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WO1998032443A1 - Ultramicro-emulsions de concentres spontanement dispersibles renfermant des esters de triterpenes pentacycliques a activite antitumorale, antivirale et antiparasitaire - Google Patents

Ultramicro-emulsions de concentres spontanement dispersibles renfermant des esters de triterpenes pentacycliques a activite antitumorale, antivirale et antiparasitaire Download PDF

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Publication number
WO1998032443A1
WO1998032443A1 PCT/CH1997/000023 CH9700023W WO9832443A1 WO 1998032443 A1 WO1998032443 A1 WO 1998032443A1 CH 9700023 W CH9700023 W CH 9700023W WO 9832443 A1 WO9832443 A1 WO 9832443A1
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Prior art keywords
weight
esters
acid
formulas
surfactant
Prior art date
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Ceased
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PCT/CH1997/000023
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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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Priority to EP97900535A priority Critical patent/EP0902685A1/fr
Priority to PCT/CH1997/000023 priority patent/WO1998032443A1/fr
Publication of WO1998032443A1 publication Critical patent/WO1998032443A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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

Definitions

  • the present invention relates to ultramicroemulsions from spontaneously dispersible concentrates with esters of pentacyclic triterpene compounds, new triterpene esters, processes for their preparation and processing into suitable pharmaceutical dosage forms, and the use of the ester-containing, spontaneously dispersible concentrates and microemulsions as medicaments with effectiveness against tumors, eczema, psoriasis, viral and parasitic infections, as well as for the prevention of tumor formation by increasing the absorption of exogenous activators, modulators and regulators.
  • esters of the selected plant-based raw materials and their transformation products surprisingly have a very good antitumor, antiviral and / or virucidal and antiparasitic activity, and they are also suitable for the treatment of eczema and psoriasis. In preventive and therapy-supporting respects, they are important because they increase the uptake of exogenous activators, modulators and regulators and thereby increase the metabolic as well as the immune performance.
  • Betulinic acid Hatchet: 10 (3), 1059; Aldrich 85.505-7
  • ENOXOLON (3-hydroxy-11-oxoolean-12-en-29-oic acid); 18 ⁇ -glycyrrhetic acid; Uralenic acid; Merck Index 11.3543 L. Ruzicka et al., Helv.Chim.Acta 26., 2143, 2278 (1943)
  • URSOLIC ACID (ß-Hydroxyurs-12-en-28 oic acid)
  • the compounds of the formulas (I) to (XI) can generally be prepared by the following processes which are known per se: a) Reaction of a compound of the formula (XII):
  • the methyl ester of 18 ⁇ -glycyrrhetinic acid can:
  • esters of the selected pentacyclic triterpene compounds of the formulas (I) to (XI) surprisingly have an excellent antitumor, antiviral, virucidal and antiparasitic activity, and they are also suitable for combating eczema, psoriasis, as well as metabolic and immune Disruptions, especially when they have been incorporated into spontaneously dispersible MARIGENOL® concentrates according to the present invention, which result in thermodynamically stable oil-in-water ultramicroemulsions diluted with distilled water, with 5% glucose solution or with Ringer's solution.
  • the present invention accordingly relates to spontaneously dispersible concentrates in advance with the antitumoral, antiviral, virucidal or antiparasitic esters of the compounds (I) to (XI), which can also induce the apoptosis of tumor or host cells.
  • the designated esters are almost water-insoluble and highly agglomerated compounds. So that such connections pass through the membrane barrier of the tumor or host cells, or the protein sheath of veins or parasites diffuse and inside the
  • Cell or the capsid can be effective, they must first be suitably solubilized in the aqueous medium.
