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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • 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
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents

Definitions

• the invention relates to the use of adapalene for modulating the expression of IL-1 ⁇ (intraplein-1 receptor accesory protein), particularly in patients with acne.
• Acne is a chronic disease related to the hormonally dependent inflammation of the pilosebaceous follicle, which involves three well-defined steps (Cunliffe WJ et al., Br J Dermatol 2000: 142: 1084-1091, Gollnick HP et al. J Dermatol 1991: 18: 489-499).
• the first stage which usually begins at puberty, corresponds to the stimulation of the production of the sebaceous glands, inducing hyper seborrhea.
• the second stage corresponds to the formation of micro comedones considered as the first elementary lesion of acne caused by abnormalities of the proliferation, adhesion and differentiation of keratinocytes in the lower part of the sebaceous duct of the hair follicle.
• the third stage corresponds to the formation of inflammatory lesions in which Propionibacterium acnes (P. acnes), an anaerobic bacterium, plays an essential role.
• P. acnes Propionibacterium acnes
• the treatments used against acne are intended to curb the development of bacteria with antiseptics such as benzoyl peroxide or antibiotics, or to reduce the secretion of sebum (retinoids).
• antiseptics such as benzoyl peroxide or antibiotics
• sebum retinoids
• the oral treatments break down into three categories: antibiotics (tetracycline and erythromycin), retinoids (especially represented by isotretinoin) and hormonal treatments combining estrogen and progestin.
• adapalene has a comedolytic action and behaves as a stimulator of the expression of IL-1ra in the skin and makes it possible in particular to increase the expression thereof. in keratinocytes.
• An object of the present invention thus relates to the use of Adapalene, or a pharmaceutically acceptable salt thereof, for preparing a medicament for increasing the expression of NL-I ra and / or inducing increased expression of NL-I ra by the cells of the epidermis and in particular by the keratinocytes.
• Another object of the invention is the use of Adapalene, or a pharmaceutically acceptable salt thereof, to prepare a medicament for increasing the expression of IL-1ra and / or inducing increased expression of NL-1 ra by epidermal acne cells.
• adapalene or a pharmaceutically acceptable salt thereof is also intended to prevent the formation of comedones in patients whose acne epidermal cells under-express NL-1 ra.
• the drug is preferably applied topically.
• it can be in the form of a gel, a lotion or a cream.
• the present invention also relates to a method for inducing an increase in the expression of NL-1 ra by the epidermal cells of a patient in need of treatment, characterized in that it is administered to said patient of Adapalene or a pharmaceutically acceptable salt thereof.
• salts of adapalene means salts formed with a pharmaceutically acceptable base, in particular mineral bases such as sodium hydroxide, potassium hydroxide and aqueous ammonia or organic bases such as lysine, arginine, N-methyl glucamine. Also meant by salts of adapalene salts formed with fatty amines such as dioctylamine and stearylamine.
• Adapalene is a chemically stable derivative of naphthoic acid.
• the chemical formula of this derivative is 6 [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid.
• Adapalene is a second-generation topical retinoid (such as tazarotene) that selectively binds to RAR ⁇ subtypes (found mainly in the epidermis) and RAR ⁇ (found mainly in dermal fibroblasts) of the nuclear acid receptor.
• retinoic acid (RAR) activating the genes responsible for cell differentiation. On the other hand, it does not bind to the binding proteins of cellular retinoic acid.
• adapalene also has activity on superficial inflammatory lesions (Millikan LE, lnt J Dermatol 2000: 39: 784-788).
• the mechanisms of anti-inflammatory activity seem in particular related to the modulation of non-specific immunity.
• adapalene inhibits the oxidative metabolism of arachidonic acid via the lipoxygenase pathway, the chemotaxis of neutrophils and the production of free radicals. It also inhibits the production of leukotrienes by the lipoxygenase pathway.
• Adapalene has been described by the Applicant in patent EP 0 199 636, the latter has also proposed a method for synthesizing this compound in patent EP 0 358 574.
• the Applicant markets the adapalene formulated at a concentration of 0.1% by weight in the form of an alcoholic lotion, an aqueous gel and a cream. These compositions are intended for the treatment of acne.
• the inventors identify in the context of the present invention, a molecule, expressed by keratinocytes, playing an essential role in the development of cutaneous inflammation: IL-1 ra.
• IL-1 is a highly active proinflammatory cytokine produced by monocytes and macrophages, but also by endothelial cells and lymphocytes. It will stimulate the production of prostaglandins, NO and chemokines.
