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
  • A61P17/10—Anti-acne agents
• • 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]

Definitions

• the invention relates to the use of adapalene to modulate the expression of CD1d or IL-10, 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. Dermatol 1991: 18: 489-499
• the first stage which usually begins at puberty, corresponds to the stimulation of sebaceous gland production, inducing hyper seborrhea.
• the second stage corresponds to the formation of micro comedones considered as the first elemental lesion of acne caused by abnormalities of proliferation, adhesion and differentiation of keratinocytes in the lower part of the sebaceous duct of the hair follicle.
• the third step is the formation of inflammatory acne lesions in which Propionibacterium acnes (P. acnes), an anaerobic bacterium, plays an essential role.
• Propionibacterium acnes P. acnes
• an anaerobic bacterium plays an essential role.
• 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 behaves as a modulator of the cytokines of the skin and makes it possible in particular to increase the innate and acquired immune responses of the skin by its action on two particular cytokines, CD1d and IL-10.
• 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 CD1 d at the level of an inflammatory skin lesion, by particularly at the level of an inflammatory acne lesion.
• the invention is directed to the use of adapalene in a patient whose inflammatory acne lesions under-express CD1d.
• Another object of the present invention is the use of Adapalene, or a pharmaceutically acceptable salt thereof, for preparing a medicament for decreasing the decrease in IL-10 intraperatinocyte production.
• the invention is directed to the use of adapalene in a patient whose acne epidermal cells over-produce IL-10.
• the target patients are preferably patients whose inflammatory acne lesions under-express CD1d and / or patients whose acne epidermal cells, especially keratinocytes, over-produce IL-10.
• Another object of the invention is the use of adapalene to prepare a medicament for modulating the immune response of the epidermis by increasing the expression of CD1 d and / or decreasing the expression of IL-1. 10 by the cells of the acne epidermis, in particular the keratinocytes
• the drug is preferably applied topically and may be in the form of a gel, lotion or cream.
• the invention therefore relates to pharmaceutical compositions comprising in a physiologically acceptable medium adapalene or a pharmaceutically acceptable salt thereof.
• the invention therefore also relates to a method for inducing an increase in the expression of IL-10 and / or decreasing the expression of CD1d by the epidermal cells of a patient in need of treatment, characterized in that said patient is administered Adapalene or a pharmaceutically acceptable salt thereof.
• 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.
• a method for preparing this compound is described in patent EP358574.
• 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.
• RAR retinoic acid
• adapalene does not bind to the binding proteins of cellular retinoic acid.
• adapalene also has activity on superficial inflammatory lesions (Millikan LE, Int 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.
• the inventors furthermore identify, in the context of the present invention, two molecules, expressed by the cells of the acne epidermis, playing an essential role in the development of cutaneous inflammation: CD1d and IL-10.
• CD1d belongs to a conserved family of non-polymorphic cell surface glycoproteins acting as antigen presenting molecules. These glycoproteins are structurally, and in terms of distance, linked to the proteins of the classical class I major histocompatibility complex.
• the CD1d molecules are capable of presenting lipid and glycolipid antigens to NKT cells.
• the expression CD1d is rapidly induced on the keratinocytes of the normal skin when the latter undergoes a physical trauma which destroys its barrier function (Aderem A. et al., Nature 2000: 406: 782-787). This shows that keratinocytes are able to function as unconventional antigen presenting cells and activate NKT cells by presenting lipid antigens using CD1 d.
• IL-10
• Human IL-10 is a 19 kDa lymphokine produced by various cell types such as B and T cells and monocytes. In normal human skin, this cytokine is not expressed in keratinocytes, but its expression can be induced by UVB irradiation or antigenic stimulation. In vitro, normal human keratinocytes express the mRNA encoding IL-10. The expression of IL-10 is increased after stimulation with alpha-MSH. This cytokine exerts immunosuppressive and anti-inflammatory effects, produced in particular via an inhibitory effect on the production of interferon-gamma (Suh DH et al., Eur J Dermatol
• adapalene induces a decrease or significantly decreases the expression of CD1 d by the cells of the acne epidermis, in particular the keratinocytes, thus increasing their cell function.
