EP0689432A1 - Ultramicro-emulsions de concentres a dispersion spontanee avec des esters d'apocarotinoles a effet pharmacologique - Google Patents

Ultramicro-emulsions de concentres a dispersion spontanee avec des esters d'apocarotinoles a effet pharmacologique

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Publication number
EP0689432A1
EP0689432A1 EP95902021A EP95902021A EP0689432A1 EP 0689432 A1 EP0689432 A1 EP 0689432A1 EP 95902021 A EP95902021 A EP 95902021A EP 95902021 A EP95902021 A EP 95902021A EP 0689432 A1 EP0689432 A1 EP 0689432A1
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EP
European Patent Office
Prior art keywords
weight
esters
formulas
apo
surfactant
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Withdrawn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
EP95902021A
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German (de)
English (en)
Inventor
Carl Eugster
Conrad Hans Eugster
Walter Haldemann
Giorgio Rivara
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Marigen SA
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Marigen SA
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Filing date
Publication date
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Publication of EP0689432A1 publication Critical patent/EP0689432A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/12—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by esterified hydroxy groups
    • 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
    • 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/14—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to ultramicroemulsions from spontaneously dispersible concentrates with esters of apocarotenols, new esters with apocarotenols, processes for their preparation and their use for the treatment of tumors, psoriasis and eczema.
  • Selected esters of apocarotenols surprisingly have a very good activity against tumors, psoriasis and eczema, especially when they have been incorporated into spontaneously dispersible concentrates which, when diluted with water, give rise to thermodynamically stable ultramicroemulsions with micelles with a hydrodynamic radius of 1. Have 5 to 3 nm. Measurements were carried out with (dynamic) quasi-elastic light scattering at the Institute for Polymers at E.T.H., Zurich (Prof. Dr. Pier Luigi LUISI and Prof. Dr. Peter SCHURTENBERGER).
  • esters with apocarotenols selected for the present invention have the formulas (I) to (IX):
  • n denotes the numbers 1, 2, 3, 4 or 5 and R2 for one of the radii of the formulas stands.
  • alkyl, alkenyl or alkapolyene groups i.e. the corresponding alkadienes, alkatrienes, alkatetraenes, alkapentaenes, alkahexaenes or alkapentaenes
  • alkynyl groups in R 1 can be straight-chain or branched.
  • R 1 is a C1 to Ci ⁇ -alkyl, a C2 to C18 alkenyl or alkapolyene, a C2 to Ci8 alkynyl group or a radical of the formulas (XII) and (XIII) denote:
  • Ri is a C4- to Ci ⁇ -alkyl, a C2- to C-
  • the compounds of the formulas (I) to (IX) can exist in various stereoisomeric or rotational forms. Examples of compounds of the formulas (I) to (IX) include:
  • the new compounds of the formulas (I) to (IX) can generally be prepared by the following known processes a) or b): a) reaction of a compound of formula (XIV)
  • R3 is a C- to C32-alkyl, a C2 to C32-alkenyl or alkapolyene, a C2 to C32-alkynyl group or a radical of the formulas (X) or (XI) stands with a chlorinating or brominating agent, such as Thionyl chloride, oxalyl chloride, and subsequent reaction with a compound of the formulas (XV) to (XXIII) at a temperature of 0 to 50 ° C with the supply of protective gas, in an inert solvent, such as e.g. Toluene or tetrahydrofuran, and in the presence of a catalyst, e.g. Pyridine, dimethylformamide or p-dimethylaminopyridine.
  • a catalyst e.g. Pyridine, dimethylformamide or p-dimethylaminopyridine.
  • the C30 alcohol was characterized as follows: unstable orange crystals with mp 148-149 ° C; ⁇ ma ⁇ (Petroleum ether): 426, 453 nm; O-acetyl compound: orange leaflets, mp 130-132 ° C, ⁇ a ⁇ (petroleum ether): 426, 452 nm; easy elimination reaction in chromatography experiments on Al2O3. No other, especially higher, esters have been described so far.
  • DIBAH diisobutylaluminium hydride
  • esters are prepared in an analogous manner with lauric acid, palmitic acid and stearic acid chloride. See technical supplement 1/2.