  • thermodynamically stable oil-in-water ultramicroemulsions with the help of specially selected and combined as a system surfactants or solubilizers on the one hand and suitable surfactants on the other hand, it is possible to achieve an optimal degree of solubilization of the therapeutically and prophylactically active esters.
  • the molecules of the designated ester compounds are dissolved in the oily inner phase and are present in the micellar core in monomeric or in oligomeric agglomerated form, which makes a very decisive difference to mere macro-emulsions (e.g. liposomes).
  • the micelles of the ester-containing inner phase of the ultramicroemulsions according to the invention are accordingly on their surface, i.e. protected at its boundary layer with a surfactant coat, which it repairs, easily diffusing through the cell membrane or the protein envelope into the interior of the tumor or host cell.
  • the diffusion through the plasma membrane of abnormal cells occurs exclusively due to thermal molecular movements; the fractal conditions on the cell membrane accommodate her. It can be shown that the speed of the diffusion process or the strength of the active substance transport is determined by the membrane of the target cell:
  • a globular "micelle" with a hydrodynamic radius of one centimeter has a volume of 4.189 cm 3 and a phase surface area of 1 2.564 cm2.
  • 1Q18 micelles with a hydrodynamic radius of only 10-6 cm (10 nm) each, which together make up the same volume of 4.1 87 cm 3 already have a total phase surface of 1 '256.4 m2 .
  • the "packing density" of a spontaneously dispersible, stable MARIGENOL® concentrate increases exponentially with the smaller particle size of the micelles.
  • the right training is crucial the inner phase, its balanced ratio 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 10% by weight of individual esters of the formulas (I) to (XI), or combinations of such esters, and
  • a pharmaceutically compatible surfactant or surfactant mixture up to 10% by weight of a vitamin or provitamin, up to 10% by weight of a stabilizer, scavenger, biological vector or penetration enhancer and carriers and the like / or diluent.
  • the surfactants or surfactant mixtures to be used according to the invention can be anion-active, cation-active, amphoteric or non-ionic. They are preferably amphoteric or non-ionic and have an HLB ratio (ie a “hydrophilic-lipophilic balance”) between 2 and 1 8; for mixtures it is preferably between 2 to 6 on the one hand and 1 0 to 15 on the other.
  • HLB ratio ie a “hydrophilic-lipophilic balance”
  • Highly preferred for the production of spontaneously dispersible concentrates according to the invention are, on the one hand, phosphoric acid ester surfactants, such as, for example: the practically anhydrous tristyryl phenol polyoxyethylene-18-phosphoric acid ester TEA salt surfactant:
  • Diphasol® 3873 (CIBA-GEIGY), or the identical Sermul® EA 188 (SERVO), a mixed emulsifier, each consisting of 50% of the two compounds with the
  • Diphasol® 3873 (CIBA-GEIGY), an alkylphenol polyglycol ether phosphate surfactant
  • Butyl mono-4-ethoxy phosphoric acid ester (Zerostat® AT, CIBA-GEIGY), or CH 3 - (CH 2 ) —CH-CH 2 -O (-CH 2 - CH 2 -O) 5 -OCH,
  • betai n associations i.e. amphoteric, salt and water-free imidazole derivatives, e.g. :
  • Me [ + ] stands for hydrogen, alkali and alkaline earth atoms and R x for C 1 -32 -alkyl or C 2-32 -alkenyl groups.
  • multi-functional glucose derivatives such as e.g.
  • Glucate® SS methyl glucose sesq uistearate
  • Glucate® SSE-20 PEG-20
  • Methyl Glucose Sesquistearate from Amerchol, Edison, N.J. , UNITED STATES.
  • solvents which can be used as hydrotropes or as co-emulsifiers can be used, e.g. :
  • an aliphatic carboxylic acid C 10 - 22
  • Hydrocarbons with a straight carbon chain C 12 -32
  • propylene glycol monolaurate and propylene glycol monomyristate such as propylene glycol monolaurate and propylene glycol monomyristate.
  • Esters of an al iphatician alcohol (. C 12 22) with lchklare Mi such as myristyl or preferably Lau ryl-lactate; Mono-, di- or triesters of Gly cerins (neutral oleum) with an ali phatic carboxylic acid (C 6. 22), such as G lyceryl- capryolat, or Miglyol® 812 neutral oil.
  • aliphatic alcohols C ⁇ 2-22
  • dodecanol tetradecanol
  • oleyl alcohol 2-hexyldecanol
  • 2-octyldecanol 2-octyldecanol
  • Ester with at least one free hydroxyl group from poly (2-1 0) glycol with an aliphatic carboxylic acid (C ⁇ - 22 ).
