EP1718296A2 - 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
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 receptorInfo
- Publication number
- EP1718296A2 EP1718296A2 EP05729371A EP05729371A EP1718296A2 EP 1718296 A2 EP1718296 A2 EP 1718296A2 EP 05729371 A EP05729371 A EP 05729371A EP 05729371 A EP05729371 A EP 05729371A EP 1718296 A2 EP1718296 A2 EP 1718296A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- receptor
- metronidazole
- composition
- use according
- rosacea
- 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- Withdrawn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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- 230000037307 sensitive skin Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- 235000013599 spices Nutrition 0.000 description 1
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- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
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- 210000001519 tissue Anatomy 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 229960001727 tretinoin Drugs 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to the field of treatment of pathologies linked to the type B receptor of Pinterleukin 8 and / or to the type 1 receptor of PACAP.
- the invention aims to provide new pharmaceutical compositions, more particularly dermatological compositions, 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 erythema, 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.
- Demodex folliculorum has an etiological role in rosacea (Erbagi et al., 1998, Int J Dermatol, vol.37, pages 421-425; Purcell et al, 1986, JA 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 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 ).
- rosacea 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, or even Helicobacter ilori infection.
- stage 2 erythematato-telangiectatic (around 30 years).
- the malar areas are diffusely red.
- stage 1 the redness is permanent.
- the chin and the middle part of the forehead can be affected.
- 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.
- Interleukin 8 receptors are receptors with seven transmembrane domains and are coupled to G proteins. Two interleukin 8 receptors have been identified, named IL-8RA or CXCR1 and IL-8RB or CXCR2.
- PACAP "Pituitary adenylate cyclase-activating peptid” has 68% identity with the intestinal vasoactive peptide (VIP), one of the members of the secretin / glucagon / GHRH family.
- VIP intestinal vasoactive peptide
- PACAP deploys pleiotropic effects throughout the body during development but also in adults. It participates in essential functions such as growth, endocrine and digestive activity, cardiovascular and respiratory control, immune responses, and circadian rhythm. It fixes and activates multiple receptor subtypes, some of which (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.
- the type 1 receptor, PAC-1 (or PVR1), is known.
- 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 the type B receptor of interleukin 8 (IL-8RB) and of the type 1 receptor of PACAP (PAC-1) in certain pathologies and in particular in rosacea. .
- the work of the Applicant has made it possible to demonstrate that the use of metronidazole resulted 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.
- the invention aims to offer a new method for 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 subject an effective amount of metronidazole in which the metronidazole is capable of influencing the binding of a ligand on at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC- receptor. 1. Consequently, the invention relates more particularly to the use of metronidazole for the preparation of a pharmaceutical composition intended for treating pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor .
- the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for treating pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor and in which metronidazole is capable of modulating the interaction of a ligand with at least one receptor chosen 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, said receptor being chosen from the group comprising the IL-8RB receptor and PAC-1 receptor.
- 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 chosen 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, intended for treating a pathology involving two receptors chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor, said receptor pathology being rosacea.
- the pharmaceutical composition which is the subject of the present invention is a dermatological composition, for topical application to the skin.
- the present invention means the treatment and / or prevention of such a pathology.
- 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 rosacea.
- 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% of metronidazole, preferably from 0.1 to 2% of metronidazole, and more preferably of the order of 0.75 to 1% of metronidazole expressed 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 are understood to mean 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, antiseborrheics, 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 include ethylenediaminetetraacetic acid (EDTA), as well as its derivatives or its salts, dihydroxyethylglycine, citric acid, tartaric acid, or mixtures thereof.
- 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.
- 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 else 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 emulsifies instantly, in which the metronidazole is added, dissolved in a small amount oil such as almond oil.
- Ointments can be formulated by mixing a solution of metronidazole in an oil such as almond oil in heated paraffin, then allowing the mixture to cool.
