EP0862427A1 - Ultramicroemulsions composees de concentres a dispersion spontanee renfermant des esters de composes de bioflavonoide a action antitumorale, antivirale, virucide et antiparasitaire - Google Patents

Ultramicroemulsions composees de concentres a dispersion spontanee renfermant des esters de composes de bioflavonoide a action antitumorale, antivirale, virucide et antiparasitaire

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Publication number
EP0862427A1
EP0862427A1 EP97917205A EP97917205A EP0862427A1 EP 0862427 A1 EP0862427 A1 EP 0862427A1 EP 97917205 A EP97917205 A EP 97917205A EP 97917205 A EP97917205 A EP 97917205A EP 0862427 A1 EP0862427 A1 EP 0862427A1
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EP
European Patent Office
Prior art keywords
weight
formulas
spontaneously dispersible
esters
compounds
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.)
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Application number
EP97917205A
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German (de)
English (en)
Inventor
Carl Eugster
Conrad Hans Eugster
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Marigen SA
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Marigen SA
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Publication of EP0862427A1 publication Critical patent/EP0862427A1/fr
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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

  • the present invention relates to ultramicroemulsions from spontaneously dispersible concentrates with lipophilic, aliphatic esters of selected, naturally occurring flavonoids (without anthocyanins and chalcones), new esters of these compounds, processes for their preparation and workup, the use of the ester-containing spontaneously dispersible concentrates for the production of medicinal products with antitumoral, antiviral, direct virucidal and / or antiparasitic activity, for combating eczema and psoriasis, as well as for tumor prophylaxis and tumor therapy, as well as for the increased absorption of exogenous activators, metabolic modulators and regulators.
  • esters of these bioflavonoid compounds surprisingly have a very good antitumor, antiviral, direct virucidal, and in some cases also an antiparasitic effect, and they are also suitable for treating eczema and psoriasis and for stimulating immune responses.
  • the therapeutic properties of such esters occur significantly more when they are incorporated into spontaneously dispersible concentrates and then diluted with distilled water or 5% glucose solution or also with physiological saline (Ringer's solution), resulting in thermodynamically stable ultramicroemulsions with micelles of a hydrodynamic radius of 2.2 to 3.0 nm.
  • the flavonoid peresters are to be regarded as "activated esters". They have the ability to transfer acyl groups to suitable nucleophilic groups, which is particularly true of the acyl group at C-5 of the flavonoid backbone. This activation can easily be seen in 1 H-NMR spectra when using solvolytic solvents: the typical hydrogen bond between OH-C-5 and the carbonyl at C-4 appears quickly at approx. 12-13 ppm. From this it can be concluded that an acylation of (R) 3 -C-SH, R-CH 2 OH and R-NH 2 groups, and possibly also of secondary alcohols and secondary amines, which are present in the cell components are, should be done quickly;
  • the basic form of the esters of bioflavonoid compounds has the general formulas (I) to (IV): Flavones:
  • R OH, OCH 3 , in different positions, such as chrysin with OH at (C-5,7) or apigenin with OH at (C-5, 7, 4 ') Flavonols:
  • R e.g. camphor oil with OH (C-5, 7, 4 '), quercetin with OH (C- 6.7 I 3 ⁇ 4 , ) I Morin with OH (C-5, 7, 2', 4 '),
  • Flavanols (2,3-dihydroflavanols):
  • R for example genistein with OH (C-5, 7, 4 ') where in the formein (I) to (IV) R for hydroxyl, a C 6 - 31 alkyl, a C 9 . 3 1 - alkenyl or a C 9 . 31 -Alkapolyenadmi stands.
  • the esterification of the base bodies mentioned can be carried out by a process known per se:
  • a chlorinating agent such as thionyl chloride or lylchlorid oxa
