EP0954322A1 - Utilisation d'un oligosaccharide en tant qu'immunomodulateur dans une composition dermato-cosmetique - Google Patents

Utilisation d'un oligosaccharide en tant qu'immunomodulateur dans une composition dermato-cosmetique

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Publication number
EP0954322A1
EP0954322A1 EP97930717A EP97930717A EP0954322A1 EP 0954322 A1 EP0954322 A1 EP 0954322A1 EP 97930717 A EP97930717 A EP 97930717A EP 97930717 A EP97930717 A EP 97930717A EP 0954322 A1 EP0954322 A1 EP 0954322A1
Authority
EP
European Patent Office
Prior art keywords
oligosaccharide
elastin
cells
lymphocytes
composition
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Withdrawn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
EP97930717A
Other languages
German (de)
English (en)
Inventor
Ladislas Robert
Alexandre Robert
Dominique Castelli
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.)
Roc AG
Roc SA
Original Assignee
Roc AG
Roc SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Roc AG, Roc SA filed Critical Roc AG
Publication of EP0954322A1 publication Critical patent/EP0954322A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to compounds useful in the field of immunology and in particular for the treatment of hyper ⁇ ensitivity reactions responsible for allergies and variou ⁇ intolerance phenomena.
  • Immunological defence against infectious agent ⁇ , toxins or neoplasms operates via the recognition of the foreign nature of an antigen (or allergen) and the activation of cellular or humoral mediators aiming to eliminate the foreign antigen.
  • this mechanism can sometimes be undesirable, when it is too intense, or takes place on encountering environmental antigens which are not intrinsically noxious; this is likewise the case during organ transplantation or tis ⁇ ue graft ⁇ .
  • the mast cells are bound to IgE antibodies by their F c receptor; the fixing of the antigen triggers the degranulation of the mast cells and the liberation of mediators (histamine, SRS-A, ECF-A) .
  • the specific antibodies react with the antigen on the surface of target cells; this causes cytolysis, either by direct action of the K cells, or by activation of the complement.
  • the antibodies (IgG or IgM) form, with the antigen and the complement, immune complexes which are deposited in the tis ⁇ ues and cause the production of chemotactic factors for polynuclear neutrophil ⁇ ; local inflammation results.
  • T lymphocytes sensitized to the antigen react with this and liberate lymphokines .
  • the lymphokines induce an inflammatory reaction and cause the influx of macrophage ⁇ .
  • lymphocytes are thus key cells in immunity with cellular or humoral mediation, especially with the secretion of antibodies.
  • Allergic ailments can be the expression of one or more types of immunological reactions.
  • oligosaccharides comprising from 2 to 6 oside residues, and having a galactose residue in the non-reducing terminal position, or derivatives of such oligosaccharides substituted by a hydrophobic residue.
  • the present invention relates to the use of oligosaccharides comprising from 2 to 6 oside residues and having a galactose residue in the non-reducing terminal position, or of their derivatives, for the preparation of immunomodulator compositions, and in particular of compositions intended for the treatment or prevention of hypersensitivity reactions .
  • Particularly appropriate oligosaccharides could be chosen from the group formed by melibiose, lactose and their derivatives capable of being obtained by addition of a hydrophobic residue.
  • Hydrophobic ⁇ ubstituents are especially understood as meaning linear or branched Ci-Cis alkyls, Ci-Ci ⁇ alkylamines, linear or branched, optionally substituted C ⁇ -C ⁇ 8 carboxylic acids, linear or branched, primary, secondary or tertiary Ci-
  • Ci8 amides and C ⁇ -C ⁇ 8 arylalkyls.
  • the oligosaccharide derivatives suited for carrying out the invention can especially belong to one of the categories mentioned below, in which the oligosaccharide corresponds to the following general formula: galactose- n ( ⁇ or ⁇ ) - (Hex)p in which n represents the position 1, 2, 3, 4 or 6, Hex represents an ⁇ - or ⁇ -linked hexose or pentose, p is a number between 1 and 5; a) - glycosides corresponding to the formulae:
  • R is an alkyl residue of 2 to 18 carbon atoms, containing 0, 1 or 2 double bonds
  • R (CH2)m m being between 2 and 8, c) - an alkyla ine acylated by an aldonic acid obtained by oxidation of an oligosaccharide
  • R has the same meaning as in formula (III) ,
  • R has the same meaning as in (III) .
