EP0868422A1 - Ultramicroemulsions constituees de concentres pouvant etre disperses de fa on spontanne, renfermant des esters de composes de baccatine-iii a effet antitumoral et antiviral - Google Patents

Ultramicroemulsions constituees de concentres pouvant etre disperses de fa on spontanne, renfermant des esters de composes de baccatine-iii a effet antitumoral et antiviral

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Publication number
EP0868422A1
EP0868422A1 EP96930006A EP96930006A EP0868422A1 EP 0868422 A1 EP0868422 A1 EP 0868422A1 EP 96930006 A EP96930006 A EP 96930006A EP 96930006 A EP96930006 A EP 96930006A EP 0868422 A1 EP0868422 A1 EP 0868422A1
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European Patent Office
Prior art keywords
iii
weight
baccatin
esters
formulas
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EP96930006A
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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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    • 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
    • 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
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to ultramicroemissions from spontaneously dispersible concentrates with esters of baccatin-III, 10-deacetylbaccati-III and 14-OH-10-deacetylbaccatin-III, these taxane esters themselves, processes for their preparation and their processing into spontaneously dispersible concentrations -traten, their use for the production of well-tolerated medicines with antitumoral and / or antiviral or virucidal 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, modulators and regulators.
  • esters of baccatin III, 10-deacetylbaccati-III and 14-OH-10-deacetylbaccatin-lil according to the invention have a very good antitumor and antiviral or virucidal activity, and they are also suitable for the treatment of eczema and Psoriasis.
  • the therapeutic properties of these esters only increase significantly if they are incorporated into spontaneously dispersible concentrates and then diluted with distilled water or 5% glucose solution or physiological saline (Ringer's solution), resulting in thermodynamically stable ultramicroemulsions. with developing micelles with a hydrodynamic radius of 2.2 to 3.0 nm.
  • R is hydrogen, acetyl or a C 6 -32-alkylcarboxyl, a C ⁇ -3 2 -
  • Alkenylcarboxyl-, a C ⁇ -s ⁇ -Alkapolyencarboxyl- or a Retmoylcarboxyl- group stand.
  • Examples of compounds of formula (I) include:
  • taxane derivatives Because of their sometimes excellent cancerostatic effects, taxane derivatives have attracted great attention.
  • the subject of this patent specification is the results of studies on the taxane derivatives baccatin-III, as well as its hydroxylated modifications 10-deacetylbaccatin-III (10-DAB) and 10-deacetyl-14 ⁇ -hydroxybaccatin-III (14-OH-10-DAB).
  • Baccatin-III was isolated for the first time from the heartwood of the yew (Taxus baccata. L.), characterized and structurally elucidated: W.R. Chan, T.G. Halsall, G.M. Hornby, A.W. Oxford, W. polebel, K. Bj ⁇ mer, G. Ferguson, J. Monteath Robertson, J.Chem.Soc, Chem.Comm. 1966.923; D.P. Della Casa de Marcano, T.G. Halsall, G.M. Hornby, ibid. 1970. 216 and 1975. 365. From a biogenetic point of view, baccatin III is the direct and specific precursor of TAXOL [P.E. Fleming, A.R. Knaggs, X.-G. He, U. Mocek, H.G. Floss, J.Amer.Chem.Soc.1994. 116, 4137].
  • Taxol (paclitaxel) is considered a potent cytostatic agent in therapeutic use [cf. Antitumor Compounds of Natural Origin: Chemistry and Biochemistry, Vol. II; Ed. Adorjan Aszalos, NCI, CRC Press, Boca Raton, 1980, pp. 170, 175] and as an anti-tumor agent; it is classified as significantly more effective than baccatin III. It remains to be seen whether this can be attributed to the esterification of the hydroxyl group at C (13) by the substituted cinnamic acid or to other factors.
