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US20100324109A1 - Composition for Topical Use - Google Patents

Composition for Topical Use Download PDF

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US20100324109A1
US20100324109A1 US12/863,251 US86325109A US2010324109A1 US 20100324109 A1 US20100324109 A1 US 20100324109A1 US 86325109 A US86325109 A US 86325109A US 2010324109 A1 US2010324109 A1 US 2010324109A1
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composition
ahr
skin
tcdd
ligands
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Jean Hilaire Saurat
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THESAN PHARMACEUTICALS Inc
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Individual
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Assigned to THESAN PHARMACEUTICALS, INC. reassignment THESAN PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SAURAT, JEAN-HILAIRE, M.D.
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • 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
    • A61K31/407—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 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a composition for topical use, intended for the treatment and/or prevention of skin function dysfunctions.
  • the present invention relates more specifically to a pharmaceutical composition for topical use, intended for the treatment and/or prevention of dysfunctions of sebaceous function, of healing, of atrophy termed “dermatoporosis (Ref Dermatology 2007.215. 284-294)”, of estrogen deprivation of the skin and of defense against infection.
  • AhR receptor aryl hydrocarbon receptor
  • TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin
  • the invention relates to compounds which are agonists of the AhR receptor and/or the proteins involved in its cellular activation pathways, these compounds acting in the context of the invention as agents for modulating skin functions, in particular sebaceous function, defense against infection, healing, atrophy termed “dermatoporosis”, and estrogen deprivation of the skin.
  • the subject of said invention is a pharmaceutical composition for topical use, intended for transiently inducing the activation of AhR receptors of skin tissues, said composition comprising an active substance chosen from metabolizable agonist ligands of AhR, and from the in situ precursors of said ligands.
  • TCDD xenotoxic AhR ligands
  • the active substance can be chosen from endogenous AhR ligands: the applicant considers that there are very probably endogenous ligands, or exogenous, in particular environmental, ligands, which give the AhR signaling pathway a physiological function. These ligands essentially have a short lifetime.
  • the subject of said invention is a composition for topical use, intended for transiently inducing the activation of AhR receptors of skin tissues, said composition comprising an active substance chosen from AhR agonist ligands with a short half-life and the in situ precursors of said ligands.
  • the ligands used in the context of the present invention preferably have half-life times in the human organism of between 2 and 96 hours, and more specifically, and according to the application, between 6 and 24 hours.
  • the present invention is therefore completely distinct from, and even antinomic to, certain prior art inventions which have proposed the use of AhR receptor antagonist ligands, with a view to preventing gene expression of the type of those that can be induced by exposure to TCDD and other xenotoxic AhR ligands.
  • These inventions described in particular in documents WO2004/041758, WO2007/060256 and WO2007/128725, were based on extrapolations drawn from in vitro experiments and on the premise that activation of the AhR pathway would by definition be harmful.
  • the activation, in humans and experimental animals, of the AhR pathway can have favorable effects for the treatment of diseases such as abnormalities of sebaceous function, of healing, of atrophy termed “dermatoporosis”, of defense against infection and of estrogen deprivation of the skin.
  • the ligands according to the invention are chosen such that they preferably meet four criteria:
  • the modulated gene may in particular be the CYP1A1 gene.
  • This modulated gene may also be one of the numerous genes described in the present application as being modulated by exposure to TCDD and the promoter of which expresses an AhR-binding site.
  • the applicant considers that the modulation of the CYP1A1 gene is proposed as a paradigm based on current observations and knowledge; thus, it does not exclude the desired effects being obtained by means of AhR ligands which do not have activation of CYP1A1 expression as their predominant effect.
  • the applicant does not exclude the possibility that certain ligands, the half-life of which departs from the numerical values indicated above, having this property of beneficial effects/toxic effects dissociation. This is because the duration of activation of the AhR receptor in the skin might not depend exclusively on the half-life of the ligand in the organism.
  • the dissociation between beneficial effect according to the invention and toxic effects is obtained by stimulating the AhR receptor in a modulated and transient manner, i.e. in a manner close to the physiological action of the nontoxic, natural endogenous/exogenous ligands.
  • This dissociation can also be obtained by the formation of a ligand, in situ, from a topically administered precursor.