  • azafrinol can be isolated as a well-crystallized compound and then also characterized in detail. Azafrinol is thus obtained by crystallization from benzene / hexane in bright light orange-yellow needles.
  • the compound is particularly sensitive to acids and loses water as a result of ring splitting. This reaction already occurs during chromatography on silica gel.
  • the mixture is cooled again to -30 ° C and a corresponding amount of DIBAH solution is added.
  • a small excess of DIBAH does not have a significant impact on the yield, but a larger excess must be avoided.
  • small pieces of ice are added to the solution very carefully until foaming no longer occurs and the precipitation of aluminum hydroxide has ended.
  • the product is filtered off with suction and the filter cake is washed with a mixture of ether / isopropyl alcohol 5: 1 dye-free.
  • the yellow-orange colored filtrate is then evaporated in vacuo and the crystalline residue is dissolved hot in toluene / isopropyl alcohol 99: 1 and, in the event of turbidity, the solution is rapidly passed through a small, wide column filtered from CaCO3. The filtrate is evaporated again and the residue is recrystallized from hot benzene / hexane or ethyl acetate / hexane. After drying at 40 ° C / 0.01 Torr, 2.2 g of bright orange needles are obtained. Mp 133-134 ° C (vacuum tube). For the analytical details cf. the technical supplement 2/2.
  • UV / VIS (Et2 ⁇ , tormented): sharp three-band spectrum with ⁇ m ax 375, 394.5, 419 nm; (Tormented benzene): 377, 402, 428 nm.
  • UV / VIS (Et2 ⁇ , tormented): sharp three-band spectrum with ⁇ m ax 375, 394.5, 419 nm; (Tormented benzene): 377, 402, 428 nm.
  • analytical data cf. the technical Supplement 2/2.
  • the apocarotenes of the formulas (I) to (IX) surprisingly have an excellent antitumor effect, especially when they have been incorporated into spontaneously dispersible concentrates which are diluted with water and thermodynamically stable ultramicroemulsions with a hydrodynamic radius of 1.5 to 3 nm. (Measurements with dynamic, quasi-elastic light scattering QLS).
  • the present invention therefore essentially also relates to spontaneously dispersible concentrates with the apocarotenes esters of the formulas (I) to (IX).
  • the apocarotenes of the formulas (I) to (IX) are almost water-insoluble and polymer agglomerated compounds. However, in order that the molecules of these compounds diffuse through the membrane barrier of the tumor cells and become effective inside the cell, such compounds first have to be solubilized in a suitable manner in the aqueous medium.
  • the formation of thermodynamically stable oil-in-water ultramicroemulsions with the aid of specially selected cosurfactants or solubilizers on the one hand and suitable surfactants on the other hand enables an optimal degree of solubilization of the apocarotenes esters to be achieved.
  • the micelles of the ultramicroemulsions according to the invention with the active substance-containing inner phase are provided with a surfactant coat on their boundary layer, which makes them easy to diffuse through the cell membrane into the interior of the cell.
  • the diffusion through the plasma membrane of the cells takes place exclusively on the basis of thermal
  • the direction which a specific diffusion process takes is determined by the difference in concentration which exists on the plasma membrane between outside and inside the individual cell. The diffusion runs along the concentration gradient until it is broken down.
  • concentration of active substance or of the active substance system (“multiple drug system") is balanced between the extracellular zone and the interior of the individual cell, and 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.
  • dm is the amount in moles of the active substance molecules penetrating a cell membrane surface q (in cm2) per time dt (in seconds) .
  • D is the diffusion coefficient and the difference in concentration over the distance dx.
  • the diffusion coefficient depends on the absolute temperature and the frictional resistance f
  • x is for a specific cell membrane a constant size, which is why they can be combined with the diffusion coefficient to form a new constant, the permeability coefficient P.
  • the expression - in the diffusion equation the flux is called J dt q and has the dimension mol per second per cm ?.
  • the negative sign on the right side of the diffusion equation indicates that the transport of the active substance molecules or the active substance system takes place in the direction of the decreasing concentration.