  • baccatin-III causes considerable difficulties when formulating it into a pharmaceutical preparation for intravenous use, but this also applies to Taxol-W.S. applies. See also Blechert and Guenard, I.e., p. 232. Baccatin III, as well as recently 10-acetylbaccatin III, were used as starting material for numerous partial syntheses. See also: Kyriacos Costa Nicolaou et al .: “Chemistry and Biology of Taxol", Angew.Chem. 1994, 106, 38-69 and 1672-1675, as well as Lutz Heide: "Pharmaceutical biology in the spotlight", pharmacy in our time / 23rd year 1994 / No. 2 (pp. 100-104).
  • 10-Deacetylbaccatin III (Formula V) was obtained from Taxus baccata needles (isolation and structure determination: G. Chauviere, D. Guenard, F. Picod, V. Senilh, P. Potier, CR Seance, Acad.Sci.Ser. 2, 1981, 293, 561) and for 10-deacetyl-14- ⁇ -hydroxybaccatin III (formula VI) their occurrence in Taxus wallichiana. Zucc, used. See, inter alia, EPA 93102633.0 / 0 559 019 of September 8, 1993 (Indena SpA, Milano), as well as: E. Bombardelli and B. Gabetta, J.Chem.S., Perkin Trans. I (1992) (21), 2925- 29; (1993) (14), 1563-6.
  • the priority patent CH 282 / 95-1 has shown that the preparation of taxol and taxol analogs to spontaneously dispersible concentrates according to the invention and the production thereof from aqueous ultramicroemulsions bring decisive improvements in the bioavailability and accordingly the bioreactivity and relative toxicity from December 4, 1995.
  • Baccatin III [according to formula (IV)] contains three, structurally very differently reactive hydroxyl groups.
  • the hydroxyl group at C (7) is attacked much faster than that at C (13), which is surprising since the OH group at C (13) is allylic in nature; steric reasons and an intramolecular hydrogen bond are responsible for this behavior.
  • the OH group at C (1) is not esterified under any known conditions.
  • the situation is different again with the hydroxylated baccatins: OH-C (10) reacts faster than OH-C (7); the OH-C (14) again slower than that at C (10). It is therefore possible to make bonds at different points during esterification.
  • esters produced are practically colorless and only vaguely fluorescent in the UV.
  • the esterification reaction can be easily followed with TLC on silica gel foils by spraying with a cerium sulfate / phosphomolybdic acid / sulfuric acid reagent and then heating over the mirror burner: the ester in question appears as a dark sepia-colored spot.
  • 10- Deacetylbaccatin-III (10-DAB) contains four and 14-HO-10-Deacetylbaccat ⁇ n-III (14-HO-10-DAB) contains five structurally very differently reactive hydroxyl groups; for the reactivity found, see the corresponding esterification approaches.
  • esters produced can be introduced very well into spontaneously dispersible concentrates according to the invention, which, when added with distilled water, 5% glucose solution or physiological saline solution, give stable oil-in-water microemulsions with globular micelles in the lowest nm range.
  • baccatin III In a well-dried three-necked flask with an N 2 inlet tube, magnetic stirrer, reflux condenser and dropping funnel, 250 mg of baccatin III are dissolved in a 0.5 ml abs. Pyridine dissolved, then mixed with a few crystals of 4-dimethylaminopyridine and diluted with 5 ml of finely powdered, dry AgCN with 5 ml of 1, 2-dichloroethane. After cooling in an ice bath to 0 ° C., 0.2 ml of lauroyl chloride are added dropwise using a syringe. The cooling bath is then removed and the mixture is heated to approx. 45 ° C. in an oil bath for 18 h.
  • the suspension is mixed with a little Celite®, diluted with ether and the suspension is filtered. The filtrate is washed in a separating funnel with dilute sulfuric acid, then with water and brine.
  • the product obtained after customary work-up namely 500 mg of a pale yellow, honey-like oil, is cleaned on a silica gel column (silica gel Merck 0.015 - 0.04 mm, column 2.3 x 20 cm) with the solvent mixture of ethyl acetate / toluene / acetone 11 : 9: 1) chromatographed. The laurate you are looking for appears fairly quickly in a narrowly defined zone. After crystallization from diisopropyl ether at ⁇ 14 ° C., colorless needles of mp 87-88.5-0 were obtained; Yield 65-70%.