  • Said active substance can be a precursor chosen from the metabolic proligands of AhR ligands.
  • Said active substance may also be a precursor that can be activated so as to give an AhR ligand under the effect either of a physical agent, in particular under the effect of UV radiation, or of any other biological process, such as metabolic activation within a skin tissue by the saprophytic or pathogenic flora.
  • FIG. 1 shows the disappearance of sebaceous glands owing to exposure to orally administered toxic doses of TCDD in humans;
  • FIG. 2 illustrates the reproduction of this phenomenon of sebaceous gland disappearance by topical application of TCDD in mice: FIG. 2 shows the disappearance of the sebaceous glands of the ear skin of C57BL/6 mice treated once a day for 45 d with 2 mcg/ml TCDD (bottom photograph) compared with the control (top photograph).
  • FIG. 3 illustrates the reduction in sebaceous glands through topical application of 4 ligands according to the invention: FIG. 3 shows the reduction in the surface area of the sebaceous glands in the ears of C57GL/6 mice treated once a day for 45 d with various ligands according to the invention.
  • FIG. 4 shows the major inhibition of the gene expression of key enzymes of sebaceous lipogenesis in humans exposed to TCDD, by analysis of the whole transcriptome (Affymetrix) in human skin exposed to TCDD: lipo/sebogenesis enzyme genes are greatly underexpressed.
  • the appendix to FIG. 4 is a table which gives the symbols of the genes of which the expression is strongly repressed compared with the controls in human skin exposed to TCDD.
  • FIGS. 5 and 6 show the healing times of superficial wounds in the absence or in the case of exposure to TCDD in humans.
  • FIG. 5 shows the percentage surface area healed as a function of time of 4 dermabrasions in the case of the presence of TCDD in the skin, in comparison with 4 controls (C1-C4).
  • FIG. 6 shows the mean values calculated on the basis of the data of FIG. 5 .
  • the time to complete healing is brought back from 9.3 (gray bars) to 5 days (black bars).
  • FIG. 7 shows the healing times of experimental wounds in a culture of human keratinocytes in vitro, treated with TCDD and with ligands according to the invention.
  • FIG. 8 shows the expression of the messenger RNAs of growth factors and of their receptors in human skin exposed to TCDD in vivo.
  • FIG. 9 shows the healing of a chronic human wound to which a solution of Trp generating AhR activation according to the invention has been applied for 10 days. Contraction of the chronic wound is noted; the arrows show the development of epithelial healing with strips of keratinocytes migrating from the edges.
  • FIG. 10 a shows the induction, in the skin, of messenger RNAs of estrogen receptors and of aromatase by exposure to TCDD in a man.
  • FIG. 10 b shows the strong ectopic and focal expression of the ER-alpha receptor protein in the pilosebaceous structures on a specimen of the skin of an individual exposed to TCDD.
  • FIG. 11 shows the concentration of estradiol (E2) in human skin exposed to TCDD, determined by ELISA on fragments of human skin.
  • FIG. 12 shows the decrease in staphylococcus sp. colonization of human skin exposed to TCDD (data over four months).
  • FIG. 13 shows the decrease in the colonization of human facial skin by Propionibacterium acnes, in skin exposed to TCDD (data over four months).
  • FIGS. 14 and 15 show the AhR receptor activation values in two cell types using various products with the aim of identifying active substances which activate AhR but the half-life of which is short.
  • FIG. 14 shows the AhR activation of HEP G2 cells by various ligands according to the invention. The values represent the percentage activation compared with that obtained with 0.01 ⁇ M TCDD, using the concentration, in ⁇ M, most active in the range tested for each substance.
  • FIG. 15 shows the AhR activation of keratinocytes by various ligands according to the invention. The values represent the percentage activation compared with that obtained with 0.01 ⁇ M TCDD, using the concentration, in ⁇ M, most active in the range tested for each substance.
  • FIG. 16 shows the activation of AhR by various extracts of common human skin bacteria in the presence of tryptophan.
  • FIG. 17 shows the induction of a specific biological activity, CYP1A1, by AhR-activating ligands according to the invention.
  • the tests are carried out using the “P450-GLO assay” kit from Promega.