  • Vitamins and provitamins are suitable as additives in the spontaneously dispersible concentrates according to the invention.
  • AII-trans-retinoic acid in 50 ml of dioxane or chloroform are added 650 mg of N, N'-carbonyldiim idazole at 15 ° C. with exclusion of air.
  • the reaction solution is left to stand at 15 ° C. for 24 hours.
  • the solution with the resulting AII-trans-retinoic acid imidazolide is then added dropwise at 20 ° C. to a solution of 900 mg of oleanolic acid, 60 mg of dimethylformamide and 50 mg of p-dimethylamino nopyridine in 50 ml of dioxane or chloroform. After heating for 3 hours at 40 ° C, the solvent is removed by vacuum distillation.
  • the preparation is made from 30,280-dilauroyl betulin analogous to a rule by L. Ruzicka et al. [Helv.Chim.Acta 1938, 21_, 1708]: the solution of 495 mg of 3,28-di-O-lauroylbetulin in 3 ml of benzene was mixed with 6.25 ml of 0.1N KOH in ethanol and while stirring Maintained at 50 ° C for 12 hours. We poured the clear solution on a silica gel column (silica gel Merck, 0.04 - 0.063 mm / 2, 6 x 43 cm, wet filled with ethyl acetate / benzene / acetone 11: 9: 1).
  • the monolaurate has an Rf value of 0.84. Yield 280 mg of colorless, very viscous oil which slowly solidifies to a semi-solid mass when dried at 50 ° C./0.01 Torr.
  • Rf (silica gel Merck, AcOEt / Toluon / Acetone 11: 9: 1): 0.84.
  • Allobetulin was prepared according to the instructions of H. Schulze and K. Pieroh (Ber. Deutsch. Chem. Ges., 1922, 55_, 2332). 0.31 and 0.47 g each of pure Allobetu lin were in 2 ml abs. Dissolved pyridine and 10 ml of 1, 2-dichloroethane, then mixed with a few crystals of 4-dimethylaminopyridine and added dropwise at room temperature via syringe with 1, 2 equivalents of acid chloride. After 2 h at RT, the mixture was heated to 50 ° C. for 30 m, then cooled, sufficient Et2 ⁇ was added and the mixture was shaken out with water, 2N HCl and brine. After drying over Na2SO4, filtering and evaporation, the mixture was taken up in benzene and the solution was filtered through a short column of activated aluminum oxide and the filtrate was evaporated.
  • the methyl ester was prepared from pure betulinic acid by esterifying its solution in THF / MeOh with an excess of freshly prepared ethereal diazomethane solution (cf. V. Bruckner, J. Koväcs, J. Kozka, J. Chem. Soc. 1 948 . 948).
  • a little 4-dimethylaminopyridine was added to pyridine and 10 ml of 1,2-dichloroethane and then acylated and worked up as above under e). 0.75 g of colorless, very viscous oil was obtained which did not crystallize at RT.
  • COMPOSITION EXAMPLES of spontaneously dispersible CONCENTRATES according to the invention which contain the active compounds of the formulas (I) to (VI) and which, if diluted with water or 5% glucose solution or physiological saline (Ringer's solution), thermodynamically stable ULTRAMICROEMULS IONS with a hyd rododynamic radius of 2.2 to 3.0 nm.
  • isopropyl myristate, isopropyl palmitate or neutral oil e.g. Mig lyol® 81 2 (DYNAMIT NOBEL or HÜLS),
  • a phosphoric acid ester surfactant e.g. Diphasol® 3873 (CI BA-GEIGY), tenside 508 (CIBA-G EIGY), Zerostat® AN or AT (CIBA-GIGY), Tinovetin® JU (CIBA-G EIGY), Soprophor® FL (RH ⁇ NE-POULENC), 5 up to 90% by weight Invadin JFC 800% (CIBA-GEIGY) and / or Tween®-20 (ICI S specialty Chemicals), up to 10% by weight of a vitamin or provitamin. up to 10% by weight of a stabilizer, radical scavenger, biological vector or penetration enhancer and carriers and / or diluents.
  • a stabilizer, radical scavenger, biological vector or penetration enhancer and carriers and / or diluents e.g. Diphasol® 3873 (CI BA-GEIGY), tenside 508 (CIBA-G EIGY), Zerostat® AN or AT (CIBA
  • ) where R4 is a C 2 - 3 i alkyl, a C 3 . 3 i -Alkenyl or a C 3-3 ⁇ -Alkapolyen- group and R5 citronellyl, farnesyl, geranyl, isophytyl or phytyl mean.
  • INVADIN® J FC 800% (CI BA-GEIGY) is an anhydrous tert. Octylphenyl polyoxyethylene ether surfactant with 9 to 10 oxyethylene groups.
  • TWEEN®-20 is a polyoxyethylene (20) sorbitan monolaurate, or the polysorbate-20 in the CTFA classification.
  • 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).
  • a biological assay system has been developed that works with microtiter plates and dilution series.