  • the concentrates which are dispersible spontaneously according to the invention contain:
  • flux enhancer a penetration enhancer
  • the surfactants or surfactant mixtures to be used according to the invention can be anionic, cationic, amphoteric or non-ionic. They are preferably photic or non-ionic and have an HLB ratio (ie a "hydrophilic-lipophilic ic balance") between 2 and 1 8; 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 also "Hydrophile-Lipophile Balance: History and recent Developments" by Pau l Becher in the Journal of Dispersion Science and Technology 5 (1), 81-96 (1 984).
  • Suitable ionic surfactants can be so-called water-soluble soaps as well as water-soluble synthetic compounds.
  • Suitable as soaps are the alkali metal, alkaline earth metal or, if appropriate, substituted ammonium salts of higher fatty acids (C-10 to C22). such as. the natural Na or K salts of oleic or stearic acid, or of natural fatty acid mixtures, which among other things Made from coconut or tallow oil.
  • the surfactants also include the fatty acid methyl taurine salts and modified and unmodified phospholipids.
  • the fatty sulfonates and sulfates are generally in the form of alkali, alkaline earth or optionally substituted ammonium salts and generally have an alkyl radical having 8 to 22 carbon atoms, alkyl also including the alkyl part of acyl radicals. Examples of these are the Na or Ca salt of Liginsulfokla re. of dodecylsulfuric acid ester and sulfonic acids from Fatty alcohol-ethylene oxide add u cts.
  • the sulfonated benzimidazole derivatives preferably contain two sulfonic acid groups and a fatty acid residue with about 8 to 22 carbon atoms.
  • Alkylaryl sulfonates are, for example, the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid or a naphthainsulfonic acid-formaldehyde
  • nonionic surfactants available are primarily the polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated or unsaturated fatty acids and alkylphenols, which groups 3 to 30 glycol ethers and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon radical and 6 can contain up to 1 8 carbon atoms in the alkyl radical.
  • nonionic surfactants are the water-soluble polyethylene oxide adducts containing 20 to 250 ethylene glycol ether groups and 10 to 100 propylene ether groups on polypropylene glycol and alkylpolypropylene glycol having 1 to 10 carbon atoms in the alkyl chain.
  • the compounds mentioned usually contain 1 to 5 ethylene glycol units per propylene glycol unit.
  • non-ionic surfactants examples include:
  • fatty acid esters of polyoxyethylene sorbitan such as polyoxyethylene sorbitan trioleate, are also suitable.
  • the cationic surfactants are primarily quaternary ammonium salts which contain at least one alkyl radical having 8 to 22 carbon atoms as N substituents and, as further substituents, low, optionally halogenated alkyl, benzyl or low hydroxyl groups. have alkyl radicals.
  • the salts are previously in the form of halides, methyl sulfates or ethyl sulfates, e.g. the stearyltrinethylammonium chloride or the benzyldi (2-chloroethyl) ethylammonium bromide.
  • phosphoric acid ester surfactants such as, for example, tristyrylphenol polyoxyethylene-18-mono / d imethylphosphoric acid ester
  • Tinovetin® JU (CIBA-GEIGY), a hydroxybiphenyl-10-ethoxy
  • Butyl-mono-4-ethoxy-phosphoric acid ester (Zerostat® AT, CIBA-GEIGY), or CH 3 - ⁇ CH 2 ) 3-CH-CH 2 -O (-CH 2 - CH 2 - O) 5 - -OCH,
  • betaine compounds i.e. amphoteric, salt and water-free imidazole derivatives, such as:
  • multi-functional glucose derivatives are also used, e.g. Glucate® SS (methyl glucose sesquistearate) and Glucamate® SSE-20 (PEG-20 methyl glucose sesquistearate) from Amerchol, Edison, N.J.
  • compositions that can be used as hydrotropes or as co-emulsifiers can be used, e.g .:
  • Polymethylbutenes may serve as examples.
  • Carboxylic acid (C ⁇ to C22). such as propylene glycol monolaurate and propylene glycol monomyristate.
  • Esters of an aliphatic alcohol (C12 to C22) with lactic acid e.g.
  • Cß to C22 aliphatic carboxylic acid
  • Glyceryl caprylate or Mig lyol® 812 neutral oil (oleum neutral).