  • the useful effect of TCDD is the gradual decrease in the size of the glands, and also the decrease in the expression of the genes of key enzymes in sebaceous lipogenesis.
  • This approach comprises the activation of AhR-dependent pathways in the sebaceous glands by means of agonists of this receptor. It involves the inhibition of sebaceous stem cell differentiation factors and of sebocyte proliferation, the inhibition of sebaceous lipogenesis enzymes, and also the local stimulation of estrogen production pathways and the local overexpression of estrogen receptors.
  • the present invention uses the effect of specific inhibition of the sebaceous gland by means of an AhR ligand for the prevention and treatment of diseases comprising a hypertrophy of these glands, such as hyperseborrhoea and acne, by inducing sebaceous gland atrophy.
  • this invention offers a spectrum of activity that is potentially identical to that of oral isotretinoin, but via topical administration.
  • the invention also identifies the key enzymes of sebaceous lipogenesis and also the factors which ensure promotion of the sebaceous stem cell as a target for AhR activators, but also potentially other chemical modulators that may have a therapeutic application.
  • the AhR ligands used to reproduce this effect are chosen on the basis of a reduction of at least 40% in the size and number of sebaceous glands, without the induction of toxic signs, and also a reduction in the expression of the key enzymes of sebaceous lipogenesis.
  • the means for obtaining the effect on sebaceous glands without inducing other toxic effects of the TCDD type, particularly the formation of hamartomatous structures (Metabolizing Acquired Dioxin Induced Skin Hamartomas, MADISH), comprise the use of compounds that transiently interact with the AhR receptor, such that the kinetics are favorable to this temporal dissociation between favorable effect and toxic effects.
  • TCDD As regards healing and atrophy of the skin termed “dermatoporosis (Ref. Dermatology 207.215. 284-294)”, the useful effect of TCDD noted by the applicant manifests itself through impressively quick wound healing. Thus, the applicant has observed that epidermal-dermal wounds, the average healing time of which is ordinarily 10 days, are covered in 3 days. This effect is in line with the induction by TCDD of several growth factors (Vascular Endothelial Growth Factor VEGF, amphiregulin, TGFb, PDGF, IGF, hepatocyte growth factor hepapoietin A; scatter factor) and of receptors thereof, and also of thrombospondin 1.
  • Vascular Endothelial Growth Factor VEGF Vascular Endothelial Growth Factor VEGF, amphiregulin, TGFb, PDGF, IGF, hepatocyte growth factor hepapoietin A; scatter factor
  • a subject of the invention is therefore a pharmaceutical composition that can be administered topically, intended for treating and preventing skin healing problems and delayed skin healing, in particular associated with dermatoporosis, this composition comprising at least one compound that interacts as an agonist with the AhR receptor.
  • the means for obtaining the desired effect without inducing other toxic effects of the TCDD type comprise the use of compounds of which the kinetics of interaction with the AhR receptor are favorable to this dissociation:
  • the invention in particular proposes in situ production from a precursor such as tryptophan (Trp) or a Trp derivative, administered in a pharmaceutical carrier, enabling transcutaneous bioavailability, followed by exposure to UV radiation, or else the application, in a chronic wound, of Trp in a suitable carrier, enabling the generation, in situ, by the medium, of AhR ligand according to the example shown in FIGS. 7 , 9 , 14 - 17 , the interaction with the AhR receptor being limited by the metabolization in situ by phase 1 enzymes.
  • a precursor such as tryptophan (Trp) or a Trp derivative
  • Trp a Trp derivative
  • a pharmaceutical carrier enabling transcutaneous bioavailability, followed by exposure to UV radiation, or else the application, in a chronic wound, of Trp in a
  • compositions that can be administered topically, intended for treating and preventing skin atrophy termed dermatoporosis (Ref. Dermatology 2007.215. 284-294), which is characterized by a depletion of hyaluronate resulting in a loss of the viscoelasticity of the skin, this composition comprising at least one compound that interacts as an agonist with the AhR receptor, or a precursor of said compound, of the type described above.