  • 1 ⁇ 4 / ml tumor cells are inactivated in RPMI 1640 culture medium with 10% fetal calf serum (GIBCO); they are sown so densely 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 then in the 1st Add 100 ⁇ l of medium to the hole. Half of this is removed and placed in the following hole, again mixed with 100 ⁇ l medium, etc.
  • a geometric series of dilutions n 1 / .. is formed.
  • the samples are incubated in the plaque assay for 3 to 5 days at 37 ° C with 3 1 ⁇ % CO2. 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 by means of scanning and absorption measurement on a spectrophotometer.
  • Betulin accounts for up to 35% of the dry weight in the white bark of Betula platyphyl la. [K. Hi rota et al., Chem. Abbstr. 1948, 42., 6090], which suggests that it assumes a protective function for the plant there.
  • the extract from the dry distillation served as a remedy for various applications, and as a "bark tar" for the manufacture of the famous Russian leather.
  • Cytofluor 2300 system Incubation 72h, Alama blue; Plate CoStar 96 treatment: 46 h; Measurement EX filter 530/25; EM filter 590/35, sensitivity 2
  • MTT methyl tetraazole salt
  • Residual values of the Zeil vitality are expressed as a% difference compared to the HIV CPE controls, the mean as zero.
  • the measured titer depends on the dose. It drops from the initial value of 300% CCID50 to 120% CCID50 and down to 2% CCID50.
  • CCID50 cell c_ulture mfective d_ose 50%.
  • CCID50 cell c_ulture mfective d_ose 50%.
  • the HIV titer is given as the reciprocal of the dilution which 4 of 8 samples from a series (50%) infected. The content of a hole is considered infected if the reading of the OD at 550 nm is lower than the mean of the 8 control holes minus 2.8 times the standard deviation (lower 95% confidence limit).
  • ergosteryl-1 0-u-decenoate and ß-sitosteryl-palm itate a very clear inhibition of replication and actual elimination can be determined in vitro as a result of the pretreatment of the strains. Your defense against infection is dose-dependent. There was no inhibition at all after treatment with pure carrier concentrate alone.
  • HIV TITER (CCID50)
  • HIV strain 21/4 (clinical isolate) + 300
  • HIV strain 4/5 (“clinical i solate") + 200
  • HIV (2 strains) + 2 ß-SITOSTERYL-PALM ITAT (mean titer from
  • 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 for 4 h at + 4 ° C. with different concentrations of the test substance C 6: o-ß-sitosterylester -4 and 10-5, incubated and then inoculated as pretreated virus suspensions on cultures of human, embryonic lung fibroblasts. Approach as a confluent culture with 120 * 000 cells per shell vial.
  • the infection was carried out by centrifugation for 45 minutes at 1500 rpm and at RT, 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; 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. This was followed by 3 washes in PBS, a second incubation with the fluorescence-labeled antibody IgG goat anti-IgG mouse. This is followed by another incubation for 30 minutes at 37 ° C., as indicated above, followed by a 3-wash with PBS. The samples are then mounted on glass slides with 50% glycerol in PBS.
  • 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 the sensitive host cells.
  • Herpes virus (herpes simplex, HSV)
  • the antiviral / virucidal effect of an aqueous microemulsion of suitable MARIGENOL ⁇ concentrates is determined using a confluent monolayer culture from VERO cells (ie "African green mon key kidney cells”).
  • the HSV titer is significantly reduced.
  • Herpes virus Herpes Sim plex, HSV
  • 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 DNA) Virus) secrete.
  • Hbs Ag a "surface antigen” from the outer shell of the virus
  • Hbe Ag a "core antigen” from the core of the DNA) Virus
  • Orientative tests in vitro were carried out with a 1% concentrate of the three test substances ß-sitosteryl palmitate, ß-sitosteryl arachidate and ergosteryl isovalerate by Prof. Dott. Antonio Ponzetto and performed by Dotta Rossana Cavallo, Università degli Studi di Torino.
  • MIC minimum inhibitory concentration
  • IC50 50% killi ng rate concentration
  • Control stimulation 1% PHA (Phytohemaggl utinin)
  • Test 1 2% concentrate containing C ⁇ 2: o-cholesteryl ester
  • Test 2 2% concentrate containing Ci 6 : o-ergosteryl ester
  • Test 3 2% concentrate containing C 5: 0 cholecalciferyl ester