  • an al iphatician carboxylic acid such as. aliphatic alcohols (C1 2 to C22). som it and others Dodecanol,
  • Tetradecanol Tetradecanol, oleyl alcohol, 2-hexyldecanol and 2-octyldecanol.
  • Esters with at least one free hydroxyl group from poly (2-10) glycol with an aliphatic carboxylic acid (C ⁇ to C22).
  • Heterocyclic compounds e.g. 1-methyl-2-pyrrolidone.
  • R4 denotes citronellyl, geranyl, farnesyl, phytyl or isophytyl and R5 denotes a C 1 -C 8 -acyl or C 2 -C 32 -alkenyl or alkapolyene group,
  • Suitable additives in the spontaneously dispersible concentrates according to the invention are vitamins and provitamins (such as vitamin A, retinol, tocopherols), as well as selected penetration enhancers (“flux enhaners”) and radial scavengers.
  • vitamins and provitamins such as vitamin A, retinol, tocopherols
  • fluorenhaners selected penetration enhancers
  • radial scavengers radial scavengers.
  • the daily dose required for pharmaceutical use is 0.001 to 25 mg / kg body weight, if possible divided into 2 to 3 individual doses.
  • the new esters with apocarotenols or the spontaneously dispersible concentrates can be combined with these compounds in the common pharmaceutical preparations and dosage forms such as dragées, tablets, capsules, powders, granules, pellets, solutions, ampoules, emulsions, creams or suppositories work in with the usual carriers and / or diluents and stabilizers.
  • the active substances or active substance mixtures forming the subject of the invention, and the spontaneously dispersible concentrates which contain these active substances or active substance mixtures, can be administered to humans orally, by injection (intravenously, subcutaneously or intramuscularly) or in another way. If they are prepared as solid dosage forms for oral use, this can take the form of tablets, granules, pellets, powders or capsules, etc.
  • the preparations can contain additives, for example a medicament carrier such as a saccharide or cellulose base, a binder such as starch paste or methyl cellulose, a filler or a disintegrant, etc. - additives being used as are customary in the production of medical or paramedical Formulations are used.
  • the active substances or active substance mixtures according to the invention reach oral administration as liquid dosage forms, they can have any form selected from aqueous preparations for internal use, from suspensions, emulsions and syrups etc. and they can also be in the form of vacuum-dried preparations which are put into solution or emulsion before being used.
  • the active substances or active substance mixtures according to the invention are prepared in the form of aqueous solutions, suspensions or oily or aqueous emulsions, preferably as microemulsions from the spontaneously dispersible concentrates conforming to the invention, they can also be injected.
  • the injection solutions are usually prepared shortly before use by dissolving or suspending the extracts or concentrates in aqueous, liquid media such as sterile water, glucose solution or physiological saline.
  • solvents, stabilizing agents, preservatives and additives for the production of isotonic solutions which are usually used can be added to an injection preparation.
  • the injection preparations obtained in this way are administered intravenously, intramuscularly, subcutaneously or in another suitable manner.
  • the present invention also relates to pharmaceutical preparations which contain the active substances or mixtures of substances and / or the described, spontaneously dispersible concentrates for combating the growth of tumor cells.
  • Medicinal preparations are those for enteral (such as oral or rectal) as well as for parenteral or topical administration to warm-blooded animals, which contain the spontaneously dispersible concentrate alone or together with a pharmaceutically usable carrier material.
  • the dosage of the concentrates according to the invention depends on the warm-blooded species, the age and the individual condition, and on the mode of administration. For example, to achieve a killing effect of tumor cells on warm-blooded animals with low body weight, such as Mice, rats and hamsters, doses in the range of about 0.1 to 50 mg / kg of body weight when administered by successive administration, and doses in the range of 0.05 to 5 mg / kg of body weight by intraperitoneal administration.
  • the oral and rectal forms of the new pharmaceutical preparations contain between 1 - 95%, preferably between 1 0 - 95%, in particular between 20 - 95% of the spontaneously dispersible concentrate according to the invention.