- compositions according to the invention mention may be made of those comprising an active phase containing (expressed as a percentage by weight):
- - 0 to 20% preferably 0 to 10%, in particular 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 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 Posay water, Bourboule water, Enghien-les-Bains water, Saint Gervais-les-Bains, water from Néris- les-Bains, water from Allevard-les-Bains, water from Digne, water from aizi Guatemala, water from Neyrac-les-Bains, water from Lons-le-Saunier, Eaux Bonnes, water from Rochefort, water from Saint Christau, water from Fumades and water from Tercis-les-bains, water from Avène or Aix les Bains water.
- floral water such as blueberry water
- natural thermal or mineral water for example chosen from Vittel water, Vichy basin water, Uriage water, Roche Posay water, Bourboule water, Enghien-les-Bains water, Saint Gervais-les-
- 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 such as, for example, that sold under the name Sepigel 305 by the company Seppic, the family of acrylic polymers coupled to hydrophobic chains such as the PEG-150 / decyl / SMDI copolymer sold under the name of Aculyn 44 ( polycondensate comprising at least as elements, a polyethylene glycol containing 150 or 180 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexylisocyanate) (SMDI), 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
- the preferred gelling agents are from the family of polyacrylamides such as Simulgel
- 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 PAC-1 receptor binding test was carried out according to the protocol described by
- the IL-8RB receptor binding test was carried out according to the protocol described by
- the binding of metronidazole to each receptor was determined by competitive experiments.
- the receptor a recombinant human protein, was incubated according to the times indicated in Table 1 below, with a single concentration of labeled specific 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 therefore induces the binding of the ligand to its IL-8RB receptor and the PAC-1 receptor.
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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
UTILISATION DU METRONIDAZOLE POUR LA PREPARATION D'UNE COMPOSITION PHARMACEUTIQUE DESTINEE A TRAITER DES PATHOLOGIES LIEES AU RECEPTEUR DE TYPE B DE L'INTERLEUKINE 8 ET/OU AU RECEPTEUR DE TYPE 1 DE PACAP USE OF METRONIDAZOLE FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION FOR TREATING CONDITIONS RELATED TO THE INTERLEUKIN 8 TYPE B RECEPTOR AND / OR PACAP TYPE 1 RECEPTOR
La présente invention concerne le domaine du traitement des pathologies liées au récepteur de type B de Pinterleukine 8 et/ou au récepteur de type 1 du PACAP. L'invention vise à fournir de nouvelles compositions pharmaceutiques, plus particulièrement dermatologiques, et comprenant à titre d'agent actif le métronidazole.The present invention relates to the field of treatment of pathologies linked to the type B receptor of Pinterleukin 8 and / or to the type 1 receptor of PACAP. The invention aims to provide new pharmaceutical compositions, more particularly dermatological compositions, 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'érythème 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 erythema, 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.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.
Selon différents travaux, Demodex folliculorum aurait un rôle étiologique dans la rosacée (Erbagi et al., 1998, Int J Dermatol, vol.37, pages 421-425; Purcell et al, 1986,
J A Acad Dermatol, vol.15, pages 1159-1162; 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).According to various studies, Demodex folliculorum has an etiological role in rosacea (Erbagi et al., 1998, Int J Dermatol, vol.37, pages 421-425; Purcell et al, 1986, JA 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 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).
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 Helicobacter ilori.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, or even Helicobacter ilori infection.
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. - 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 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. - 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.
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.- stage 4 of rhinophyma (around 50 years or later). This late phase mainly affects men, unlike the other stages. The nose is enlarged, 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. 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 récepteurs de l'interleukine 8 sont des récepteurs à sept domaines transmembranaires et sont couplés à des protéines G. Deux récepteurs de l'interleukine 8 ont été identifiés, nommés IL-8RA ou CXCR1 et IL-8RB ou CXCR2.Interleukin 8 receptors are receptors with seven transmembrane domains and are coupled to G proteins. Two interleukin 8 receptors have been identified, named IL-8RA or CXCR1 and IL-8RB or CXCR2.