• the antigens in question are in particular the lipid, glycolipid and bacterial antigens present in the epidermis or the follicle, and among them the P. acnes antigens.
• adapalene induces a decrease or significantly decreases the expression of IL-10 in the epidermis of normal skin and in acne lesions, which facilitates activation of T cells by increasing interactions between Langherans cells and T lymphocytes
• modulations make it possible to increase the interactions between dendritic cells and T lymphocytes and reinforce the antimicrobial activity against P. acnes.
• modulation is meant an effect on the expression or activity of IL-I gene 1 10 and / or CD1d or their respective promoter or alternatively on the expression of these genes occurs.
• expression product of the gene proteins or any product resulting from the transcription and / or translation of said gene.
• activity is meant biological activity.
• promoter activity of the gene is meant the ability of the promoter to induce the transcription of the DNA sequence under the control of said promoter.
• the invention thus relates to the use of adapalene to prepare a composition for modulating the immune response of the epidermis by increasing the expression of CD1d and / or decreasing the expression of IL-10 by the acne epidermis, in particular keratinocytes.
• adapalene under the action of adapalene, the expression of CD1d is significantly increased in the cells of the epidermis and in particular in the keratinocytes, thus increasing their function as antigen-presenting cells.
• I 1 II 10 being an immunosuppressive cytokine having an inhibitory role in the activation and proliferation of T cells, the decrease of this cytokine induced adapalene increases immune responses.
• a particular object of the invention relates to the use of Adapalene, or a pharmaceutically acceptable salt thereof, for preparing a pharmaceutical composition for increasing the expression of CD1d at the level of a cutaneous lesion, in particular at level of an inflammatory acne lesion.
• increase it is meant an increase, an over-expression, an increase in the level of expression of the CD1d gene or an overproduction of its expression product (mRNA, protein).
• Another particular object of the invention relates to the use of Adapalene, or a pharmaceutically acceptable salt thereof, for preparing a pharmaceutical composition for decreasing IL-10 intraperatinocyte production.
• decrease is meant a decrease, a reduction, a retro-regulation, a inhibition or a suppression (total or partial) of the expression of the gene of IL-10 or its product of expression (mRNA, protein) .
• partial inhibition it can be understood a reduction of at least 25% of the activity and preferably 35% even more preferred of at least 50%.
• the pharmaceutical compositions used here are intended to be used, in order to treat acne, optimally, in patients whose lesions inflammatory acne-like sub-express CD1 d and / or in patients whose acne epidermal cells, especially keratinocytes, over-produce IL-10.
• the pharmaceutical composition comprises adapalene or a pharmaceutically acceptable salt thereof in a physiologically acceptable medium.
• the composition according to the invention advantageously 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 0.1 and 0.4% by weight. adapalene weight, 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.
• additives can be present in the composition in a proportion of 0 to 20% by weight relative to the total weight of the composition.
• Such a composition 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.
• 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 of 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 family of modified starches such as modified
• 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%.
• compositions are suitable for the treatment of inflammatory lesions of any type of acne, namely in particular vulgar, comedonal, polymorphic, rosacea acne, nodulocystic acne, acne conglobata, senile acne, secondary acne such as solar acne, medication, occupational or occupational acne.
• Inflammatory lesions of acne a skin biopsy (1 x 1.5 cm) was obtained under local anesthesia from a superficial inflammatory lesion (papule) of the back in 8 patients suffering from moderate acne and not undergoing no topical (for 15 days) or general treatment (for one month, or three months for isotretinoin). The collected fragments were immediately cultured. Healthy human skin: Healthy skin fragments from 8 healthy donors were obtained from breastplasty (plastic surgery) or foreskin (infant surgery).
• KGM culture without hydrocortisone PromoCell GmbH, Heidelberg, Germany.
• the culture medium was supplemented with two different concentrations of adapalene (Galderma, Sophia Antipolis, France): 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. Culture supernatants were stored at -80 ° C for subsequent measurement of protein secretion by an ELISA assay technique.