  • Estrogens are endogenous hormones that are very important in many skin functions: estrogen deprivation leads to problems with each of these functions. It is in particular a factor involved in dermatoporosis. It is moreover known that the local administration of estrogens is a conventional means, which is nevertheless not without risk, for combating hyperseborrhoeic conditions and androgenetic alopecia. Exposure to TCDD leads, in the skin, to a strong expression of the genes for estrogen receptors and for the aromatase enzyme ( FIG. 10 ), and also an increase in cutaneous estradiol ( FIG. 11 ).
  • a subject of the invention is therefore a pharmaceutical composition that can be administered topically, intended for treating and preventing skin function problems associated with estrogen deprivation, this composition comprising at least one compound that interacts as an agonist with the AhR receptor.
  • the means for obtaining the desired effect on estrogen expression without inducing other toxic effects of the TCDD type comprise the use of compounds of which the kinetics of interaction with the AhR receptor are favorable to this dissociation: the invention in particular proposes in situ production from a precursor such as tryptophan or a Trp derivative, administered in a pharmaceutical carrier enabling transcutaneous penetration, followed by exposure to UV radiation, the interaction with the AhR receptor being limited by the metabolization in situ by phase 1 enzymes.
  • a subject of the invention is therefore a pharmaceutical composition that can be administered topically, intended for treating and preventing the effects of bacterial skin infections, in particular in individuals with a high susceptibility, and also other situations involving chronic carriers, this composition comprising at least one compound that interacts as an agonist with the AhR receptor.
  • the means for obtaining the desired effect on skin infections without inducing other toxic effects of the TCDD type comprise the use of compounds in which the kinetics of interaction with the AhR receptor are favorable to this dissociation: the invention in particular proposes in situ production from a precursor such as tryptophan or a Trp derivative, administered in a pharmaceutical carrier enabling transcutaneous penetration, followed by exposure to UV radiation, or else the generation, in situ, by the medium, of AhR ligand according to the example shown in FIGS. 7 , 9 , 14 - 17 . It will in particular be noted that certain saprophytic and pathogenic strains of the skin surface generate AhR activation which is potentiated by the presence of tryptophan ( FIG. 16 ).
  • the ligands are chosen in that they preferably meet four criteria:
  • FIG. 1 shows the number of sebaceous glands per square centimeter on various areas of the human body, which is distributed from 50 to 900 depending on areas and individuals. Thus, on the face of an adult, the number is between 400 and 900/cm 2 .
  • FIG. 1 shows that, when there is exposure to TCDD, the sebaceous glands disappear in all the areas studied.
  • 3 to 10 skin biopsies were analyzed after fixing with formol and staining with hematin-eosin. At least 10 sections per block were analyzed. Out of a total of 62 biopsies, totaling 620 sections, no sebaceous gland could be observed, whereas the number and structure of the sweat glands and the hairs were conserved.
  • the effect on the sebaceous glands can be reproduced in animals by topical application of TCDD.
  • a 95% reduction in the number of sebaceous glands can be observed in C57BL/6 mice after 45 days of application of 2 mcg/ml TCDD ( FIG. 2 ).
  • the reduction in the surface area of the sebaceous glands in the ears of C57BL/6 mice treated once a day for 45 d with various ligands according to the invention can be studied.
  • the surface area of the sebaceous glands is measured on three serial sections per animal.
  • a reduction of greater than 40% is sought, and obtained here with a concentration, a treatment time and an application frequency considered to be minimal.
  • Isotretinoin is shown by way of example of a product used for the topical and systemic treatment of acne.
  • FIG. 16 shows the activation of AhR of HEP G2 cells by various extracts of common human skin bacteria in the presence of tryptophan (trp)
  • F1 G+ flora
  • F2 G+ flora
  • PA P. acnes
  • SE S. epidermidis.
  • the activation value of 25.00 on the Y-axis corresponds to 1 ⁇ 6 of the AhR stimulation by 10 nM TCDD in this same system (157.00). It can be seen that, in particular with P. acnes, an increase in the activation is observed with the addition of tryptophan (trp).
  • the applicant carried out a test by applying a gel containing 1% tryptophan to the face of two hyperseborrheic men for 3 weeks, and observed a decrease in the seborrhea which could be evaluated at 40% of the starting value using sebumetric measurement of the casual sebum levels.