Le PACAP, "Pituitary adenylate cyclase-activating peptid", possède 68% d'identité avec le peptide intestinal vasoactif (VIP), un des membres de la famille sécrétine / glucagon / GHRH. Le PACAP déploie des effets pléiotropes à travers tout l'organisme durant le développement mais aussi chez l'adulte. Il participe à des fonctions essentielles comme la croissance, l'activité endocrine et digestive, le contrôle cardiovasculaire et respiratoire, les réponses immunitaires, et le rythme circadien. Il se fixe et active de multiples sous-types de récepteurs dont certains (type II) ont la particularité de fixer également le VIP avec une même haute affinité. Ces récepteurs sont largement distribués dans le cerveau et les tissus périphériques. Parmi les récepteurs du PACAP, on connaît le récepteur de type 1 , PAC-1 (ou PVR1).PACAP, "Pituitary adenylate cyclase-activating peptid", has 68% identity with the intestinal vasoactive peptide (VIP), one of the members of the secretin / glucagon / GHRH family. PACAP deploys pleiotropic effects throughout the body during development but also in adults. It participates in essential functions such as growth, endocrine and digestive activity, cardiovascular and respiratory control, immune responses, and circadian rhythm. It fixes and activates multiple receptor subtypes, some of which (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.
Le PACAP et IL-8 ont tous les deux une implication dans l'inflammation. En effet, PACAP diminue la libération des cytokines pro-inflammatoires et inhibe l'activation des neutrophiles.PACAP and IL-8 both have an implication in inflammation. PACAP decreases the release of pro-inflammatory cytokines and inhibits the activation of neutrophils.
Le métronidazole, 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 métronidazole est réduit en dérivés capables d'altérer la structure ADN de ces cellules.
Les travaux de la Demanderesse ont permis de mettre en évidence l'implication du récepteur de type B de l'interleukine 8 (IL-8RB) et du récepteur de type 1 du PACAP (PAC-1) dans certaines pathologies et notamment dans la rosacée.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 the type B receptor of interleukin 8 (IL-8RB) and of the type 1 receptor of PACAP (PAC-1) in certain pathologies and in particular in rosacea. .
Les travaux de la Demanderesse ont permis de mettre en évidence que l'utilisation du métronidazole avait pour conséquence la modulation de la fixation de ligands naturels sur les récepteurs choisis parmi le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1.The work of the Applicant has made it possible to demonstrate that the use of metronidazole resulted 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.
Comme indiqué précédemment, l'invention vise à offrir une nouvelle méthode de traitement de pathologies impliquant au moins un récepteur choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1. Cette méthode de traitement consiste à administrer à un sujet une quantité efficace de métronidazole dans laquelle le métronidazole est capable d'influencer la fixation d'un ligand sur au moins un récepteur choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1. En conséquence, l'invention se rapporte plus particulièrement à l'utilisation du métronidazole pour la préparation d'une composition pharmaceutique destinée à traiter les pathologies impliquant au moins un récepteur choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1.As indicated above, the invention aims to offer a new method for 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 subject an effective amount of metronidazole in which the metronidazole is capable of influencing the binding of a ligand on at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC- receptor. 1. Consequently, the invention relates more particularly to the use of metronidazole for the preparation of a pharmaceutical composition intended for treating pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor .
Plus particulièrement, l'invention se rapporte à l'utilisation du métronidazole pour la préparation d'une composition pharmaceutique destinée à traiter les pathologies impliquant au moins un récepteur choisi dans le groupe comprenant le récepteur IL- 8RB et le récepteur PAC-1 et dans laquelle le métronidazole est capable de moduler l'interaction d'un ligand avec au moins un récepteur choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1.More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition intended for treating pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor and in which metronidazole is capable of modulating the interaction of a ligand with at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor.