  • the oligosaccharide or its derivative such as defined above will be used to prepare a composition containing, in addition, pharmaceutically acceptable excipients suited to administration by the external topical route.
  • the applicant has found that the reactions involved in the disorders associated with hypersensitivity can be correlated with the fixation, on a specific lymphocyte receptor, of peptides resulting from the degradation of elastin, especially kappa-elastin.
  • the subjects having skins said to be "sensitive” or hyperreactive are more and more numerous in the population. Such a skin reddens or smarts easily, and its reactivity threshold is lowered with respect to other skins.
  • the subject experiences cutaneous discomfort, associated with erythema, and a fine desquamation can take place.
  • compositions containing oligosaccharides according to the invention melibiose, lactose, or their derivatives, partially or totally suppress cellular proliferation, in particular of the previously stimulated lymphocytes; they can likewise inhibit the potentialization and liberation of lytic enzymes .
  • the compositions will preferably be formulated in vehicles not comprising any perfume or allergenic agents .
  • the compositions could be in the form of solutions, gels, lotions, creams, W/O or O/ emulsions, or multiple emulsions or in liposomal form. They will be adapted by the person skilled in the art, preferably using emollients or mild surfactants.
  • the compositions are particularly suited to the treatment or to the prevention of intolerance and/or allergic reactions of the skin and/or of the mucous membranes.
  • compositions according to the invention are intended to prevent or to decrease the formation of free radicals.
  • the oligosaccharides or their derivatives could be associated with other agents enabling the skin to be protected and/or hydrated, such as hyaluronic acid, vitamin E, glycol extract of G. JbiloJba, ⁇ orbitol, glucosaminoglycans, alginate ⁇ , etc.; they can likewise be associated with vegetable oils to nourish the skin and/or with active emollients and salves such as, for example, extracts of cat grape, althaea, oats, linden, camomile, sweet clover, Ruscu ⁇ , procyanidols, ⁇ -bisabolol, coconut oil, 18- ⁇ -glycyrrhetinic acid.
  • active emollients and salves such as, for example, extracts of cat grape, althaea, oats, linden, camomile, sweet clover, Ruscu ⁇ , procyanidols, ⁇ -bisa
  • the oligosaccharides and their derivatives such as defined above are used for the preparation of a composition which additionally contains pharmaceutically acceptable excipients, suited for administration by the parenteral or enteral route.
  • the efficacy of the oligosaccharides according to the invention is based on their surprising activity on cell- mediated immune reactions.
  • compositions prepared according to the invention are particularly useful for the treatment or prevention of hypersensitivity reactions mediated by lymphocytes.
  • oligosaccharides having a galactose residue in the non-reducing terminal position, and their derivatives substituted by a hydrophobic residue can be utilized as adjuvants limiting the hypersensitivity reactions capable of being provoked by another active principle.
  • the invention likewise relates to a method of cosmetic treatment of hyperreactive skins, characterized in that a composition containing at least one oligosaccharide comprising from 2 to 6 oside residues, and having a galactose residue in the non-reducing terminal position, or a derivative of such an oligo ⁇ accharide substituted by a hydrophobic residue, is applied by the topical route in a cosmetically acceptable vehicle.
  • Particularly preferred compounds for putting this method into practice are melibiose, lactose and their derivatives capable of being obtained by addition of a hydrophobic residue.
  • the examples which follow are intended to illustrate the invention.
  • Fig. 1 Inhibition by lactose and melibiose of the activity of stimulation of lymphocyte proliferation by K-elastin.
  • concentrations of lactose and of melibiose are 1 ⁇ g/ml, 10 ⁇ g/ml, 100 ⁇ g/ml, 1 mg/ml and 2 mg/ml.
  • Fig. 3 Inhibition by lactose and melibiose of the expression of cathepsin G activity of lymphocytes stimulated with 2 ⁇ g/ml of K-elastin. Activity in the culture medium.