  • FIG. 4 shows the considerable reduction of messenger RNAs of several sebaceous lipogenesis enzymes in human skin exposed to TCDD. This observation identifies a new target for medicaments aimed at modulating sebaceous function, a concept exemplified here by AhR activation.
  • FIG. 5 shows the percentage of surface area healed as a function of time of 4 dermabrasions in the case of the presence of TCDD in the skin (TCDD1-4, 930 to 2900 ppt TCDD measured by gas chromatography/mass spectrometry) in comparison with 4 controls (C1-C4).
  • FIG. 6 shows the mean values calculated from the data of FIG. 5 .
  • the time to complete healing is reduced from 9.3 to 5 days.
  • FIG. 7 shows, in a model of wound healing in vitro on a culture of human keratinocytes, that the gap in the culture is repaired with TCDD and with active substances according to the invention in proportions similar to what is observed after application of growth factors.
  • the wound is induced by means of an incision with a yellow micropipette tip (10-200 ⁇ l).
  • Migration index value obtained with the ligand/that of the control without ligand.
  • Trp Tryptophan
  • FIG. 8 shows the ratio (RT PCR) on fragments of human skin containing 1800 ppt of TCDD, measured by gas chromatography/mass spectrometry, in comparison with the controls.
  • FIG. 9 is representative of a series of 10 cases of chronic wounds on legs exhibiting dermatoporosis.
  • FIG. 10 a shows the RT PCR ratios on fragments of human skin containing 1800 ppt of TCDD, measured by gas chromatography/mass spectrometry, in comparison with the controls: exposing a man to high doses of TCDD significantly increases, in the skin, the expression of messenger RNAs of estrogen receptors and of associated proteins, and also of aromatase, thus corresponding to a state of hyperestrogenism.
  • FIG. 10 a shows the RT PCR ratios on fragments of human skin containing 1800 ppt of TCDD, measured by gas chromatography/mass spectrometry, in comparison with the controls: exposing a man to high doses of TCDD significantly increases, in the skin, the expression of messenger RNAs of estrogen receptors and of associated proteins, and also of aromatase, thus corresponding to a state of hyperestrogenism.
  • FIG. 10 a shows the RT PCR ratios on fragments of human skin containing 1800 ppt of TCDD, measured by
  • FIG. 11 shows the increase in the concentration of estradiol (E2) in human skin exposed to TCDD, determined by ELISA on fragments of human skin containing 1800 ppt of TCDD (measured by gas chromatography/mass spectrometry) in comparison with the controls (f ⁇ 40: women under the age of 40; f>40: women over the age of 40; males 50 years old).
  • FIG. 12 the colonization of human skin by staphylococcus sp (number of CFU, colony forming units, per cm 2 ) is very greatly decreased in the event of exposure to TCDD.
  • This figure shows the values obtained on 4 samples taken 1 month apart from a human individual expressing more than 900 ppt of TCDD in the skin, measured by gas chromatography/mass spectrometry. The same effect is observed on P. acnes colonization, and illustrated in FIG. 13 .
  • FIGS. 14 , 15 and 16 show AhR activation in HEP G2 cells and normal human keratinocytes (NHKs) stably transfected with the lentivector plox-XRE TATA-Luc.
  • the Hep G2 cells are cultured in DMEM (Gibco)+10% fetal bovine serum+penicillin+streptomycin, the NHKs in keratinocyte SFM medium (Gibco)+penicillin+streptomycin.
  • DMEM Gibco
  • keratinocyte SFM medium Gibco
  • the Hep G2 cells are seeded into 12-well plates in a proportion of approximately 30,000 cells/cm 2 .
  • the NHKs are seeded into 6-well plates in a proportion of approximately 15,000 cells/cm 2 .
  • the medium is replaced with fresh medium and the cells are transduced with the lentivector plox-XRE TATA-Luc.
  • the cells are subcultured and maintained in culture, and tested for their reactivity to TCDD.
  • the tests are carried out using the luciferase reporter assay system kit from Promega.
  • the cells are seeded at a density of approximately 60% confluence, and then treated, at D1, with the test substance diluted to various concentrations in the appropriate culture medium.
  • the cells are lysed in CLB buffer, and the lysate is clarified by centrifugation for 5 min at 10 000 g.