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Abstract

L'invention concerne des concentrés spontanément dispersibles renfermant des esters sélectionnés de composés triterpéniques pentacycliques à activité antitumorale, antivirale et antiparasitaire, des ultramicro-émulsions aqueuses de tels concentrés, un procédé de fabrication de ces esters et leur traitement, ainsi que leur utilisation comme agents pour la production d'une préparation systémique pharmaceutique efficace contre les tumeurs, eczémas, psoriasis, infections virales et parasitaires, pour la prophylaxie à long terme des tumeurs et pour l'absorption renforcée des activateurs, modulateurs et régulateurs exogènes.
PCT/CH1997/000023 1997-01-24 1997-01-24 Ultramicro-emulsions de concentres spontanement dispersibles renfermant des esters de triterpenes pentacycliques a activite antitumorale, antivirale et antiparasitaire Ceased WO1998032443A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP97900535A EP0902685A1 (fr) 1997-01-24 1997-01-24 Ultramicro-emulsions de concentres spontanement dispersibles renfermant des esters de triterpenes pentacycliques a activite antitumorale, antivirale et antiparasitaire
PCT/CH1997/000023 WO1998032443A1 (fr) 1997-01-24 1997-01-24 Ultramicro-emulsions de concentres spontanement dispersibles renfermant des esters de triterpenes pentacycliques a activite antitumorale, antivirale et antiparasitaire

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PCT/CH1997/000023 WO1998032443A1 (fr) 1997-01-24 1997-01-24 Ultramicro-emulsions de concentres spontanement dispersibles renfermant des esters de triterpenes pentacycliques a activite antitumorale, antivirale et antiparasitaire

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000041676A1 (fr) * 1999-01-12 2000-07-20 Merck Sharp & Dohme Limited Systeme auto-emulsionnant spheronise destine a des agents hydrophobes et sensibles a l'eau
GB2362649A (en) * 2000-05-25 2001-11-28 Univerzita Palackeho V Olomouc Triterpenoid derivatives
WO2001090096A3 (fr) * 2000-05-23 2002-03-07 Univerzita Palackeho V Olomouc Derives triterpenoides
WO2002026761A1 (fr) * 2000-09-29 2002-04-04 Regents Of The University Of Minnesota Triterpenes ayant une activite fongicide dirigee contre les levures
WO2002026762A1 (fr) * 2000-09-29 2002-04-04 Regents Of The University Of Minnesota Triterpènes dotés d'une activité antibactérienne
WO2002055087A1 (fr) * 2001-01-12 2002-07-18 Bsp Pharma Dihydro-triterpenes dans le traitement d'infections virales, de maladies cardiovasculaires, d'inflammations, d'hypersensibilite ou de douleurs
EP1266658A3 (fr) * 1997-05-16 2004-05-26 The Board Of Trustees Of The University Of Illinois Utilisation de dérivés de l'acide bétulinique pour le traitement et la prévention du mélanome
US7144875B2 (en) 2000-09-29 2006-12-05 Regents Of The University Of Minnesota Methods of treating fungal infections using lupeol
WO2006097337A3 (fr) * 2005-03-18 2007-08-23 Bionetworks Gmbh Inhibiteurs de la 11$g(b)-hydroxysteroide deshydrogenases
EP1878445A4 (fr) * 2005-04-19 2008-06-25 Shanghai Tianbo Biotechnology Procede, formulation et utilisation de medicaments ou de nutriments avec une absorption orale amelioree
WO2009155070A3 (fr) * 2008-05-30 2010-02-11 Novelix Pharmaceuticals, Inc. Compositions et procédés pour le traitement d’inflammation et de lésions hyperkératotiques
US11826374B2 (en) 2018-01-04 2023-11-28 Amryt Research Limited Betulin-containing birch bark extracts and their formulation