  • lymphocytes used for these experiments were obtained starting from circulating human blood and likewise from human tonsil after tonsillectomy .
  • the isolation of the peripheral lymphocytes is carried out as follows: 5 ml of blood were deposited (in 15 ml centrifugation tubes) on Ficoll-paque plus (Pharmacia) with care before separating the two phases, then centrifuged at 3000 rpm (say 600 g) for 40 min at ambient temperature (20 °C) .
  • the layer containing the lymphocytes and the monocytes is recovered and mixed with 10 ml of RPMI medium and centrifuged at 2200 rpm (say 400 g) for 10 min at 20 °C.
  • the sediment is resuspended in 0.5 ml of RPMI, then an additional 4.5 ml of RPMI are added and a new centrifugation is carried out at 1500 rpm (say 400 g) for 10 min at 20°C.
  • the final sediment is taken up in 10 ml of RPMI and the cells are counted.
  • the monocytes and acrophages are eliminated by adhesion on a plastic surface (incubation for 2 hours in a C0 2 /O a incubator) .
  • PMNs are resuspended in 1% polyvinyl alcohol (PVA) in
  • DPBS Dulbecco's modified phosphate-buffered saline
  • the cells are counted and can be lysed to liberate the lytic enzymes (elastase, cathepsin) by addition of 0.1% Triton X-100 in 1 M NaCl at 0°C for 20 min, followed by centrifugation for 20 min at 0°C. The supernatant contains the enzymes .
  • the lytic enzymes elastase, cathepsin
  • Freshly removed tonsils are cut into small pieces under sterile conditions, in 10 ml of RPMI.
  • the tissue suspension is filtered on a coarse filter in order to remove the largest tissue debris.
  • the suspension is placed in a test tube and allowed to sediment for 15 min at ambient temperature.
  • the supernatant is placed on Ficoll-paque plus and centrifuged as described for lymphocytes derived from blood.
  • the monocytes are eliminated as described for the lymphocytes derived from blood.
  • the sediment containing the lymphocytes is resuspended and the cells are counted after two centrifugations as described.
  • the lymphocytes obtained starting from tonsils are approximately 50% of the type T and 50% of the type B.
  • the lymphocytes of blood origin are approximately 80% of type T and 20% of type B.
  • lymphocytes isolated as described above are cultured in 24-well Costar plates, 500 ⁇ l of cell suspension/well (5 x 10 s cells/ml or 2.5 x 10 s cells) in RPMI 1640 medium (Eurobio) made up with 10% foetal calf serum (ATGC) , 2 mM glutamine (Gibco) , penicillin and streptomycin (500 U/ml, 0.25 mg/ml), and phyto- haemagglutinin (SIGMA) 5 ⁇ g/ml.
  • RPMI 1640 medium Eurobio
  • ATGC foetal calf serum
  • Gibco 2 mM glutamine
  • penicillin and streptomycin 500 U/ml, 0.25 mg/ml
  • SIGMA phyto- haemagglutinin
  • the cell suspension After incubation for 4 days under cell culture conditions (37°C, C0 2 /0 2 incubator) the cell suspension is recovered with a pipette, centrifuged at 400 g for 10 min at 20°C and the cell sediment is taken up in 0.5 ml of RPMI (without
  • a sterile solution of x-elastin (75 kD, Solabia) is added at the concentration indicated (for example 2 ⁇ g/ml) to cells put back into culture in the medium without FCS for 2.5 hours at 37 °C. After incubation, the plates are gently agitated, and the cells are recovered by pipetting and counted. The suspension is centrifuged for 10 min at 4°C at 1500 rpm (say 400 g) , and the supernatant is distributed in 1 ml Eppendorf tubes at a rate of 500 ⁇ l per tube and kept at -40°C if it is not used immediately for enzymatic determinations.
  • x-elastin 75 kD, Solabia
  • the cell sediment is resuspended in extraction buffer (0.1% Triton X-100, 1 M NaCl, 0.02% NaN 3 0.01% Brij 35, pH 8) . 1 ml per 10 s cells, agitated for 15 min at 1600 g at 0°C and the supernatant obtained by centrifugation as described above is redistributed in Eppendorf tubes and kept at - 40 °C for the enzymatic determinations.