L'invention concerne également l'utilisation du métronidazole pour la préparation d'une composition pharmaceutique telle que définie précédemment et dans laquelle le métronidazole module la fixation d'au moins un ligand naturel sur son récepteur, ledit récepteur étant choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1.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, said receptor being chosen from the group comprising the IL-8RB receptor and PAC-1 receptor.
Plus particulièrement, l'invention se rapporte à l'utilisation métronidazole pour la préparation d'une composition pharmaceutique telle que définie précédemment,
destinée à traiter une pathologie impliquant au moins un récepteur choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1.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 chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor.
L'invention se rapporte également à l'utilisation métronidazole pour la préparation d'une composition pharmaceutique telle que définie précédemment, destinée à traiter une pathologie impliquant deux récepteurs choisis dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1 , ladite pathologie étant la rosacée.The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, intended for treating a pathology involving two receptors chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor, said receptor pathology being rosacea.
Plus particulièrement, la composition pharmaceutique objet de la présente invention est une composition dermatologique, pour application topique sur la peau.More particularly, the pharmaceutical composition which is the subject of the present invention is a dermatological composition, for topical application to the skin.
Par traitement de pathologies impliquant au moins un récepteur choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1 , on entend selon la présente invention le traitement et/ou la prévention d'une telle pathologie. En particulier, ces pathologies impliquant au moins un récepteur choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1 sont la rosacée, le psoriasis, les inflammations aiguës et chronique, les maladies autoimmunes et les chocs septiques. Plus particulièrement, il s'agira de la rosacée.By treatment of pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor, the present invention means the treatment and / or prevention of such a 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 rosacea.
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 œuvre 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 œuvre 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 œuvre de l'invention, la composition est destinée au traitement du quatrième stade de la rosacée.
Suivant un mode préférentiel de mise en œuvre, la composition contient 0,0001 à 20% de métronidazole, de préférence de 0,1 à 2% de métronidazole, et plus préférentiellement de l'ordre de 0,75 à 1% de métronidazole exprimé en poids par rapport au poids total de la composition.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% of metronidazole, preferably from 0.1 to 2% of metronidazole, and more preferably of the order of 0.75 to 1% of metronidazole expressed by weight relative to the total weight of the composition.
Bien entendu la présente invention concerne, outre l'utilisation du métronidazole, l'utilisation de dérivés de celui-ci. On entend par dérivés des composés qui se distinguent du métronidazole, 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. Derivatives are understood to mean 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 métronidazole 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 anesthesiques, 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, antiseborrheics, 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 métronidazole. 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.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.
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. Ces additifs peuvent être présents dans la composition à raison de 0 à 20 % en poids par rapport au poids total de la composition.
On peut citer comme exemples d'agents séquestrants, l'acide éthylènediamine tétracétique (EDTA), ainsi que ses dérivés ou ses sels, la dihydroxyethylglycine, l'acide citrique, l'acide tartrique, ou leurs mélanges.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. 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. Examples of sequestering agents that may be mentioned include ethylenediaminetetraacetic 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.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.
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 %.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 dans 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.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 else microemulsions, micro-capsules, micro-particles or vesicular dispersions of ionic and / or non-ionic type.
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 le métronidazole, dissout dans une petite quantité d'huile telle que l'huile d'amande.
Les pommades peuvent être formulées en mélangeant une solution de métronidazole dans une huile telle que l'huile d'amande dans de la paraffine chauffée, puis en laissant refroidir le mélange.Preferably the creams can be formulated from a mixture of mineral oil, or a mixture of beeswax and water which emulsifies instantly, in which the metronidazole is added, dissolved in a small amount oil such as almond oil. Ointments can be formulated by mixing a solution of metronidazole in an oil such as almond oil in heated paraffin, then allowing the mixture to cool.