  • Suitable pharmaceutically usable carriers for the oral forms are mainly fillers such as sugar (eg lactose, sucrose, mannitol or sorbitol), cellulose preparations and / or calcium phosphates (eg tri-calcium or calcium hydrogen phosphate), and also binders such as starch paste and use of ao Corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose, hydroxyl methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone and / or disintegrants (if desired), such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked Poly ⁇ vinyl pyrrolidone, agar, alginic acid or a salt thereof, such as Sodium alginate.
  • sugar eg lactose, sucrose, mannitol or sorbitol
  • cellulose preparations and / or calcium phosphates
  • the flow regulating agents are e.g. the polyethylene glycols No. 200 to 600 and higher are suitable.
  • the gelatin capsules preferred as a dosage form in humans are provided with suitable coatings, with, inter alia, concentrated sugar solutions (which may contain Arabian gum, talc, Pc. Yvinylpyrrolidone, polyethylene glycol and / or titanium dioxide), lacquer solutions (aqueous or those that have been prepared using organic solvents) or enteric-resistant trains from solutions of suitable cellulose preparations, such as microcrystalline cellulose (Avicel®), acetylcellulose phthalate, hydroxylmethylcellulose phthalate (Metolose®), hydroxylpropylmethylcellulose acetate succinate (AQOAT®) or a copolymer such as Eudragit® L30D.
  • suitable cellulose preparations such as microcrystalline cellulose (Avicel®), acetylcellulose phthalate, hydroxylmethylcellulose phthalate (Metolose®), hydroxylpropylmethylcellulose acetate succinate (AQOAT®) or a copolymer such as Eudragit® L30D.
  • Plug-in capsules made of gelatin and a plasticizer, such as glycerol or sorbitol, are suitable as a pharmaceutical dosage form which is particularly suitable according to the invention and can be used orally.
  • the soft or hard gelatin capsules, as well as those made from AQOAT® (hydroxypropyl methyl cellulose acetate succinate), can be the spontaneously dispersible concentrate according to the invention in a mixture with fillers such as lactose, binders such as starch and / or lubricants such as talc or Magnesium stearate and optionally with stabilizers and antioxidants such as Contain ⁇ -, ß- or ⁇ -tocopherol.
  • suitable liquids such as liquid polyethylene glycols No. 200 to 600 can be recommended as a diluent, but stabilizers and antioxidants can also be added.
  • the concentrates according to the invention are mixed with distilled water.
  • Viscosity-increasing substances such as Na carboxymethyl cellulose, sorbitol, mannitol and / or dextran, and optionally also stabilizers and antioxidants can be added to the resulting aqueous injection microemulsion.
  • the pharmaceutical preparations for parenteral use preferably contain between 0.1 to 60%, and mainly between 1 to 40% of the spontaneously dispersible concentrate according to the invention.
  • topically applicable preparations which are primarily suitable for the prophylaxis and therapy of skin cancers, are for example creams, ointments, pastes, pomades, foams, tinctures and solutions which contain between 0.01 to 70% of the concentrate according to the invention.
  • creams and oil-in-water emulsions that contain more than 50% water old oil bases are used primarily as fatty alcohols, e.g. lauryl, cetyl or stearyl alcohol, liquid to solid waxes, e.g. isopropyl myristate, wool or beeswax and / or hydrocarbons such as petroleum jelly (petrolatum) or paraffinoel.
  • Suitable for emulsifying these oily bases are primarily surface-active, pharmaceutically compatible substances with predominantly hydrophilic properties, such as, for example, nonionic emulsifiers, and in advance fatty acid esters of polyalcohols or ethylene oxide adducts (such as polyglycerol fatty acid esters or polyethylene sorbitan fatty acid esters) with an H LB value of below 8.
  • Additives to the water phase include agents which reduce the drying of the creams, for example polyalcohols such as glycerin, sorbitol, propylene glycol and / or polyethylene glycols No. 200 to 600, also preservatives, fragrances, etc.
  • Ointments are water-in-oil emulsions that contain up to 70%, but preferably between 20 and 50% water or aqueous phases. Hydrogen primarily comes as the fat phase, e.g. Vaseline, paraffinoel and / or hard paraffins in question, which suitable hydroxide compounds to improve water retention, such as Fatty alcohols or esters, including cetyl alcohol or wool wax alcohols, are included.
