EP1718285A2 - Verwendung einer verbindung zur modulierung mindestens eines empfängers ausgewählt aus einer gruppe aus einem interleukin 8 typ b rezeptor und pacap-1 rezeptor zur herstellung einer pharmazeutischen zusammensetzung zur behandlung von rosacea - Google Patents

Verwendung einer verbindung zur modulierung mindestens eines empfängers ausgewählt aus einer gruppe aus einem interleukin 8 typ b rezeptor und pacap-1 rezeptor zur herstellung einer pharmazeutischen zusammensetzung zur behandlung von rosacea

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Publication number
EP1718285A2
EP1718285A2 EP05729353A EP05729353A EP1718285A2 EP 1718285 A2 EP1718285 A2 EP 1718285A2 EP 05729353 A EP05729353 A EP 05729353A EP 05729353 A EP05729353 A EP 05729353A EP 1718285 A2 EP1718285 A2 EP 1718285A2
Authority
EP
European Patent Office
Prior art keywords
receptor
composition
rosacea
use according
treatment
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Withdrawn
Application number
EP05729353A
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English (en)
French (fr)
Inventor
Fabrizio Dolfi
Irina Safonova
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galderma Research and Development SNC
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Galderma Research and Development SNC
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Publication date
Application filed by Galderma Research and Development SNC filed Critical Galderma Research and Development SNC
Publication of EP1718285A2 publication Critical patent/EP1718285A2/de
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Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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

Definitions

  • the present invention relates to the field of rosacea treatment.
  • the invention aims to provide new pharmaceutical compositions, more particularly dermatological compositions, useful for the treatment of rosacea and comprising as active agent a modulating compound of at least one receptor chosen from the group comprising the type B receptor interleukin 8 and the PACAP type 1 receptor.
  • 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. This facial vascular anomaly results in 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, J Am Acad Dermatol, vol.15, pages 1159-1162; Sibenge et al., 1992, J Am Acad Dermatol, vol. 26, pages 590-593). It seems that Demodex folliculorum causes or 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 infection with Helicobacter pilori.
  • 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.
  • Minor forms of rosacea can be treated with active ingredients such as anti-seborrheics and anti-infectives, for example benzoyl peroxide, retinoic acid, metronidazole.
  • active ingredients such as anti-seborrheics and anti-infectives, for example benzoyl peroxide, retinoic acid, metronidazole.
  • 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 usefulness of the receptor modulator compounds chosen from the group comprising the type B receptor of interleukin 8 and the type 1 receptor of PACAP in the treatment of rosacea.
  • 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 peptide"
  • VIP intestinal vasoactive peptide
  • PACAP deploys pleiotropic effects throughout the body during development but also in adults. It participates in essential functions like growth, endocrine and digestive activity, control cardiovascular and respiratory, 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
  • the work of the Applicant has made it possible to demonstrate the involvement of the receptors chosen from the group comprising the type B receptor of interleukin 8 and the type 1 receptor of PACAP in the treatment of rosacea. This activity has been demonstrated by the use of metronidazole which results 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 the treatment of rosacea, which consists in administering to a subject suffering from this pathology an effective amount of a modulating compound of at least one receptor chosen from the group comprising IL-8RB receptor and PAC-1 receptor.
  • the invention relates more particularly to the use of a modulating compound of at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor for the preparation of a pharmaceutical composition intended to treat rosacea.
  • the invention also relates to the use of a compound which modulates the IL-8RB receptor and the PAC-1 receptor for the preparation of a pharmaceutical composition intended for treating rosacea.
  • Modulator according to the present invention means any molecule which increases 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. More particularly, the pharmaceutical composition which is the subject of the present invention is a dermatological composition, for topical application to the skin.
  • 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 an antagonist as defined above, preferably from 0.1 to 2%, and more preferentially of the order of 0.75 to 1 % of a modulator as defined above expressed by weight relative to the total weight of the composition.
  • the present invention relates, in addition to the use of a modulator as defined above, the use of derivatives thereof.
  • derivatives means compounds which are distinguished from a modulator as defined above, by substitution, addition or deletion of one or more chemical groups.
  • compositions of the invention comprise, in addition to a modulator as defined above, 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.
  • the modulating compound is not metronidazole.
  • the composition of the present invention also contains metronidazole.
  • the invention also relates to a method of identifying a modulating compound of at least one receptor chosen from the group comprising the IL-8RB receptor and the PAC-1 receptor: a) bringing the specific radiolabelled ligand into contact with the recombinant human protein of the PAC-1 and / or IL-8RB receptor in a sample; b) bringing the radiolabelled specific ligand and the excess non-radiolabelled specific ligand into contact with the recombinant human protein of the receptor in another sample; c) Addition of the compound to be tested in the two samples; d) Measurement of radioactivity by counting the scintillation in the two samples; e) Calculation of the difference in radioactivity measured in the two samples; f) Selection of said compounds for which an increase in radioactivity is obtained in step e) relative to the control value obtained with the receptors not brought into contact with the compound to be tested.
  • compositions of the invention may also comprise any additive usually used in the pharmaceutical, dermatological field, compatible with a modulator as defined above. 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, inorganic 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, inorganic 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
  • 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 ethylenediaminetetraacetic acid (EDTA), as well as its derivatives or its salts, dihydroxyethylglycine, citric acid, tartaric acid, or mixtures thereof.
  • EDTA ethylenediaminetetraacetic 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.
  • 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 can 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 nonionic type.
  • the creams can be formulated from a mixture of mineral oil, or a mixture of beeswax and water which instantly emulsifies, in which the modulator as defined above is added dissolved in a small amount of oil such as almond oil.
  • the ointments can be formulated by mixing a solution of said modulator 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):
  • 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 Maizines, 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-B
  • 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, the one sold under the name Sepigel 305 by the company Seppic, the family of acrylic polymers coupled to hydrophobic chains such as PEG-150 / decyl / SMDI copolymer sold under the name 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 starch modified potato sold under the name
  • 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 the modulator as defined above in an appropriate ratio, in a gel of carbomer, poloxamer or cellulosic type.
  • metronidazole as a modulator of the receptors chosen from the group comprising the PAC-1 receptor and the IL-8RB receptor.
  • Example 1 Measurement of the binding to the IL-8RB and PAC-1 receptors
  • the 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.
  • the 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.
  • 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 to the PAC-1 receptor.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP05729353A 2004-02-20 2005-02-17 Verwendung einer verbindung zur modulierung mindestens eines empfängers ausgewählt aus einer gruppe aus einem interleukin 8 typ b rezeptor und pacap-1 rezeptor zur herstellung einer pharmazeutischen zusammensetzung zur behandlung von rosacea Withdrawn EP1718285A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0401716A FR2866565A1 (fr) 2004-02-20 2004-02-20 Utilisation d'un modulateur du il-8rb et/ou pac-1 pour le traitement de la rosacee
PCT/FR2005/000366 WO2005079770A2 (fr) 2004-02-20 2005-02-17 Utilisation d'un compose modulateur d'au moins un recepteur choisi parmi le recepteur de type b de l'il 8 et de type 1 de pacap pour la preparation d'une composition pharmaceutique pour traiter la rosacee