A titre d'exemples de compositions selon l'invention, on peut citer celles comprenant une phase active contenant (exprimé en pourcentage en poids) :As examples of compositions according to the invention, mention may be made of those comprising an active phase containing (expressed as a percentage by weight):
- 0 à 90 %, préférentiellement 5 à 25 %, notamment 10 à 20 %, d'eau ;- 0 to 90%, preferably 5 to 25%, especially 10 to 20%, of water;
- 0 à 10 %, préférentiellement 0 à 2 %, notamment 0 à 0,5 %, de tensioactif ;- 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 ; - 0,0001 à 20 %, préférentiellement 0,1 à 2% de métronidazole ; et une phase aqueuse comprenant un gélifiant et de l'eau.- 0 to 20%, preferably 0 to 10%, in particular 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.
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 Posay, 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 aizières, 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.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 Posay water, Bourboule water, Enghien-les-Bains water, Saint Gervais-les-Bains, water from Néris- les-Bains, water from Allevard-les-Bains, water from Digne, water from aizières, water from Neyrac-les-Bains, water from Lons-le-Saunier, Eaux Bonnes, water from Rochefort, water from Saint Christau, water from Fumades and water from Tercis-les-bains, water from Avène or Aix les Bains water.
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.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 such as, for example, that sold under the name Sepigel 305 by the company Seppic, the family of acrylic polymers coupled to hydrophobic chains such as the PEG-150 / decyl / SMDI copolymer sold under the name of Aculyn 44 ( polycondensate comprising at least as elements, a polyethylene glycol containing 150 or 180 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexylisocyanate) (SMDI), 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 mixtures thereof.
Les gélifiants préférés sont issus de la famille des polyacrylamides tel que le SimulgelThe preferred gelling agents are from the family of polyacrylamides such as Simulgel
600 ou le Sepigel 305 ou leurs mélanges.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 %.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%.
Les gels peuvent être préparés de préférence en dispersant ou en dissolvant le métronidazole dans un rapport approprié, dans un gel de type carbomère, poloxamère ou cellulosique.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 métronidazole.Other advantages and characteristics of the invention will appear from the examples below concerning the activity of metronidazole.
Exemple 1 - Activité du métronidazoleExample 1 Activity of Metronidazole
1) Protocole :1) Protocol:
Le test de liaison au récepteur PAC-1 a été réalisé suivant le protocole décrit parThe PAC-1 receptor binding test was carried out according to the protocol described by
Cauvin et al., 1991 , Regul Peptides, vol.35, pages 161-173.Cauvin et al., 1991, Regul Peptides, vol.35, pages 161-173.
Le test de liaison au récepteur IL-8RB a été réalisé suivant le protocole décrit parThe IL-8RB receptor binding test was carried out according to the protocol described by
White et al., 1998, J Biol Chem, vol.273, pages 10095-10098.White et al., 1998, J Biol Chem, vol. 273, pages 10095-10098.
2) Conditions expérimentales :2) Experimental conditions:
La liaison de métronidazole sur chaque récepteur a été déterminée par des expériences de compétition. Le récepteur, protéine humaine recombinante, a été incubé selon des temps indiqués dans le tableau 1 ci-dessous, avec une simple concentration de ligand spécifique marqué, en présence du métronidazole 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, a recombinant human protein, was incubated according to the times indicated in Table 1 below, with a single concentration of labeled specific 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 métronidazole (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).
Tableau 2Table 2
Le métronidazole induit donc la liaison du ligand à son récepteur IL-8RB et le récepteur PAC-1.
Metronidazole therefore induces the binding of the ligand to its IL-8RB receptor and the PAC-1 receptor.
Claims
REVENDICATIONS
1) Utilisation du métronidazole pour la préparation d'une composition pharmaceutique destinée à traiter les pathologies impliquant au moins un récepteur choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1.1) Use of metronidazole for the preparation of a pharmaceutical composition intended for treating pathologies involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor.