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Cited By (18)

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EP1266658A3 (fr) * 1997-05-16 2004-05-26 The Board Of Trustees Of The University Of Illinois Utilisation de dérivés de l'acide bétulinique pour le traitement et la prévention du mélanome
US6630150B1 (en) 1999-01-12 2003-10-07 Merck Sharp & Dohme Limited Spheronized self-emulsifying system for hydrophobic and water-sensitive agents
WO2000041676A1 (fr) * 1999-01-12 2000-07-20 Merck Sharp & Dohme Limited Systeme auto-emulsionnant spheronise destine a des agents hydrophobes et sensibles a l'eau
AU769541B2 (en) * 1999-01-12 2004-01-29 Merck Sharp & Dohme Limited Spheronised self-emulsifying system for hydrophobic and water-sensitive agents
WO2001090096A3 (fr) * 2000-05-23 2002-03-07 Univerzita Palackeho V Olomouc Derives triterpenoides
GB2362649A (en) * 2000-05-25 2001-11-28 Univerzita Palackeho V Olomouc Triterpenoid derivatives
WO2002026762A1 (fr) * 2000-09-29 2002-04-04 Regents Of The University Of Minnesota Triterpènes dotés d'une activité antibactérienne
US6642217B2 (en) 2000-09-29 2003-11-04 Naturtek, Llc Triterpenes having human antifungal and antiyeast activity
US6689767B2 (en) 2000-09-29 2004-02-10 Regents Of The University Of Minnesota Triterpenes having antibacterial activity
WO2002026761A1 (fr) * 2000-09-29 2002-04-04 Regents Of The University Of Minnesota Triterpenes ayant une activite fongicide dirigee contre les levures
US7144875B2 (en) 2000-09-29 2006-12-05 Regents Of The University Of Minnesota Methods of treating fungal infections using lupeol
WO2002055087A1 (fr) * 2001-01-12 2002-07-18 Bsp Pharma Dihydro-triterpenes dans le traitement d'infections virales, de maladies cardiovasculaires, d'inflammations, d'hypersensibilite ou de douleurs
WO2006097337A3 (fr) * 2005-03-18 2007-08-23 Bionetworks Gmbh Inhibiteurs de la 11$g(b)-hydroxysteroide deshydrogenases
EP1878445A4 (fr) * 2005-04-19 2008-06-25 Shanghai Tianbo Biotechnology Procede, formulation et utilisation de medicaments ou de nutriments avec une absorption orale amelioree
WO2009155070A3 (fr) * 2008-05-30 2010-02-11 Novelix Pharmaceuticals, Inc. Compositions et procédés pour le traitement d’inflammation et de lésions hyperkératotiques
AU2009260485B2 (en) * 2008-05-30 2015-01-29 Novelix Pharmaceuticals, Inc. Compositions and methods for treatment of inflammation and hyperkeratotic lesions
US11826374B2 (en) 2018-01-04 2023-11-28 Amryt Research Limited Betulin-containing birch bark extracts and their formulation
US12268695B2 (en) 2018-01-04 2025-04-08 Amryt Pharmaceuticals Designated Activity Company Betulin-containing birch bark extracts and their formulation

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