  • esters of the bioflavonoid compounds according to formulas (I) to (IV) surprisingly have an excellent antitumor, antiviral, virucidal and also antiparasitic activity, and are also suitable for combating eczema and psoriasis and for compensating metabolic disorders .
  • These effects occur primarily when they have been incorporated into spontaneously dispersible MARIGENOL® concentrates according to the invention which, when diluted with distilled water, 5% glucose solution or also Ringer's solution, result in thermodynamically stable oil-in-water ultramicroemulsions.
  • the present invention relates in advance to spontaneously dispersible concentrates with antitumoral, antiviral, virucidal or antitrypanosomal active esters of the formulas (I) to (IV).
  • These esters are almost water-insoluble and highly agglomerated compounds.
  • they in order that such compounds can diffuse through the membrane barrier of the tumor or host cells or also through the protein envelope of viruses and become effective in the interior of the cell or the virus, they must first have been suitably solubilized in the aqueous medium.
  • spontaneously dispersible concentrates and the thermodynamically stable oil-in-water ultramicroemulsions produced from them enables the new ester to be optimally solubilized.
  • selected cosurfactants or solubilizers and, on the other hand, suitable surface-active compounds (surfactants) are used and combined to form a balanced system and then diluted.
  • the micelles of the inner phase of such ultramicroemulsions are accordingly protected on their surface with an elastic surfactant coat, which they repair, easily diffusing through the cell membrane into the interior of the tumor or host cell, or through the protein envelope of viruses.
  • the diffusion through the plasma membrane of tumor or host cells or through the capsid of viruses occurs exclusively due to thermal molecular movements.
  • the direction that a specific diffusion process takes is determined by the difference in concentration which exists on the plasma membrane between outside and inside the tumor or host cell or on the protein envelope. The diffusion continues along the concentration gradient until it is broken down. The concentration of active substance or an active substance system is balanced between the extracellular zone and the interior of the individual tumor or host cell or a virus, whereby delayed release effects can also occur. Such diffusion processes take place independently of any energy supply. They have no relation to cellular metabolic energy.
  • the speed of the diffusion process or the strength of the active ingredient transport through the membrane of the tumor or host cell are determined:
  • a globular "micelle" with a hydrodynamic radius of one centimeter has a volume of 4.189 cm 3 and a phase surface area of 12.564 cm2.
  • point 1018 micelles with a hydrodynamic radius of only 10-6 C m (10 nm) which together make up the same volume of 4.189 cm 3 have a total surface area of Phase 1 '256.4 m2 on.
  • the "packing density" of a spontaneously dispersible, stable MARIGENOL® concentrate increases in an exponential manner with the smaller particle size of the micelles.
  • the decisive factors are the correct formation of the inner phase, its balanced relationship to the total concentrate and the selection of the appropriate surfactants.
  • the concentrates which are spontaneously dispersible according to the invention contain: 0.1 to 5% by weight of individual esters of the formulas (I) to (IV), or a combination of such esters, and 5 to 25% by weight of a pharmaceutically acceptable solubilizer or solvent mixture serving as a hydrotrope, ie serving as a co-emulsifier,
  • a stabilizer 0 to 10% by weight of a stabilizer, radical scavenger or penetration enhancer.
  • the oil-in-water ultramicroemulsions which can be used according to the invention contain:
  • the surfactants or surfactant mixtures to be used according to the invention can be anionic, cationic, amphoteric or non-ionic. They are preferably amphoteric or non-ionic and have an HLB ratio (i.e. a "hydrophilic-lipophilic balance") between 2 and 18; for mixtures it is preferably between 2 to 6 on the one hand and 10 to 15 on the other. HLB values provide information about the hydrophilic and lipophilic properties of an emulsifier. See . also "Hydrophile-Lipophile Balance: History and recent Developments" by Paul Becher in the Journal of Dispersion Science and Technology 5 (1), 81-96 (1984).
  • phosphoric ester surfactants such as, for example: the practically anhydrous tristyrylphenol polyoxyethylene-18-phosphoric acid ester triethanolamine salt surfactant (TEA salt surfactant):
  • Diphasol® 3873 (CIBA-GEIGY), or the identical Sermul® EA 1 88 (SERVO), a mixed emulsifier, each consisting of 50% of the two compounds with the
  • Diphasol® 3873 (CIBA-GEIGY), an alkylphenol polyglycol ether phosphate surfactant surfactant 508 (CIBA-GEIGY)
  • Butyl mono-4-ethoxy phosphoric acid ester (Zerostat® AT, CIBA-GEIGY), or CH 3 - (CH 2 -CH-CH 2 -O (-CH 2 - CH - O) "OCH 3
  • betaine compounds i.e. amphoteric, salt and water-free imidazole derivatives, e.g. :
  • Polysorbate compounds are also used, e.g. Tween® 20-85 (Atlas Chem. Ind.lnc; or ICI Specialty Chemicals) and so-called “multifunctional glucose derivatives", such as e.g. Glucate® SS (methyl glucose sesquistearate) and Glucamate® SS E-20 (PEG-20 methyl glucose sesquistearate) from Amerchol, Edison, N.J., U.S.A.
  • hydrotrope i.e.
  • Pharmaceutical compatible solvents serving as co-emulsifiers can be used, e.g. :
  • Esters of an aliphatic alcohol with lactic acid such as myristyl, lauryl lactate or, preferably, (C ⁇ 2. 22); Mono-, di- or triesters of Gly cerins such as glyceryl caprylic lat with an aliphatic carboxylic acid (C 6. 22), or Miglyol® 812 neutral oil (Oleum neutral).
  • an aliphatic carboxylic acid C6-22
  • aliphatic alcohols C 1 2. 22
  • dodecanol, tetradecanol, oleyl alcohol, 2-hexyldecanol and 2-octyldecanol C 1 2. 22
  • Esters with at least one free hydroxyl group from poly (2-10) glycol with an aliphatic carboxylic acid (C 6 - 2 2).
  • Monoether from a polyethylene glycol with an aliphatic alcohol (C ⁇ _- ⁇ ) ⁇ such as polyoxyethylene (C 10 ) octyl ether.
  • Heterocyclic compounds such as 1-methyl-2-pyrrolidone.
  • Zwitterionic compounds Good buffer
  • such as' zBEPES "with formula: 4- (2-hydroxyethyl) piperazin-1-ethanesulfonic acid, or" CHAPS "with formula: 3- [(3-cholamido-propyl) -dimethyl-ammonio ] propane sulfonate or biots: wherein R 2 is an aliphatic C 2 .
  • alkyl is a C 3 - 3 i alkenyl or alkapolyen group and R 3 is citronellyl, farnesyl, geranyl, isophytyl or phytyl, and straight-chain carboxylic acid esters of DL- ⁇ -tocopherol, especially the undecenoate and the laurat.
  • Vitamins and provitamins such as, for example, vitamin A acid, retinol, tocopherols
  • penetration enhancers fluoride enhancers
  • radical scavengers are suitable as additives in the spontaneously dispersible concentrates according to the invention.
  • the extract which is usually pale yellow in color, is briefly dried over anhydrous Na 2 S0 4 or MgS0, then filtered and evaporated in vacuo.
  • the resulting oily or crystalline product is then transferred to a suitable crystallization vessel and recrystallized from 2-propanol or from benzene / acetonitrile or from dichloromethane / acetonitrile. Colorless to pale yellow colored peresters of the flavonoids used are obtained. They are dried at 40-55 ° C and 0.01 Torr.
  • the esterification is carried out according to regulation A. However, the resulting suspension is placed directly on a dry-packed column of 100 to 150 ml of silica gel 60 (0.063-0.200 mm, Merck 7734), prewashed with benzene / acetone 99: 1, and then developed with the same solvent. The fast-running, pale lemon-yellow main zone is collected, evaporated in vacuo and the mostly crystalline residue is recrystallized as indicated under 1.1.
  • the flavonoids used were dried at 130 ° C / 0.001 Torr for 20 h.
  • Propanol can be used for recrystallization.
  • H-0-C (5) can be conveniently carried out by NMR using the band at approx. 12.5 ppm.