  • the luciferase activity is measured in 20 microliters of lysate as recommended by the supplier, using the luminoskan luminometer (Thermo).
  • FIG. 14 shows the AhR activation in HEP G2 cells with various ligands according to the invention.
  • the values represent the percentage activation compared to that obtained with 0.01 ⁇ M TCDD, using the concentration, in ⁇ M, most active in the range tested for each substance. It is noted that ethyl ⁇ -carboline-3-carboxylate (B-CCE), tryptophan, rutaecarpine, hispidin and FICZ exhibit the greatest activities.
  • FIG. 15 shows, with the same representation, the activity of the same ligands on normal human keratinocytes. Similar results are noted.
  • FIG. 16 shows the AhR activation in HEP G2 cells with various extracts of common human skin bacteria in the presence of tryptophan (trp); F1: G+ flora; F2: G+ flora; PA: P. acnes; SE: S. epidermidis.
  • the activation value 25.00 on the Y-axis corresponds to 1 ⁇ 6 of the AhR stimulation by 10 nM TCDD in this same system (157.00). It is seen that, in particular with P. acnes, an increase in the activation is observed with the addition of tryptophan.
  • the tests are carried out using the P450-GLO assay kit from Promega.
  • the cells are seeded at a density of approximately 60% confluence, and then treated at D1 with the test substance diluted to various concentrations in the appropriate culture medium.
  • the CYP1A1 activity is measured as recommended by the supplier, using the nonlytic protocol on a cell monolayer.
  • TCDD TCDD-dependent biological activity
  • FIG. 17 shows, likewise, the induction of this AhR-dependent biological activity with ligands according to the invention, said ligands being carvedilol, B-CCE and rutaecarpine.

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EP20080150554 EP2082736A1 (fr) 2008-01-23 2008-01-23 Composition pharmaceutique à usage topique
EP08150554.7 2008-01-23
PCT/IB2009/050271 WO2009093207A1 (fr) 2008-01-23 2009-01-23 Composition a usage topique

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US14/536,521 Expired - Fee Related US9463182B2 (en) 2008-01-23 2014-11-07 Composition for topical use
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013019857A2 (fr) 2011-08-01 2013-02-07 Alnylam Pharmaceuticals, Inc. Procédé permettant d'améliorer le taux de succès des greffes de cellules souches hématopoïétiques
US20140221648A1 (en) * 2011-06-27 2014-08-07 Galderma Research & Developement Th17 differentiation markers for acne and uses thereof
WO2015046627A1 (fr) * 2013-09-30 2015-04-02 国立大学法人九州大学 Promoteur de cicatrisation
JP2015523553A (ja) * 2012-05-15 2015-08-13 テサン・ファーマシューティカルズ、インコーポレイテッド 治療用皮脂抑制活性を有するＡｈＲ受容体のリガンドを同定する方法、および前記リガンド
WO2016069780A1 (fr) * 2014-10-28 2016-05-06 Oregon State University Composés et méthodes pour supprimer une réponse auto-immune
JP2019513818A (ja) * 2016-03-10 2019-05-30 マイケル アインジガー， 皮膚美白剤としてのマラセジン（ｍａｌａｓｓｅｚｉｎ）及びその類似体
US10760129B2 (en) 2011-06-27 2020-09-01 Galderma Research & Development Th17 differentiation markers for acne and uses thereof
US12458577B2 (en) 2018-08-24 2025-11-04 Versicolor Technologies, Llc Photoprotective compositions containing Malassezia-derived compounds and/or chemical analogs thereof
US12497385B2 (en) 2018-04-12 2025-12-16 Versicolor Technologies, Llc Photoprotective compositions containing Malassezia-derived compounds and/or chemical analogs thereof

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2082736A1 (fr) 2008-01-23 2009-07-29 Jean Hilaire Saurat Composition pharmaceutique à usage topique