  • Circular dichroism (CH 2 CI 2l RT): 230.8 ( ⁇ r.27.0), 258.6 (0), 300.2 (-12.4).
  • iR. (CH 2 CI 2 : 3628w and 3570w (OH); 3049m, 2926s, 2852m (methyl and methylene groups), 1736 ss, and 1725ss [carbonyls]
  • the non-polar compound turned out to be 10-deacetyl-14ß-hydroxybaccat ⁇ n-7,10,14-tr ⁇ laurate, the polar one as 10-deacetyl-14ß-hydroxybaccat ⁇ n-III-7,10-dilaurate; the medium polar compound was determined as the 10-deacetyl-14ß-hydroxy-10,14-dilau rat after comparing the spectra.
  • Circular dichroism (CH ? CI ?. RT): 229.4 ( ⁇ 19.2), 257.6 (0), 299.6 (-7.9) I_R 3575w OH); 2043w-m, 2853s (methylene and methyl groups), 1733 ss, broad [carbonyls]
  • esters of selected baccatin compounds of the formulas (I) to (III) surprisingly have an excellent antitumor and antiviral or virucidal activity and are also suitable for the treatment of eczema, psonasis and metabolic disorders, especially when they are in accordance with the invention , spontaneously dispersible concentrates have been incorporated, which dilute with distilled water, 5% glucose solution or Ringer's solution, result in thermodynamically stable oil-in-water ULTRAMICRO-EMULSIONS.
  • the present invention accordingly also relates to spontaneously dispersible concentrates with antitumoral and / or antiviral or virucidal esters of selected baccatin compounds of the formulas (I) to (III).
  • the esters according to the invention with baccatin compounds of the formulas (I) to (IM) are almost water-insoluble and highly agglomerated compounds. So that such compounds diffuse through the membrane barrier of the tumor or host cells and can become effective inside the tents, they first have to be solubilized in a suitable manner in the aqueous medium.
  • thermodynamically stable oil-in-water ultramicroemulsions With the help of specially selected cosurfactants 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 new esters.
  • the micelles of the inner phase containing baccatin ester 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 into the interior of the tumor or host line, or through the protein envelope of viruses.
  • the diffusion through the outer membrane of such cells takes place exclusively due to thermal molecular movements.
  • the direction that a specific diffusion process takes is determined by the difference in concentration that exists on the plasma membrane between outside and inside the tumor or host cell. The diffusion continues along the concentration gradient until it is broken down. Between the extracellular zone and the interior of the individual target cell, the concentration of active substance or of the active substance system ("multiple drug system") is compensated, whereby delayed release effects (“slow release effects”) can also occur. Such diffusion processes take place independently of any energy supply. They have no relation to cellular metabolic energy. Your speed or the strength of the drug transport through the membrane of the tumor or host cell is determined:
  • a globular "micelle" with a hydrodynamic radius of one centimeter has a volume of 4.189 cm3 and a phase surface of 12.564 cm 2 .
  • 1018 micelles with a hydrodynamic radius of only 10-6 cm (IQ nm), which together make up the same volume of 4.189 cm 3 already have a total phase surface of 1,256.4 ⁇ .2.