  • UV 230 (16 * 000), 270 (48 * 100), sh. 295 (24 * 600), 327 (15 * 700)
  • UV 230 (25 * 700), 268 (36 * 000), 307 (21 * 600), 338 (20 * 100).
  • UV 232 (24 * 200), 248 (23 * 500), 286 (14 * 400), sh. 304 (13 * 300).
  • IR 2921 ss, 2850 s, 1767 s, 1652 s, 1622 s (only slight differences from the corresponding quercetin derivative).
  • IR 2962 ss, 2933 s, 2870 m, 1770 ss, 1657 s, 1616 ss.
  • a trilaurate (13a) can be obtained under forced acylation conditions, but this proves to be so unstable during processing that a more or less complete transition into the 7,4'-dilaurate (1 3b) occurs.
  • Palmitoyl 70%
  • Diphasol® 3873 (CIBA-GEIGY), surfactant 508 (CIBA-GEIGY), Zerostat® AN or AT (CIBA-GEIGY), Tinovetin® JU (CIBA-GEIGY), Soprophor® FL (RH ⁇ NE-POULENC), 5 to 90 weights % Invadin JFC 800% (CIBA-GEIGY) and / or TWEEN®-20 to TWEEN®-85 (ICI SPECIALTIES), and optionally 0 to 10% by weight of a vitamin or provitamin,
  • a penetration enhancer 0 to 10% by weight of a penetration enhancer, radical scavenger or stabilizer.
  • R - COO - R (from left) where R is a C 2 . 3 ⁇ alkyl, a C 3 . 3 ⁇ alkenyl or a C 3 . 31 is an alcapolyen group and R 3 is citronellyl, farnesyl, geranyl, isophytyl or phytyl,
  • Soprophor® FL or Diphasol® 3873 35 to 45% by weight of Soprophor® FL or Diphasol® 3873.
  • CHAPS (Fluka 26 * 680; Merck Index 11.2034) is a zwitterionic compound with the formula: 3 - [(3-cholamido-propyl) -dimethylammonio] propane sulfonate.
  • HEPES is a good buffer: 4- (2-hydroxyethyl) piperazin-1-ethanesulfonic acid.
  • TWEEN® 20 is a polyoxyethylene (20) sorbitan monolaurate surfactant (CAS No. 9005-64-5). [Polysorbate 20 in the CTFA Classification].
  • TWEEN® 80 is a polyoxyethylene (20) sorbitan monooleate surfactant (CAS No. 9005-65-6). [Polysorbate 80 in the CTFA Classification].
  • TWEEN® 85 is a polyoxyethylene (20) sorbitan trioleate surfactant [Polysorbate 85 in the CTFA Classification].
  • Metolose® 90 SH-4000 (Shin-Etsu Chemical) 90.0 g
  • MSR gastric juice resistance.
  • the pellets / granules according to a) can also be filled directly into capsules, which are made from AQOAT® (HPMC-AS-M or HPMC-AS-N), and sealed with acetone / ethanol 1: 1, and so the functions adequately control the MSR and the delayed release (retard). Biological tests.
  • composition examples a) and b) The antitumor effect of spontaneously dispersible concentrates according to composition examples a) and b) is confirmed on the basis of the following test results:
  • a biological assay system has been developed that works with microtiter plates and dilution series.
  • Each 10 / ml tumor cells are inactivated in culture medium RPMI 1640 with 10% fetal calf serum (GIBCO); they are sown so leaky that they can grow in non-confluent monolayers during the assay.
  • the sample is added after 6 to 24 hours, with 100 ⁇ l per row, which is Add 100 ⁇ l medium to the hole. Half of this is removed and placed in the following hole, again mixed with 100 ⁇ l of medium, etc.
  • a geometric dilution series nV_ is formed.
  • the samples are incubated in the plaque assay for 3 to 5 days at 37 ° C. with 3V_% CO 2 . Then dye / fix with 0.1% crystal violet (Fluka, Buchs) in a solution of 70% methanol, 1% formaldehyde, 29% water. The evaluation is carried out on a microscope, magnification 300 times. The largest cytotoxic dilution is determined. The quantitative evaluation can also be carried out using scanning and absorption measurement on a spectrophotometer.
  • IDENTIFICATION % vitality after 48 hours with 2% MARIG ENOL® CONCENTRATES, added once to the medium as an aqueous ultra-microemulsion.
  • Dilution 1:10 10,000 ppm concentrate, 200 ppm active substance; Etc.
  • IDENTIFICATION % vitality after 48 hours with 1% MARIGENOL® CONCENTRATES, added once to the medium as an aqueous ultra-emulsion.
  • Dilution 10 ⁇ 3 1 * 000 ppm concentrate, 10 ppm active substance; Etc .
  • HIV I II B complex Use of the HIV I II B complex at an average concentration of 300 CCIDso / rnl. Incubation for 3 hours at 4 ° C in the presence of the antiviral or virucidal microemulsion. Then transfer to the MT4 cells. A clear, dose-dependent inhibitory effect can be demonstrated compared to the non-infected controls.