WO2013142378A1 (fr) * 2012-03-17 2013-09-26 The Regents Of The University Of California Diagnostic rapide et traitements personnalisés de l'acné
EP3177365A4 (fr) * 2014-08-06 2018-01-10 Thesan Pharmaceuticals, Inc. Agonistes de la voie du récepteur ahr ayant une activité sébosuppressive et procédé d'identification desdits agonistes
EP3167892A1 (fr) 2015-11-10 2017-05-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour la prévention ou le traitement de maladies intestinales inflammatoires
KR20190017751A (ko) 2016-04-21 2019-02-20 네이키드 바이옴, 인크. 피부 장애의 치료를 위한 조성물 및 방법
WO2018065132A1 (fr) 2016-10-04 2018-04-12 Institut National De La Recherche Agronomique Utilisation d'un agoniste ahr pour le traitement préventif ou curatif du syndrome métabolique et des troubles associés
WO2018151442A1 (fr) * 2017-02-17 2018-08-23 서강대학교 산학협력단 Composition permettant de soulager, de prévenir ou de traiter une atopie
EP3875098A1 (fr) 2020-03-04 2021-09-08 Institut National De Recherche Pour L'agriculture, L'alimentation Et L'environnement Utilisation de bactéries coprococcus pour le traitement du syndrome métabolique et de maladies intestinales inflammatoires

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4672074A (en) * 1983-01-10 1987-06-09 Harendza Harinxma Alfred J Ointment and process for treating skin lesions
US6555573B2 (en) * 2000-12-21 2003-04-29 The Quigley Corporation Method and composition for the topical treatment of diabetic neuropathy
US20090028804A1 (en) * 2005-11-28 2009-01-29 Symrise Gmbh & Co. Kg AhR mediators

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3729568A (en) * 1969-09-23 1973-04-24 Johnson & Johnson Acne treatment
IT1318425B1 (it) * 2000-03-24 2003-08-25 D B P Dev Biotechnological Pro Impiego del resveratrolo per il trattamento di eczema desquamativo,acne e psoriasi.
AU2002248422B2 (en) 2001-02-14 2006-07-06 Wisconsin Alumni Research Foundation Preparations and use of an Ah receptor ligand, 2-(1' H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester
AU2003209130B2 (en) * 2002-02-12 2008-06-05 Wisconsin Alumni Research Foundation Synthesis of indole thiazole compounds as ligands for the AH receptor
US20030166583A1 (en) * 2002-02-22 2003-09-04 Oliver Yoa-Pu Hu Dermal cytochrome P450 1A inhibitors and enhancers
EP1418164A1 (fr) 2002-11-07 2004-05-12 Institut National De La Sante Et De La Recherche Medicale (Inserm) Nouveaux derivés de stilbène et leur utilisation en tant que antagonistes des ligands du recepteur des arylhydrocarbures
AU2004273552B2 (en) * 2003-09-23 2010-12-16 Origin Biomed Inc. Anhydrous topical formulation for polyphenols
DE102006011747A1 (de) 2006-03-13 2007-09-27 Symrise Gmbh & Co. Kg Dermatologische und/oder kosmetische Zubereitungen
EP1842541A1 (fr) 2006-03-29 2007-10-10 G.I.M.-Gesellschaft Für Innovative Medizin Gmbh Nfg Ohg Composé et extraits de plantes et leur utilisation
ES2421191T3 (es) * 2006-05-03 2013-08-29 Symrise Ag Antagonistas del receptor de Ah
US20090208432A1 (en) 2006-05-03 2009-08-20 Symrise Gmbh & Co., Kg AH Receptor Antagonists
KR100879558B1 (ko) * 2007-07-31 2009-01-22 라이브켐 주식회사 디벤조­파라­디옥신 유도체를 유효성분으로 함유한 피부보호 및 개선제
EP2082736A1 (fr) 2008-01-23 2009-07-29 Jean Hilaire Saurat Composition pharmaceutique à usage topique
CN101953838A (zh) 2010-08-13 2011-01-26 李岱 吴茱萸次碱用于治疗银屑病的应用