  • 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 (III), 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, a radical scavenger or one
  • pharmaceutical active ingredients are to be understood as all active ingredients that can normally be used in human medicine. These include e.g. : Beta blocker
  • Pindolol [1- (4-indolyloxy) -3-isopropylamino-2-propanol] propanolol [1-isopropylamino-3- (1-naphthyloxy) -2-propanol] oxprenolol [1- (o-allyloxyphenoxy) -3-isopropylamino- 2-propanol] metoprolol [di - ⁇ (+ -) - 1- (isopropylamino) -3- [p- ⁇ 2-methoxyethyl) - phenoxy-2-propanol] -L (+) tartrate ⁇ ]
  • Acetazolamide [5-acetamido-1,3,4-thiadiazole-2-sulfonamide] hydrochlorothiazide [6-chloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-7-sulfonamide-1, 1-dioxide]
  • Chlorotalidone [1-oxo-3- (3-sulfamyl-4-chlorophenyl) -3-hydroxy-isoindoline] metolazone [7-chloro-1, 2,3,4-tetrahydro-2-methyl-4-oxo-3- o-tolyl-6-quinazoline sulfonamide]
  • Weak sedative [6-chloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-7-sulfonamide-1, 1-dioxide]
  • Chlorotalidone [1-oxo-3- (3-sulfamyl-4-chlor
  • Chloroquinaldol [5,7-D ⁇ chlor-8-hydroxy-ch ⁇ nald ⁇ n]
  • Diamthazole [6 (-) 2-dimethylamino-ethoxy- ( ⁇ -dimethylamino-) - benzothiazole-dihydrochloride]
  • Flumethasone pvalate [6 ⁇ , 9-difluoro-11ß, 17.21-tr ⁇ hydroxy-16 ⁇ -methyl-pregna-1, 4-d ⁇ en-3.20, d ⁇ on-21-p ⁇ valate]
  • PTN Pentaerythrityl tetranitrate
  • Pindolol [1- (4-indolyloxy-3-isopropylamino-2-propanol] cytostatics
  • Cyclophosphamide [N, N-bis ( ⁇ -chloroethyl) amino-1-oxa-3-aza-2-phosphocyclohexane-2-oxide] Anti-inflammatory agents
  • Dexamethasone [9-fluoro-11 ⁇ , 17.21 -trihydroxy-16 -methyl-p reg na- 1,4-diene-3,20-dione]
  • Cinnazarin [1-trans-cinnamyl-4-diphenylmethyl-piperazine]
  • Pentoxyfylline [3,7-dimethyl-1- (5-oxo-hexyl) xanthine] antirythmics
  • Disopyramide [4-diisopropylamino-2-phenyl-2- (2-pyridyl) butyramide] anti-gout agent
  • Chlorophenamine [ ⁇ 3- (p-chlorophenyl) -3- (2-pyridyl) propyldimethylamine]
  • Betahistine [2- ⁇ 2-methylaminoethyl ⁇ pyridine]
  • Metoclopramide [4-amino-5-chloro-N- (2-diethylaminoethyl) -2-methoxy-benzamide] antihypertensive agents
  • Taxol (Paclitaxel) Baccatin III
  • 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 and 6 on the one hand and 10 and 15 on the other. HLB values provide information about the hydrophilic and lipophilic properties of an emulsifier. See “Hydrophile-Lipophile Balance: History and recent Developments" by Paul Becher in the Journal of Dispersion Science and Technology 5 (1), 81-96 (1984).
  • phosphoric acid ester surfactants such as: the tristyrylphenol polyoxyethylene-18-phosphoric acid ester TEA salt
  • Diphasol® 3873 (CIBA-GEIGY), an alkylphenol polyglycol ether
  • betaine compounds i.e. amphoteric, salt and water-free imidazole derivatives, such as:
  • multi-functional glucose derivatives are also used, such as e.g.
  • Glucate® SS methyl glucose sesquistearate
  • Glucamate® SSE-20 PEG-20 Methyl glucose sesquistearate, in the CTFA Classification
  • Amerchol Edison, NJ, USA
  • Good results can also be achieved in some cases using non-ionogenic compounds from the "TWEEN®” range (Atlas Chem. Ind., Inc. ; or ICI Specialty Chemicals), so-called polyoxyethylene sorbitan esters or "polysorbates” 20 to 85 compounds in the CTFA Classification [Fluka 93'773 to 93 * 783].
  • compositions can be used as hydrotropes or as co-emulsifiers, e.g .:
  • a ahphatician carboxylic acid C 10 22
  • Esters of an ahphatic alcohol (C 12 22 ) with lactic acid such as, for example, My ⁇ styl or preferably lauryl lactate; Monoesters, diesters or testers of glycine with an ahphatic carboxylic acid (C s 22 ), such as glyceryl caprylate, or
  • C S 22 ahphatic carboxylic acid
  • Esters with at least one free hydroxyl group from poly (2-10) glycol with an ahphatic carboxylic acid (C 6 22 ), monoether from a polyethylene glycol with an ahphatic alcohol (C 12 18 ), such as polyoxyethylene (C ⁇ >) - octyl ether.