• IL-1 is transcribed from three genes carried by chromosome 2 and that exhibit numerous homologies: IL-1 alpha, IL-I 1 1 beta and IL-1ra. These 3 proteins bind to the IL-1 receptor that includes two types:
• the receptor I is composed of two subunits I * IL-I R1 and I * IL-I R AcP
• IL-1 RII the type II receptor
• the IL-1 molecule binds to both parts of the type I receptor and thus induces activation of its TIR cytoplasmic domain (ToII receptor-like).
• IL-1 ra binds only to the IL-1 R1 portion and then prevents activation of the intracellular signal. The effects of IL-I are blocked.
• Type II receptor binding does not result in intracellular signaling.
• the type I receptor is found on very many cells while the type II receptor is expressed mainly on neutrophils, monocytes and B cells.
• IL-1 Ra is secreted by the liver as a protein of the acute phase and therefore plays a role of modulator of the inflammatory response.
• adapalene induces an increase in the expression of IL-1 ra by the cells of the epidermis, in particular the keratinocytes of inflammatory acne lesions.
• increase it is meant an increase, an overexpression, a rise in the expression level of the IL-10 gene or an overproduction of its expression product (mRNA, protein).
• IL-1ra is a cytokine receptor antagonist with I 1 IL-1 alpha, it exerts anti-inflammatory effects on the skin.
• the inventors have demonstrated that blocking the receptor I 'LI I alpha, IL-1ra prevents the formation of comedones which would otherwise be induced by I 1 IL-1 alpha.
• the invention thus relates to the use of a modulator compound for the expression of IL-1ra, such as adapalene or a pharmaceutically acceptable salt thereof, for preparing a medicament for increasing the expression of IL-1 ra by the cells of the epidermis, and more particularly by the keratinocytes.
• a particular object of the invention is the use of a modulator compound for the expression of IL-1 ⁇ , such as adapalene or a pharmaceutically acceptable salt thereof, for preparing a medicament for increasing expression of IL-1 ra by acne epidermal cells, in particular by keratinocytes of a cutaneous lesion, in particular of an inflammatory acne lesion.
• Another particular subject of the invention relates to the use of a modulator compound, more particularly stimulating, of the expression of IL-1ra, such as adapalene or a pharmaceutically acceptable salt thereof, for to prepare a drug intended to prevent the formation of comedones in patients whose acne epidermis cells, in particular keratinocytes, under-express NL1 RA.
• a modulator compound more particularly stimulating, of the expression of IL-1ra, such as adapalene or a pharmaceutically acceptable salt thereof, for to prepare a drug intended to prevent the formation of comedones in patients whose acne epidermis cells, in particular keratinocytes, under-express NL1 RA.
• the drugs used herein are intended to be used, for treating acne, optimally, in patients whose acne epidermis cells, especially keratinocytes, under-express NL1 RA.
• the present invention also relates to a pharmaceutical composition.
• the pharmaceutical composition comprises a compound modulating the expression of IL-1ra, such as adapalene or a pharmaceutically acceptable salt thereof, in a physiologically acceptable medium.
• One skilled in the art can easily determine and prescribe the required amount of therapeutically active agent. For example, it may start with doses of therapeutically active agent at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• the composition according to the invention comprises between 0.001 and 5% and advantageously between 0.01 and 1% by weight of adapalene relative to the total weight of the composition, preferably between 0.03 and 0.5%, preferably between 0.1 and 0.4% by weight of adapalene, more preferably 0.3% by weight of adapalene.
• the composition may furthermore comprise any additive usually used in the cosmetic or pharmaceutical field, such as penetrating agents, wetting liquid surfactants, sequestering agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants , dyes, bases or usual acids, mineral or organic, perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA , soothing and protective agents for the skin such as allantoin.
• any additive usually used in the cosmetic or pharmaceutical field such as penetrating agents, wetting liquid surfactants, sequestering agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants , dyes, bases or usual acids, mineral or organic, perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA , soothing and protective agents for the skin such as allantoin
• additives can be present in the composition in a proportion of 0 to 20% by weight relative to the total weight of the composition.
• compositions may be administered by any known route, conventionally associated with the treatment (using adapalene) of a dermatological disorder, Le., Topically, enterally, parenterally or ocularly.
• the treatment is administered topically.
• the pharmaceutical composition is preferably in the form of a gel, lotion or cream.
• the composition is in the form of an aqueous gel.
• aqueous gel is meant a composition containing, in an aqueous phase, a viscoelastic mass formed from colloidal suspensions (gelling agent).
• gelling agents of the family of polyacrylamides such as the mixture Sodiumacryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 sold under the name Simulgel 600 by the company Seppic, the polyacrylamide / isoparaffin mixture C13-14 / laureth- 7, 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 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-cyclohexyl isocyanate)) (SMDI), 35% by weight in a mixture of propylene glycol (39%) and water (26%)), the family of modified starches such as modified potato starch sold under the name
• the gelling agent as described above may be used at preferential concentrations ranging from 0.1 to 15% and, more preferably, from 0.5 to 5%.