  • extraction buffer 0.1% Triton X-100, 1 M NaCl, 0.02% NaN 3 0.01% Brij 35, pH 8
  • 1 ml per 10 s cells agitated for 15 min at 1600 g at 0°C and the supernatant obtained by centrifugation as described above is redistributed in Eppendorf tubes and kept at - 40 °C for the enzymatic determinations.
  • the synthetic substrate used for determining the enzymatic activity of elastase- type is Me-O-Suc-Ala- Ala-Pro-Val-pNA.
  • 50 ⁇ l of culture medium or 20 ⁇ l of cell lysate are mixed with the buffer (100 mM tris-HCl, 0.05% CaCl 2 , 0.02% NaN 3 , 0.01% Brij 35, pH 8) up to 190 ⁇ l, then with 10 ⁇ l of 85 mM substrate solution (in N-methylpyr- rolidone) for a total volume of 200 ⁇ l .
  • the optical density is read immediately at 410 n and then after 4, 24, 48 and 72 hours' incubation at 37°C.
  • the elastase activity is expressed in nM of substrate hydrolysed per
  • the passages of calcium produced by the addition of elastin peptides to the white cells of the blood can be considered as an indication of the intracellular signal triggering a set of cellular functions.
  • One of these is the entry of cells into proliferation. It has been shown that this was the case for hviman skin fibroblasts in the presence of elastin peptides (Ghuysen- Itard et al, CR. Acad. Sci., 1992, 315 : 473-478).
  • the results reported in Table 1 show that a stimulation analogous to the proliferation of lymphocytes was observed.
  • a maximum stimulation is observed at 2 ⁇ g/ml of elastin peptides and a little weaker stimulation with 10 ⁇ g/ml of elastin peptides .
  • This experiment is carried out under the culture conditions such as described above, in the presence of phytohaemaglutinin (PHA) .
  • PHA phytohaemaglutinin
  • elastin peptides exert a cytotoxic activity at high concentrations (a thousand times higher than the concentration stimulating cell proliferation and the salting-out of the lytic enzymes) .
  • Example 2 Effect of lactose and of melibiose on reactions mediated by the elastin receptor of lymphocytes
  • Example 3 Quantification of the elastin receptor in subpopulations of human lymphocytes
  • - 1st antibody 67 kD elastin/laminin anti-receptor antibody (bovine) (type: IgM) produced in mice (Elastin Products Company) .
  • - 2nd antibody mouse anti-IgG + IgM (H + L) antibody produced in goats, labelled by rhodamine (TRITC) (Jackson I munoresearch Laboratories) (for fluorescence microscopy) .
  • TRITC rhodamine
  • 2nd antibody anti-IgM antibody (F(ab') 2 of mice produced in goats, labelled by r-phycoerythrin (Chemicon) ) (for flow cytometry) .
  • Human lymphocytes are isolated from tonsils (as described in Example 1) and cultured in the presence of 5 ⁇ g/ml of phytohaemagglutinin (to activate them) and for certain cultures with 2 ⁇ g/ml of kappa-elastin of high molecular weight (75 kD) in an RPMI 1640 medium with 10% foetal calf serum (FCS) . After 48 to 120 hours' incubation at 37 °C, the lymphocytes are washed three times with RPMI medium containing 2% FCS and then centrifuged (400 g, 10 minutes at 4°C) . Next, the cells are counted and the cell density is adjusted to 10 7 cells/ml with RPMI medium containing 2% FCS.
  • FCS foetal calf serum
  • a volume (100 ⁇ l) of cell suspension of human lymphocytes (approximately 10 6 cells) is incubated with 10 ⁇ l of solution of the first antibody (diluted to 1:100) for 30 minutes in an ice bath.
  • 10 ⁇ l of solution of the first antibody (diluted to 1:100) for 30 minutes in an ice bath.
  • 1.5 ml of cold RPMI are added to 2% FCS and then the cells are washed in a refrigerated centrifuge at 4°C (at 400 g for 10 minutes) .