2) Utilisation selon la revendication 1 , caractérisée en ce que le métronidazole module la fixation d'au moins un ligand naturel sur son récepteur, ledit récepteur étant choisi dans le groupe comprenant le récepteur IL-8RB et le récepteur PAC-1 .2) Use according to claim 1, characterized in that metronidazole modulates the binding of at least one natural ligand to its receptor, said receptor being chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor.
3) Utilisation selon la revendication 1 ou 2, caractérisée en ce que la pathologie impliquant au moins un récepteur choisi dans le groupe comprenant le récepteur IL- 8RB et le récepteur PAC-1 est la rosacée.3) Use according to claim 1 or 2, characterized in that the pathology involving at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor is rosacea.
4) Utilisation selon l'une quelconque des revendications 1 à 3, caractérisée en ce que ladite composition pharmaceutique est une composition dermatologique pour application topique.4) Use according to any one of claims 1 to 3, characterized in that said pharmaceutical composition is a dermatological composition for topical application.
5) Utilisation selon l'une quelconque des revendications 1 à 4, caractérisée en ce que la composition est destinée au traitement d'au moins un stade de la rosacée.5) Use according to any one of claims 1 to 4, characterized in that the composition is intended for the treatment of at least one stage of rosacea.
6) Utilisation selon l'une quelconque des revendications 1 à 5, caractérisée en ce que la composition est destinée au traitement du premier stade de la rosacée.6) Use according to any one of claims 1 to 5, characterized in that the composition is intended for the treatment of the first stage of rosacea.
7) Utilisation selon l'une quelconque des revendications 1 à 6, caractérisée en ce que la composition est destinée au traitement du deuxième stade de la rosacée.7) Use according to any one of claims 1 to 6, characterized in that the composition is intended for the treatment of the second stage of rosacea.
8) Utilisation selon l'une quelconque des revendications 1 à 7, caractérisée en ce que la composition est destinée au traitement du troisième stade de la rosacée.8) Use according to any one of claims 1 to 7, characterized in that the composition is intended for the treatment of the third stage of rosacea.
9) Utilisation selon l'une quelconque des revendications 1 à 8, caractérisée en ce que la composition est destinée au traitement du quatrième stade de la rosacée.9) Use according to any one of claims 1 to 8, characterized in that the composition is intended for the treatment of the fourth stage of rosacea.
10) Utilisation selon l'une quelconque des revendications 1 à 9, caractérisée en ce que la composition contient de l'ordre de 0,0001 à 20% de métronidazole, de préférence de
0,1 à 2% de métronidazole, et plus préférentiellement de l'ordre de 0,75 à 1% en poids de métronidazole .10) Use according to any one of claims 1 to 9, characterized in that the composition contains of the order of 0.0001 to 20% of metronidazole, preferably of 0.1 to 2% of metronidazole, and more preferably of the order of 0.75 to 1% by weight of metronidazole.
11) Utilisation selon l'une quelconque des revendications 1 à 10, 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 anesthesiques, 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.11) Use according to any one of claims 1 to 10, characterized in that said composition also contains another active agent selected from the group of antibiotics, antibacterials, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergics, retinoids, anti-free radicals, antipruritics, keratolytics, antiseborrheics, antihistamines, sulfides, immunosuppressive or antiproliferative products.
12) Utilisation selon l'une quelconque des revendications 1 à 11 , 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 autobronzants, des agents apaisants et protecteurs de la peau, des agents propénétrants, des gélifiants ou un mélange de ceux-ci.