• the medicaments and compositions as described above are suitable for the treatment of inflammatory lesions of any type of acne, namely in particular vulgar, comedonal, polymorphic, rosacea acne, nodulocystic acnes, conglobata acnes, senile acnes, secondary acnes. such as solar acne, medicated, professional or occupational acne.
• the invention was carried out on the basis of biopsies taken from acne patients in order to find themselves in the conditions closest to the studies carried out in vivo.
• a skin biopsy (1 x 1.5 cm) was obtained from inflammatory papules of back injuries of 8 acne patients (under no local treatment for 15 days or general for 1 month, or 3 months for isotretinoin). The collected fragments were immediately cultured.
• the fragments of healthy skin and acne skin were incubated at 37 ° C in a humid atmosphere and in the presence of 5% CO 2 for 24 hours in KGM culture medium without hydrocortisone (PromoCell, Heidelberg, Germany).
• the culture medium was supplemented with 2 different concentrations of Adapalene (Galderma, Sophia Antipolis): 10 -7 M and 10 -6 M.
• the culture medium alone served as a control medium.
• the explants were removed from the culture medium and then frozen in liquid nitrogen for immunohistochemical study.
• the culture supernatants were frozen at -80 ° C. in order to evaluate the protein secretion by an ELISA assay technique.
• IL-1 ⁇ was evaluated by immunoperoxidase technique in healthy skin explants of 8 healthy donors and acne skin of 8 patients.
• cryostat sections 5 ⁇ m thick were made from the skin explants and then fixed with acetone at 4 ° C. for 10 minutes. After saturation of the nonspecific sites with bovine albumin (BSA) for 30 minutes at room temperature, the slides were incubated for 30 minutes at room temperature and in a humid atmosphere in the presence of the corresponding primary antibody [anti-IL monoclonal antibody.
• BSA bovine albumin
• the slides were read under a Leitz microscope by 2 investigators.
• IL-1 ra Protein secretion of IL-1 ra (patients only) in culture supernatants of acne skin and healthy skin explants, incubated with or without Adapalene, was assessed by ELISA using IL-1ra Cytoscreen kit detection (Biosource Europe SA, Nivelles, Belgium) and following the supplier's instructions.
• the paired Wilcoxon test was used for statistical analysis and p ⁇ 0.05 (compared to control medium) was considered significant.
• - IL-1 ra is very weakly to weakly expressed in the epidermis of healthy donors, its expression intensity being on average 0.8 (+/- 0.7).
• the average performed on 8 healthy donors does not demonstrate a modulatory effect of Adapalene on the expression of NL-I ra in the epidermis of healthy donors.
• the intensity of expression of this cytokine is indeed 0.9 (+/- 0.5) with 10 '7 M Adapalene and 0.8 (+/- 0.4) with 10 ' 6 M Adapalene.
• the intensity of expression of IL-1 ra is therefore similar in the skin of healthy donors and in acne skin.
• Adapalene increases the expression of this cytokine in the epidermis of acne patients. This effect is dose-dependent and maximal at the concentration of 10 ⁇ 6 M.
• the intensity of expression is indeed 0.8 (+/- 0.8) with 10 '7 M Adapalene and 0.9 (+/- 0.7) with 10 ⁇ 6 M Adapalene.
• the amount of IL-1ra secreted into the culture supernatants was in average of 600 pg (+/- 362), an increase of 2.6% compared to the control medium and of 564pg (+/- 255) in the presence of Adapalene 10 '6 M, a decrease of 3.5% compared to the control medium.
• the amount of IL-1R secreted in the culture supernatants of the acne skin explants incubated with the control medium is, on average, 1145 ⁇ g (+/- 404).
• the secretion of IL-1 ra is therefore on average higher in acne patients compared to healthy donors.
• the secreted amount of IL-1 ra is on average 1,196 pg (+/- 422), an increase of 4.4% relative to the control medium and 1,161 pg (+/- 409) in the presence of Adapalene 10 '6 M, an increase of 1.4% relative to the control medium.
• IL-1ra is a cytokine antagonist receptor I IL-1 alpha and 1 which exerts anti-inflammatory effects on the skin (D Suh et al, 2002). By blocking the receptor I IL-1 alpha 1, IL-1ra prevents the formation of comedones which would otherwise be induced by I 1 IL-1 alpha.

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• 2007
  • 2007-11-20 EP EP07858720A patent/EP2097076A1/de not_active Withdrawn
  • 2007-11-20 WO PCT/FR2007/052367 patent/WO2008062135A1/fr active Application Filing
• 2009
  • 2009-05-19 US US12/468,641 patent/US20100130614A1/en not_active Abandoned

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