  • Heterocychic compounds such as 1-methyl-2-pyrrole
  • R 5 is a C 2 31 alkyl, a C 3 31 alkenyl or alkapolyene group
  • R 6 citronellyl, farnesyl, geranyl, isophytyl or Phytyl mean
  • all technical surfactants were cleaned by means of filtration or chromatography over neutral aluminum oxide using an inert solvent such as tetrahydrofuran, ethyl alcohol or methylene chloride.
  • Suitable additives in the spontaneously dispersible concentrates according to the invention are vitamins and provitamins (such as, for example, vitamin A acid, retinol, tocopherols), and also selected penetration enhancers ("flux enhancers”) and radical scavengers.
  • COMPOSITION EXAMPLES of spontaneously dispersible CONCENTRATES according to the invention which contain active ingredients of the formulas (I) to (III) and which, when diluted with water or 5% glucose solution or physiological saline (Ringer's solution), thermodynamically stable ULTRAMICROEMULSIONS with a hydrodynamic radius up to 3.0 nm.
  • isopropyl myristate, isopropyl palmitate or neutral oil e.g. Migiyol® 812 (Dynamite Nobel or Hüls)
  • a phosphoric acid ester surfactant e.g. Diphasol® 3873 (CIBA-GEIGY), tenside 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 Polysorbate 20-85 (ICI SPECIALTY CHEMICALS),
  • Diphasol® 3873 CIBA-GEIGY
  • CIBA-GEIGY tenside 508
  • Tinovetin® JU CIBA-GEIGY
  • Soprophor® FL Rh ⁇ ne-Poulenc
  • a penetration enhancer 0 to 10% by weight of a penetration enhancer, a stabilizer and / or auxiliaries.
  • coconellyl-10-undecenoate (Cn i-citronellyl ester) or citronellyl-10-laurate (C 12 o -cetronellyl ester)
  • N.B. INVADIN® JFC 800% (CIBA-GEIGY) is an anhydrous tert.
  • SOPROPHOR® FL (RH ⁇ NE-POULENC) is a t ⁇ styrylphenol polyoxyethylene 18-phosphoric acid ester, TEA salt surfactant,
  • TWEEN®-20 (ICI Specialty Chemicals) is a non-ionogenic polyoxyethylene sorbitan ester compound. "Polysorbates” -20.
  • Metolose® 90 SH-4000 (Shin-Etsu Chemical) 90.0 g
  • NB 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). O 98/13359 - 2, 4. - PCT / CH96 / 00329
  • a biological assay system has been developed that works with microtiter plates and dilution series.
  • Each 1 ⁇ 4 / 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 during the assay in so-called non-confluent monolayers.
  • the sample is added after 6 to 24 hours, with 100 ⁇ l per row, which is mixed with 100 ⁇ l medium in the 1st hole. Half of this is removed and placed in the next hole, again mixed with 100 ⁇ l medium, etc.
  • a geometric thinning row nVi is created.
  • the samples are incubated in the plaque assay for 3 to 5 days at 37 ° C with 3Vi% C0 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 by means of scanning and absorption measurement on a spectrophotometer.
  • TAXOL-W.S. ME 1 100 64 * 000 256 * 000 256 * 000 A.S. 6.4 million 25.6 million 25.6 million
  • BACCATIN III-W.S. ME 1 100 128 * 000 128 * 000 1 million A.S. 12.8 million 12.8 million 100 million
  • BACCATIN 111-7,13- ME 1 100 128 * 000 256 * 000 1 million DIUNDECENOAT A.S. 12.8 million 25.6 million 100 million
  • BACCATIN III-ME 1 100 128 * 000 128 * 000 256 * 000 7.13-DILAURATE A.S. 12.8 million 12.8 million 25.6 million
  • BACCATIN III-7-a.t.- ME 1 100 128 * 000 256 * 000 256 * 000 RETINATE A.S. 12.8 million 25.6 million 25.6 million
  • TAXOL-WS ME 1 100 256 * 000 256 * 000 0.0117
  • BACCATIN-Ill-ME 1 1 * 000 160 * 000 640 * 000 * 0.0130
  • BACCATIN-Ill-ME 1 1 * 000 320 * 000 640 * 000 * 0.0124
  • DILAURAT AS 4 million 8 million 131.2 MICROEXPOSITION EXPOSITION .S.