12) Use according to any one of claims 1 to 11, 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 skin, penetrating agents, gelling agents or a mixture of these.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0401721A FR2866569B1 (en) | 2004-02-20 | 2004-02-20 | USE OF THE METRONIDAZOLE FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION FOR TREATING PATHOLOGIES ASSOCIATED WITH THE INTERLEUKINE 8 TYPE B RECEPTOR AND / OR THE PACAP TYPE 1 RECEPTOR |
| PCT/FR2005/000370 WO2005089750A2 (en) | 2004-02-20 | 2005-02-17 | 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1718296A2 true EP1718296A2 (en) | 2006-11-08 |
Family
ID=34833946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP05729371A Withdrawn EP1718296A2 (en) | 2004-02-20 | 2005-02-17 | 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 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20080221189A1 (en) |
| EP (1) | EP1718296A2 (en) |
| JP (1) | JP2007523133A (en) |
| KR (1) | KR20060124707A (en) |
| CN (1) | CN1921852A (en) |
| AU (1) | AU2005224123A1 (en) |
| BR (1) | BRPI0506550A (en) |
| CA (1) | CA2553932A1 (en) |
| FR (1) | FR2866569B1 (en) |
| RU (1) | RU2006133534A (en) |
| WO (1) | WO2005089750A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2961695B1 (en) * | 2010-06-29 | 2012-07-06 | Galderma Res & Dev | USE OF COMPOUNDS IN THE TREATMENT OR PREVENTION OF SKIN DISORDERS |
| WO2012142145A1 (en) * | 2011-04-12 | 2012-10-18 | Dow Pharmaceutical Sciences | Methods of treating skin conditions exhibiting telangiectasia |
Family Cites Families (8)
| 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 |
| FR2722098B1 (en) * | 1994-07-06 | 1996-08-23 | Cird Galderma | NEW MEDICINES BASED ON METRO-NIDAZOLE OR A SYNERGETIC MIXTURE OF METRONIDAZOLE AND CLINDAMYCIN |
| 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 |
| US6365616B1 (en) * | 1998-08-31 | 2002-04-02 | Sentron Medical, Inc. | Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases |
| DE60037892T2 (en) * | 1999-07-16 | 2009-01-15 | Shoei Co., Ltd. | NITROIMIDAZOL PREPARATIONS FOR EXTERNAL USE FOR THE TREATMENT OF ATOPIC DERMATITIS |
| MXPA03009995A (en) * | 2001-05-09 | 2004-06-30 | Univ Michigan | Use of compositions for treating rosacea. |
| 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 FR0401721A patent/FR2866569B1/en not_active Expired - Fee Related
-
2005
- 2005-02-17 EP EP05729371A patent/EP1718296A2/en not_active Withdrawn
- 2005-02-17 CA CA002553932A patent/CA2553932A1/en not_active Abandoned
- 2005-02-17 CN CNA2005800055751A patent/CN1921852A/en active Pending
- 2005-02-17 US US10/590,031 patent/US20080221189A1/en not_active Abandoned
- 2005-02-17 BR BRPI0506550-0A patent/BRPI0506550A/en not_active Application Discontinuation
- 2005-02-17 RU RU2006133534/15A patent/RU2006133534A/en unknown
- 2005-02-17 KR KR1020067016588A patent/KR20060124707A/en not_active Withdrawn
- 2005-02-17 AU AU2005224123A patent/AU2005224123A1/en not_active Abandoned
- 2005-02-17 WO PCT/FR2005/000370 patent/WO2005089750A2/en not_active Ceased
- 2005-02-17 JP JP2006553618A patent/JP2007523133A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2005089750A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0506550A (en) | 2007-02-27 |
| US20080221189A1 (en) | 2008-09-11 |
| WO2005089750A3 (en) | 2006-05-04 |
| AU2005224123A1 (en) | 2005-09-29 |
| KR20060124707A (en) | 2006-12-05 |
| CA2553932A1 (en) | 2005-09-29 |
| WO2005089750A2 (en) | 2005-09-29 |
| CN1921852A (en) | 2007-02-28 |
| FR2866569B1 (en) | 2007-08-24 |
| JP2007523133A (en) | 2007-08-16 |
| FR2866569A1 (en) | 2005-08-26 |
| RU2006133534A (en) | 2008-03-27 |
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