (en) | 2008-03-27 |
| US20070238772A1 (en) | 2007-10-11 |
| WO2005089749A3 (en) | 2006-05-04 |
| JP2007523132A (en) | 2007-08-16 |
| FR2866568A1 (en) | 2005-08-26 |
| CN1921850A (en) | 2007-02-28 |
| CA2554637A1 (en) | 2005-09-29 |
| WO2005089749A2 (en) | 2005-09-29 |
| BRPI0506557A (en) | 2007-04-17 |
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