  • the solution of the second antibody conjuggated to TRITC (diluted in cold RPMI to 1:200) is added to the plug. After gentle agitation of the suspension, it is incubated at 4°C for 30 minutes. Next, 1.5 ml of cold RPMI are added to 2% FCS and the suspension is centrifuged at 400 g at 4°C for 10 minutes. At the end of this last washing, the lymphocytes are resuspended in the residual medium after having removed the supernatant by decantation. Smears are then made on slides and dried in the air.
  • the slides After fixing with absolute ethanol for 5 minutes, the slides are rehydrated by immersion in several baths of PBS and mounted in buffered glycerol (9 volumes of glycerol and 1 volume of PBS). This post-fixation procedure increases the brightness of the immunofluorescence .
  • microscopic fields are examined alternatively under ultraviolet illumination and in visible light.
  • the lymphocytes are suspended in 1 ml of PBS and the cells are analysed by cytofluorimetry.
  • CD 3 The CD 3 complex is expressed by all mature human
  • T cells has molecular weights of between 16 and 28 kD composed of 5 chains ( ⁇ , ⁇ , e, ⁇ , ⁇ ) associated with the T-cell receptor in a non-covalent manner. It is involved in the transmission of activation signals.
  • CD 4 recognizes the class II MHC molecules during the interaction of CD4+ cells with cells presenting the antigen or target cells. It is a glycoprotein of 59 kD belonging to the immunoglobulin superfamily. It is found in the "helper/inducer" subpopulation of T lymphocytes (45% of the lymphocytes of peripheral blood) .
  • the CD 8 molecule (T8, 30/32 kD) is a glycoprotein formed of two peptide chains. It is found in the cytotoxic/suppressor subpopulation of the T lymphocytes (20-35% of the lymphocytes of the peripheral blood) . It is also present on NK cells and on 30% of the "null" cells of the peripheral blood.
  • CD 15 antigen 3FAL, X-haptene, SSEA
  • SSEA lacto-N-fucopentose III
  • At least 5 major antigens of CD 15 are present on the surface of poly- nuclear cells (approximately 90% of the circulating human granulocytes) and on part of the circulating monocytes (30-60%) . This antigen is absent from the surface of normal lymphocytes .
  • the CD20 antigen is a phosphoprotein of 35/37kD. It is present on all normal B cells of the peripheral blood, of the tonsil and of the bone marrow.
  • the CD25 molecule corresponds to the low-affinity receptor of interleukin-2. It is a glycoprotein of 55 kD expressed by activated lymphocytes (T and B) but also by activated macrophages.
  • the T lymphocytes expressing CD45RO are memory T lymphocytes (or primed T cells) (45% of the T lymphocytes of the peripheral blood) .
  • the CD4+/CD45RO+ cells produce "helper" signals. These are early producers of IL-2 and IFN- ⁇ .
  • lymphocyte suspension 100 ⁇ l of the lymphocyte suspension (already labelled or not) are taken with the 67 kD anti-receptor antibody of elastin at a cell density of 10 7 cells/ml.
  • lymphocytes - those which express the 67 kD elastin/laminin receptor - show a specific immunofluorescence under the experimental conditions described above (positive cells) .
  • the percentage of positive cells on the 4th day of culture is evaluated by fluorescence microscopy:
  • melibiose is more effective than lactose for desorbing the 67 kD subunit of the lymphocyte elastin receptor: lactose desorbs 66 ⁇ of the receptor and melibiose 76% under the experimental conditions used.
  • DO on the day of separation of the lymphocytes
  • D2 , D3 , D5 on the second; third; fifth day after separation of the lymphocytes .
  • CDx+R57kD cells labelled simultaneously with the anti-CDx antibody and with anti-subunit antibody of the 67 kD elastin receptor. Note: The sum of the percentages does not give 100% since a cell can simultaneously express several receptors . In this experiment, the nature of the lymphocyte subclass expressing the elastin receptor in the presence and in the absence of elastin peptides was determined by double labelling.
  • CD4+ and CD45R0+ lymphocytes which in the presence of elastin peptides strongly increased the expression of the elastin receptor. It is a matter in that case of a subpopulation of cells considered as helper and memory cells. The coupling of the elastin receptor by positive retroaction to its own synthesis after its activation would thus be specific to these cells.