EP2664919A1 (fr) 2012-05-15 2013-11-20 Jean Hilaire Saurat Une méthode pour identifier les ligands du récepteur AhR possédant une activité sebosuppressive thérapeutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4672074A (en) * 1983-01-10 1987-06-09 Harendza Harinxma Alfred J Ointment and process for treating skin lesions
US6555573B2 (en) * 2000-12-21 2003-04-29 The Quigley Corporation Method and composition for the topical treatment of diabetic neuropathy
US20090028804A1 (en) * 2005-11-28 2009-01-29 Symrise Gmbh & Co. Kg AhR mediators

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
Aziz et al. (July 2005 The FASEB Journal vol. 19 no. 9 1193-1195) *
Berberat et al. (Inflamm Bowel Dis, Volume 11, Number 4, April 2005) *
Denison (Chemico-Biological Interactions 141 (2002) 3-24 *
Dvorakova (Cancer Chemother Pharmacol (1999) 43: 331-335) *
Heath-Puglioso (Biochemistry 1998, 37, 11508-11515) *
Katiyar (Carcinogenesis vol. 22 no. 2 pp. 287-294, 2001) *
Keyse and Tyrrell (Proc. Nati. Acad. Sci. USA Vol. 86, pp. 99-103, January 1989) *
Phelan et al. (Arch Biochem Biophys. 1998 Sep 1;357(1):155-63) *
Srivastava (Cancer Letters 134 (1998) 91-95) *
Trommer and Neubert (J Pharm Pharmaceut Sci 8(3):494-506, 2005) *
Ubaidulla et al. (AAPS PharmSciTech 2007; 8 (1) Article 2; published January 19, 2007) *

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US20140221648A1 (en) * 2011-06-27 2014-08-07 Galderma Research & Developement Th17 differentiation markers for acne and uses thereof
WO2013019857A2 (fr) 2011-08-01 2013-02-07 Alnylam Pharmaceuticals, Inc. Procédé permettant d'améliorer le taux de succès des greffes de cellules souches hématopoïétiques
JP2015523553A (ja) * 2012-05-15 2015-08-13 テサン・ファーマシューティカルズ、インコーポレイテッド 治療用皮脂抑制活性を有するＡｈＲ受容体のリガンドを同定する方法、および前記リガンド
US20170042856A1 (en) * 2012-05-15 2017-02-16 Thesan Pharmaceuticals, Inc. Method and composition for treating acne
WO2015046627A1 (fr) * 2013-09-30 2015-04-02 国立大学法人九州大学 Promoteur de cicatrisation
WO2016069780A1 (fr) * 2014-10-28 2016-05-06 Oregon State University Composés et méthodes pour supprimer une réponse auto-immune
US10308649B2 (en) 2014-10-28 2019-06-04 Oregon State University Compounds and methods to suppress autoimmune response
JP2019513818A (ja) * 2016-03-10 2019-05-30 マイケル アインジガー， 皮膚美白剤としてのマラセジン（ｍａｌａｓｓｅｚｉｎ）及びその類似体
JP2020183449A (ja) * 2016-03-10 2020-11-12 マイケル アインジガー， 皮膚美白剤としてのマラセジン（ｍａｌａｓｓｅｚｉｎ）及びその類似体
US11104644B2 (en) 2016-03-10 2021-08-31 Versicolor Technologies, Llc Malassezin and analogs thereof as skin brightening agents
JP7261771B2 (ja) 2016-03-10 2023-04-20 マイケル アインジガー， 皮膚美白剤としてのマラセジン（ｍａｌａｓｓｅｚｉｎ）及びその類似体
JP2023082220A (ja) * 2016-03-10 2023-06-13 マイケル アインジガー， 皮膚美白剤としてのマラセジン（ｍａｌａｓｓｅｚｉｎ）及びその類似体
US11987555B2 (en) 2016-03-10 2024-05-21 Versicolor Technologies, Llc Malassezin and analogs thereof as skin brightening agents
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US12428374B2 (en) 2016-03-10 2025-09-30 Versicolor Technologies, Llc Malassezin and analogs thereof as skin brightening agents
US12497385B2 (en) 2018-04-12 2025-12-16 Versicolor Technologies, Llc Photoprotective compositions containing Malassezia-derived compounds and/or chemical analogs thereof
US12458577B2 (en) 2018-08-24 2025-11-04 Versicolor Technologies, Llc Photoprotective compositions containing Malassezia-derived compounds and/or chemical analogs thereof

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US20150216840A1 (en) 2015-08-06
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US20150005373A1 (en) 2015-01-01
WO2009093207A1 (fr) 2009-07-30

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