Publications (1)

Publication Number Publication Date
EP1718285A2 true EP1718285A2 (de) 2006-11-08

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Application Number Title Priority Date Filing Date
EP05729353A Withdrawn EP1718285A2 (de) 2004-02-20 2005-02-17 Verwendung einer verbindung zur modulierung mindestens eines empfängers ausgewählt aus einer gruppe aus einem interleukin 8 typ b rezeptor und pacap-1 rezeptor zur herstellung einer pharmazeutischen zusammensetzung zur behandlung von rosacea

Country Status (5)

Country Link
US (1) US20080033060A1 (de)
EP (1) EP1718285A2 (de)
CA (1) CA2553188A1 (de)
FR (1) FR2866565A1 (de)
WO (1) WO2005079770A2 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010007175A2 (en) * 2008-07-18 2010-01-21 Galderma Research & Development Pacap signaling pathway modulators for treating inflammatory skin diseases with a neurogenic component, and more particularly rosacea and composition containing them
FR2961695B1 (fr) * 2010-06-29 2012-07-06 Galderma Res & Dev Utilisation de composes dans le traitement ou la prevention de troubles cutanes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005079770A2 *

Also Published As

Publication number Publication date
CA2553188A1 (fr) 2005-09-01
WO2005079770A2 (fr) 2005-09-01
FR2866565A1 (fr) 2005-08-26
WO2005079770A8 (fr) 2005-10-27
US20080033060A1 (en) 2008-02-07

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