  • Example 4 Protection against the cytotoxic effect of kappa-elastin of low molecular weight on lymphocytes
  • the cell suspension is diluted with RPMI containing 5 mM glutamine and 10% FCS such that the concentra- tion is 10 ⁇ cells/2 ml.
  • the lymphocytes are put into culture in 24-well Costar plates (500 ⁇ l of cell suspension/well at a concentration of 10 6 cells/2 ml) in complemented RPMI
  • the table shows the percentage of dead cells in the presence of elastin peptides and the protection against cell death by lactose and melibiose. This protection is close to 100%: the overmortality (compared with the control without K -elastin) is 32.1% with 2 mg/ml of elastin peptides. In the presence of lactose or of melibiose this overmortality is 1.3% (96% protection).

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  • Pharmacology & Pharmacy (AREA)
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  • Dermatology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation d'au moins un oligosaccharide comprenant 2 à 6 restes oside et présentant un reste galactose dans la position terminale non réductrice, ou un dérivé de cet oligosaccharide substitué par un reste hydrophobe, dans la préparation d'un médicament immunomodulateur. L'invention concerne également une composition dermato-cosmétique et un traitement cosmétique des peaux hyperréactives.
EP97930717A 1996-07-31 1997-07-30 Utilisation d'un oligosaccharide en tant qu'immunomodulateur dans une composition dermato-cosmetique Withdrawn EP0954322A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9609649 1996-07-31
FR9609649A FR2751876B1 (fr) 1996-07-31 1996-07-31 Utilisation d'un oligosaccharide comme immunomodulateur, composition dermato-cosmetique et methode de traitement cosmetique
PCT/IB1997/000951 WO1998004270A1 (fr) 1996-07-31 1997-07-30 Utilisation d'un oligosaccharide en tant qu'immunomodulateur dans une composition dermato-cosmetique

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EP0954322A1 true EP0954322A1 (fr) 1999-11-10

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EP (1) EP0954322A1 (fr)
JP (1) JP2000516591A (fr)
KR (1) KR20000029754A (fr)
CN (1) CN1228705A (fr)
AU (1) AU3457697A (fr)
BR (1) BR9710630A (fr)
CA (1) CA2262564A1 (fr)
CZ (1) CZ29599A3 (fr)
FR (1) FR2751876B1 (fr)
HU (1) HUP9903904A3 (fr)
NZ (1) NZ333985A (fr)
PL (1) PL331478A1 (fr)
RU (1) RU99104398A (fr)
SK (1) SK12199A3 (fr)
WO (1) WO1998004270A1 (fr)

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US11328621B2 (en) 2013-10-25 2022-05-10 Red Pinnace Limited Dietary regime for treatment of acne and other inflammatory skin conditions
KR101689875B1 (ko) 2014-08-28 2016-12-26 (주)셀아이콘랩 펩타이드와 아미노산의 혼합물을 함유하는 아토피 개선용 화장료 조성물
KR101689877B1 (ko) 2014-08-28 2016-12-26 (주)셀아이콘랩 아토피 개선용 화장료 조성물
KR102046566B1 (ko) 2018-08-09 2019-11-19 박정혜 피부 가려움 개선용 화장료 조성물

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FR2751876A1 (fr) 1998-02-06
KR20000029754A (ko) 2000-05-25
CZ29599A3 (cs) 1999-06-16
CA2262564A1 (fr) 1998-02-05
PL331478A1 (en) 1999-07-19
AU3457697A (en) 1998-02-20
NZ333985A (en) 2000-09-29
FR2751876B1 (fr) 1998-12-31
BR9710630A (pt) 2000-01-11
HUP9903904A2 (hu) 2000-04-28
RU99104398A (ru) 2001-02-20
JP2000516591A (ja) 2000-12-12
CN1228705A (zh) 1999-09-15
WO1998004270A1 (fr) 1998-02-05
HUP9903904A3 (en) 2000-05-29
SK12199A3 (en) 2000-01-18

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