  • Cf. also: A. Bergamini, CF. Perna, et al. : A tetrazolium-based colorimetric assay for quantification of HIV-induced cytopathogenicity in monocyte-macrophages exposed to macrophage colony-stimuiating factor. J.Virol. Methods, 1992: 40 (3), 275-86.
  • CMV Cytomegalovirus
  • the test was carried out with human, embryonic lung fibroblasts as host cells, which were then infected with the CMV strain AD 169.
  • the strain "CVM umano AD169" was formulated as a 1% concentrate and then diluted to an aqueous microemulsion 10 '3 , 10 ' 4 and for 4 h at + 4 ° C with different concentrations of the test substance C 1 6 op-sitosterylester 10 s , incubated and then inoculated as pretreated virus suspensions on cultures of human, embryonic lung fibroblasts. Approach as a confluent culture with 1 20 * 000 cells per shell vial.
  • the infection was carried out by centrifugation at 1,500 rpm and at RT for 45 minutes, whereupon the injection suspension was removed and 1 ml of culture medium MEM with 2% fetal calf serum (as in the case of cultivation) was added. would give; the infected cells were then kept at 37 ° C. and under a 5% CO 2 atmosphere for 20 hours.
  • the medium was removed, the cells were collected, fixed with 2% acetone-methanol (2: 1) and washed 3 times with PBS.
  • the quantification was carried out by means of immunofluorescence measurement.
  • the vials were mixed with the monoclonal antibody "Anti-P-72 CMV” (an immediate precursor protein of the CMV, which can be detected in the infected cells after 6 hours) and incubated for 30 minutes at 37 ° C. in a moist atmosphere.
  • controls were prepared with infected cells, which were prepared under the same conditions but without pretreatment with the test substance.
  • the nuclei positive for the CMV-specific antigen are counted using a fluorescence microscope at 25x magnification in the aqueous phase.
  • a dose-dependent, direct virucidal effect can be clearly determined.
  • the virus is no longer virulent enough to infect sensitive host cells.
  • aqueous microemulsion of suitable MARIGENOL® concentrates is determined using a confluent culture of VERO cells (i.e. "African green monkey kidney cells”).
  • the antiviral effect correlates with the number of "plaques” of lysed cells treated with a test substance which are still formed in the culture medium MEM + 2% FCS.
  • the reduction in viral titer is given as a percentage of the controls (21 plaques per cell).
  • MT4 lymphocytes are a human, leukemia-transformed T-line line. Repeat the test with fluorescence labeling as in the CMV test. See 4.1 above
  • CONTROLS CONCENTRATION CONCENTRATION CONCENTRATION Number of MICROEMULSION MICROEMULSION infected cells 1: 1 * 000 1: 10 * 000 1: 100 * 000
  • HBV Hepatitis B virus
  • the tests were carried out with immortalized liver hematoma cells which, after infection with the hepatitis B virus, the two antigens Hbs Ag (a "surface antigen” from the outer shell of the virus) and Hbe Ag (a "core antigen” from the core of the Secrete DNA virus).
  • Hbs Ag a "surface antigen” from the outer shell of the virus
  • Hbe Ag a "core antigen” from the core of the Secrete DNA virus.
  • Orientative experiments in vitro were carried out with a 1% concentrate of the three test substances ß-sitosteryl palmitate, ß-sitosteryl arachidate and ergosteryl isovalerate from Prof. Dott. Antonio Ponzetto and performed by Dotta Rossana Cavallo, University of Torino.
  • the characteristic peak appears after about 5 minutes.
  • micellar capillary zone electrophoresis micellar capillary zone electrophoresis
  • MECC micellar capillary zone electrophoresis
  • M monocytes (macrophages)
  • N neutrophil granulocytes
  • E eosinophilic granulocytes
  • Test 1 2% concentrate containing C ⁇ 2: o-cholesteryl ester Test 2 2% concentrate containing C ⁇ 6: o-ergosteryl ester Test 3 2% concentrate containing C ⁇ : 0 -cholecalciferyl ester (vitamin D 3 -iso-valerate )
  • EP1 100 100 20> 100 90 d