  • Dilutions First line calculated for microemulsion Second line calculated for active substance content Concentration information for the concentrate: in mmol (initial concentration or in pmol (highest still cell-toxic dilution)
  • N.B . Composition of the 1% concentrates: 1% by weight of active substance 12% by weight of Cn.-CITRONELLYL-ESTER 87% by weight of Invadin JFC 800% / Soprophor FL 1: 1
  • micellar capillary zone electrophoresis (Beckman Instruments, P / ACE System 2100 or the BioFocus integrator from Bio-Rad).
  • M monocytes (macrophages)
  • N neutrophil granulocytes
  • E eosinophilic granulocytes
  • Test 1 2% concentrate containing C 12: 0- cholesteryl ester
  • Test 2 2% concentrates containing C 16: o-ergosteryl ester
  • Test 3 2% concentrates containing C 5: 0 cholecalciferyl ester
  • a TAXOL-WS formulated as a spontaneously dispersible MARIGENOL® concentrate, which forms an aqueous U / fra / n / iVroemulsion
  • B TAXOL-WS formulated as a conventional concentrate, which only forms an aqueous macroemulsion C BACCATIN-III-WS, as spontaneous dispersible MARIGENOL®
  • Formulated concentrate which forms an aqueous l> / tram / frroemulsion D BACCATIN-III-WS, formulated as a conventional concentrate, which only forms a watery liquid emulsion MICRO / EXPOSURE EXPOSURE
  • CONCENTRATE 1 100 effective to effective up to 1: 1: with 1% ACTIVE ACTIVE SUBSTANCE
  • the formation of the concentrate according to the invention is far superior in effect to the conventional formulation.
  • their bioreactivity is 30 times that of 48 h exposure and more than 125 times that which has been customary and achievable so far.
  • MARIGENOL® concentrates formulated with C 1 ⁇ i-Citronellylester as coemulsifier and with a 1: 1 surfactant mixture Invadin JFC 800% / Soprophor FL.
  • the aqueous emulsion was measured 1: 100 (CMC limit for the homogeneous distribution of the surfactants) of the 1% concentrates using dynamic light scattering (DLS) in 3 angular positions (60 °, 90 ° and 120 °), with 10 individual measurements each , on a specially equipped "Fiberoptic Spectrometer" of the Institute for Polymers, ETH, Zurich.
  • DLS dynamic light scattering
  • MT4 lines an eternalized T cell line, which is very sensitive to the HIV cytopathogenic effect "CEP" from a 24 h old culture were suspended at a concentration of 2x1 ⁇ 5 / ml, in 1.2 ml aliquots in
  • Polypropylene tubes are divided and pelleted by centrifugation.
  • pellets were then either infected with 200 ul of a stock solution of
  • HIV III B cells (titer: 600 CCIDso / ml) or mock-infected with pure medium, incubated for 90 min at 37 ° C and then mixed with 1 ml of pure medium to reset the initial cell concentration and the HIV concentration to 100 CCIDso / bring ml.
  • CCIDso / ml 50% c_ell c_ulture
  • HIV strain 21/4 ("Clinical isolate") + 300
  • HIV strain 4/5 (Clinical i solate) + 200
  • HIV (2 strains) + 50 ß-SITOSTERYL PALMITAT 100 ppm (mean titer from 2 strains)
  • CMV Human Cytomegahe Virus
  • 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 for 4 hours at + 4 ° C with different concentrations of the test substance C 16 o-ß-sitosterylester, formulated as a 1% concentrate and then diluted to a watery microemulsion 10-3, o- 4 un ( j 10-5. Incubated and then inoculated as pretreated virus suspensions on cultures of human, embryonic lung fibroblasts. Approach as confluent culture with 120,000 cells per shellvial.