• the primary antibodies [an anti-human IL-10 monoclonal mouse IgGI (Diaclone, Besançon, France), a rabbit polyclonal anti-CD1d antibody (Santa Cruz Biotechnology Inc.)] were used, in immunohistochemistry, to 2 ⁇ g / ml (anti-IL-10 antibody) or 5 ⁇ g / ml (anti-CD1d antibody).
• Negative control mouse IgGI at 2 ⁇ g / ml (DAKO, Copenhagen, Denmark) or secondary antibody alone were used as controls.
• Cutaneous Section Immunohistochemistry Samples of frozen specimens (5 ⁇ m thick) were cut with a cryostat and then fixed with acetone at 4 ° C for 10 minutes. After saturation of non-specific sites with TBS (Tris-buffered saline) / BSA (Bovine Serum Albumin) at 0.1%, for 30 minutes at room temperature, the slides were incubated for 30 minutes with the primary antibodies at room temperature, in a humid atmosphere. and in the dark. The sections were then washed again for 15 min in 0.1% TBS / BSA / 0.05% Tween 20 and then incubated with a biotinylated secondary antibody (DAKO) for 30 min, at room temperature and in a humid atmosphere, then washed and incubated.
• TBS Tris-buffered saline
• BSA Bovine Serum Albumin
• Cytokine Assays IL-10 concentrations were measured in culture supernatants using a solid-phase Enzyme Linked-Immuno-Sorbent Assay (ELISA) sandwich kit obtained from BioSource (International Inc, Ca, USA).
• ELISA Enzyme Linked-Immuno-Sorbent Assay
• the slides were read at 450 nm using an Emax reader (Molecular Devices, CA, USA).
• the sensitivity of the assay IL-10 was less than 1 pg / ml and the minimum detectable level of IL-I 1 10 was 7.8 pg / ml.
• CD1d expression is low to moderate (1.7 +/- 0.4) in all epidermis of healthy human skin incubated in control medium.
• Healthy human skin explants the average expression of the cytokine is low in the epidermis incubated with a control medium (1 .3 +/- 0.7).
• IL-10 is mainly expressed by the cytokines of the basal layer of the epidermis.
• the addition of adapalene significantly decreases the expression of IL-10 in a dose-dependent manner.
• cytokine The expression of the cytokine is average (1.9 +/- 0.4) in the basal layer of the acne epidermis incubated with the control medium. It is slightly stronger in the acne epidermis (1 .9 +/- 0.4) than in the healthy epidermis (1.3 +/- 0.7).
• the expression of IL-10 decreases significantly and dose-dependent in the presence of adapalene.
• cytokine levels were measured in explant supernatants.
• Human Healthy Skin The mean level of IL-10 in healthy human skin explant supernatants incubated with control medium was 17.8 ⁇ g / ml (+/- 20.9). The addition of 10 -7 M adapalene increases the secretion of IL-10. No modulation is observed with 10 ⁇ 6 M adapalene.
• the invention confirms, on the one hand, that CD1d is exhaled by healthy human skin keratinocytes from a region of the body other than the scalp (Aderem A. et al., Nature 2000: 406: 782-787).
• the results presented in the present invention show a high level of expression in superficial keratinocytes located near the lipid-rich stratum corneum.
• the inventors have demonstrated expression of CD1d in the other layers of the epidermis including basal keratinocytes (Kawai K et al., J Dermatol Sci 2002: 30: 185-194).
• CD1 d-expressing cells The presentation of a lipid antigen in the skin by CD1 d-expressing cells is of primary importance in the host defense against pathogens
• adapalene By modulating, preferably by increasing the expression of CD1d by acne epidermal cells, especially keratinocytes, adapalene stimulates their NK activity against lipid and / or bacterial antigens present in the epidermis or the follicle and among them P. acnes.
• IL-10 is an immunosuppressive cytokine that inhibits activation and proliferation of T cells via inhibition of antigen presenting cells including Langerhans cells (Moore KW et al., Annu Rev Immunol 2001: 19: 683-765). Inhibition of ICAM-1 and other accessory molecules by IL-10 appears to be an important mechanism inhibiting the antigen-presenting function of Langerhans cells (Chatelain R.

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• 2007
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