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Abstract

L'invention concerne des concentrés à dispersion spontanée renfermant des esters de composés de bioflavonoïde à action antitumorale, antivirale, virucide et antiparasitaire. L'invention concerne également des ultramicroémulsions aqueuses de ces concentrés, de nouveaux esters de composés de bioflavonoïde sélectionnés, un procédé de production et de préparation correspondant ainsi que leur utilisation comme agent pour la production de médicaments agissant contre les maladies virales et parasitaires, les tumeurs, l'eczéma et le psoriasis, pour une prophylaxie durable contre les tumeurs et pour une absorption accrue d'activateurs exogènes, de modulateurs et régulateurs métaboliques.
EP97917205A 1996-09-18 1997-04-28 Ultramicroemulsions composees de concentres a dispersion spontanee renfermant des esters de composes de bioflavonoide a action antitumorale, antivirale, virucide et antiparasitaire Withdrawn EP0862427A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
WOPCT/CH96/00323 1996-09-18
CH9600323 1996-09-18
PCT/CH1997/000168 WO1998011889A1 (fr) 1996-09-18 1997-04-28 Ultramicroemulsions composees de concentres a dispersion spontanee renfermant des esters de composes de bioflavonoide a action antitumorale, antivirale, virucide et antiparasitaire

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EP0862427A1 true EP0862427A1 (fr) 1998-09-09

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EP97917205A Withdrawn EP0862427A1 (fr) 1996-09-18 1997-04-28 Ultramicroemulsions composees de concentres a dispersion spontanee renfermant des esters de composes de bioflavonoide a action antitumorale, antivirale, virucide et antiparasitaire
EP97917206A Withdrawn EP0863746A1 (fr) 1996-09-18 1997-04-28 Peresters de glycoside de bioflavonol et leur preparation en concentres et ultramicroemulsions a action pharmacologique

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US6180661B1 (en) 1997-04-28 2001-01-30 Marigen, S.A. Bioflavonol-glycoside peresters and their incorporation into pharmacologically active concentrates and ultramicroemulsions
FR2778663B1 (fr) * 1998-05-15 2001-05-18 Coletica Nouveaux esters de flavonoides,leur utilisation en cosmetique, dermopharmacie, en pharmacie et en agro-alimentaire
PL205635B1 (pl) * 2001-04-09 2010-05-31 Inst Farmaceutyczny Nowe pochodne genisteiny i zawierające je środki farmaceutyczne
CN101513402B (zh) 2001-08-10 2012-03-21 盐野义制药株式会社 抗病毒药
CN1853728A (zh) * 2005-04-19 2006-11-01 上海天博生物科技有限公司 一种改善药物或营养物口服吸收的方法、配方及其应用
CN102250171B (zh) * 2010-05-21 2014-06-11 广东东阳光药业有限公司 芦丁酯类化合物及其在药物中的应用
CN107648216B (zh) * 2010-07-27 2021-03-30 波士顿大学管理委员会 作为新型癌症疗法的芳烃受体(AhR)调节剂

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JPS58131911A (ja) * 1983-01-27 1983-08-06 Sansho Seiyaku Kk クエルセチンの脂肪酸エステルを有効成分とする色白化粧料
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FR2706478B1 (fr) * 1993-06-14 1995-09-08 Ovi Sa Compositions de dérivés phénoliques, leur préparation et leurs applications comme anti-oxydants.
FR2715565B1 (fr) * 1994-01-31 1996-03-15 Oreal Composition cosmétique ou dermatologique stabilisée contenant plusieurs précurseurs d'un même actif pour maximaliser sa libération, son utilisation.

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EP0863746A1 (fr) 1998-09-16
WO1998011889A1 (fr) 1998-03-26

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