  • the infection was centrifuged for 45 minutes at 1500 rpm and at RT was completed, the suspension for injection 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 h.
  • 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 "Ant ⁇ -P-72 CMV" (an immediate precursor protector of the CMV, which can be detected after 6 hours in the infected cells) and incubated for 30 minutes at 37 ° C in a humid 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-time 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 paid for with the aid of 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.
  • CONTROLS CONCENTRATION CONCENTRATION CONCENTRATION Number of anti-MICROEMULSION MICROEMULSION MICROEMULSION genes (anti P-72) 1: 1 * 000 1: 10 * 000 1: 100 * 000
  • Herpes virus (herpes simplex, HSV)
  • the antiviral / virucidal effect of a watery microemulsion of suitable MARIGENOL® concentrates is determined using a confluent monolayer culture of VERO cells (ie "Af ⁇ can green monkey kidney cells”).
  • Herpes virus (herpes simplex, HSV)
  • CONTROLS CONCENTRATION CONCENTRATION CONCENTRATION Number of MICROEMULSION MICROEMULSION MICROEMULSION infected cells 1: 1 * 000 1: 10,000 '1: 100 * 000

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des ultramicroémulsions constituées de concentrés pouvant être dispersés de façon spontanée renfermant de nouveaux esters de baccatine-III, 10-déacétylbaccatine-III et 14-OH-10-déacétylbaccatine-III ainsi que ces taxanesters, un procédé de production correspondant et, un procédé pour les préparer sous forme de concentrés pouvant être dispersés de façon spontanée, la fabrication de médicaments ayant une bonne tolérance et une action antitumorale, antivirale et virucide pour combattre le psoriasis et l'eczéma, prévenir et traiter les tumeurs, lutter contre les maladies virales et accroître l'absorption d'activateurs, de modulateurs et de régulateurs exogènes.
EP96930006A 1996-09-24 1996-09-24 Ultramicroemulsions constituees de concentres pouvant etre disperses de fa on spontanne, renfermant des esters de composes de baccatine-iii a effet antitumoral et antiviral Withdrawn EP0868422A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CH1996/000329 WO1998013359A1 (fr) 1996-09-24 1996-09-24 Ultramicroemulsions constituees de concentres pouvant etre disperses de façon spontanne, renfermant des esters de composes de baccatine-iii a effet antitumoral et antiviral

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EP0868422A1 true EP0868422A1 (fr) 1998-10-07

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EP96930006A Withdrawn EP0868422A1 (fr) 1996-09-24 1996-09-24 Ultramicroemulsions constituees de concentres pouvant etre disperses de fa on spontanne, renfermant des esters de composes de baccatine-iii a effet antitumoral et antiviral

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US (1) US6057359A (fr)
EP (1) EP0868422A1 (fr)
WO (1) WO1998013359A1 (fr)

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MXPA03006404A (es) * 2001-01-18 2004-12-02 Upjohn Co Composiciones quimioterapeuticas de microemulsion de paclitaxel con biodisponibilidad oral mejorada.
US7182950B2 (en) * 2002-06-12 2007-02-27 Nutralease Ltd. Nano-sized self-assembled liquid dilutable vehicles
US20040147534A1 (en) * 2003-01-23 2004-07-29 Foote Mary Ann Topical composition and method for treating occlusive wounds
EP2468741A1 (fr) * 2010-12-16 2012-06-27 Bel/Novamann International s.r.o. Nouveaux dérivés de quercetin, leur procédé de préparation, les compositions pharmaceutiques qui les contiennent et leur utilisation
DE202020002122U1 (de) 2020-04-14 2020-06-15 Van Ba Dam Desinfektionsmittel und Anti-Virus-Staticum

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Also Published As

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US6057359A (en) 2000-05-02

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