  • suitable hydroxide compounds to improve water retention such as Fatty alcohols or esters, including cetyl alcohol or wool wax alcohols, are included.
  • emulsifiers with an HLB value of 8 to 16, e.g. Sorbitan fatty acid esters (such as sorbitan isostearol) are added.
  • Additions to the water phase include Humectants, such as polyalcohols (glycerin, propylene glycol, sorbitol and / or polyethylene glycols No. 200, 400, 600); also preservatives, fragrances, etc.
  • Fatty ointments are anhydrous and contain mainly hydrocarbons, e.g. Paraffin, petroleum jelly and / or liquid paraffins; natural or partially synthetic fats such as e.g. Coconut fatty acid triglyceride, further: fatty acid partial esters of glycerin, such as e.g. the fatty alcohols, emulsifiers and / or additives mentioned in connection with the ointments which increase the water absorption capacity.
  • hydrocarbons e.g. Paraffin, petroleum jelly and / or liquid paraffins
  • natural or partially synthetic fats such as e.g. Coconut fatty acid triglyceride
  • fatty acid partial esters of glycerin such as e.g. the fatty alcohols, emulsifiers and / or additives mentioned in connection with the ointments which increase the water absorption capacity.
  • Pastes are creams and ointments with secretion-absorbing powder components, such as metal oxides (for example titanium oxide or zinc oxide), talc and / or aluminum silicates, which have the task of forming existing moisture or secretions.
  • metal oxides for example titanium oxide or zinc oxide
  • talc for example titanium oxide or zinc oxide
  • aluminum silicates which have the task of forming existing moisture or secretions.
  • Foams are administered from pressure containers and are oil-in-water emulsions of the spontaneously dispersible concentrates according to the invention, in the form of aerosols, halogenated hydrocarbons (such as chlorofluoro-low-alkane: for example dichlorodifluoromethane and dichlorotetrafluoroethane) being used as blowing agents.
  • halogenated hydrocarbons such as chlorofluoro-low-alkane: for example dichlorodifluoromethane and dichlorotetrafluoroethane
  • there may be the usual additives such as preservatives, etc.
  • the ⁇ -apo-8'-carotenol-10-undecenoate is obtained with a melting point of 76-77 ° C, according to S internally from 75 "C; UV ⁇ max. 425 nm (in methylene chloride); Rf value in TLC with hexane / ethyl acetate (80:20) 0.92.
  • azafrinyl-10-undecenoate is also prepared in an analogous manner:
  • the main zone is eluted with toluene / isopropyl alcohol (99: 1), the filtrate is brought to dryness in vacuo. After recrystallization from benzene / hexane and AcOEt / hexane, bright yellow, very acid sensitive needles with an mp of 135 ° C. are obtained. Formation of azafrin-10'-ol [undec-10-enoyl] ester.
  • a phosphoric acid re-surfactant e.g. Diphasol® 3873 (CIBA-G EIGY), surfactant 508 (CIBA-G EIGY), Zerostat® AN or AT (CIBA-G EIGY), Tinovetin® JU (CIBA-GEIGY), Soprophor® FL (Rhône-Poulenc) 5 to 90% by weight Invadin JFC 800% (CIBA-GEIGY).
  • a phosphoric acid re-surfactant e.g. Diphasol® 3873 (CIBA-G EIGY), surfactant 508 (CIBA-G EIGY), Zerostat® AN or AT (CIBA-G EIGY), Tinovetin® JU (CIBA-GEIGY), Soprophor® FL (Rhône-Poulenc) 5 to 90% by weight Invadin JFC 800% (CIBA-GEIGY).
  • a penetration enhancer or a stabilizer and carriers and / or diluents 0 to 10% by weight of a penetration enhancer or a stabilizer and carriers and / or diluents.
  • Soprophor® FL 35 to 45% by weight of Soprophor® FL.
  • R4 is citronellyl, geranyl, farnesyl, phytyl or isophytyl and R5 is a C 1 -C 8 -acyl or C 2 to C32 alkenyl or alkapolyene group,
  • Invadin® JFC 800% 35 to 45% by weight Diphasol 3873 or Soprophor® FL.
  • 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 appropriately control the MSR and the delayed release (retard).
  • a biological assay system has been developed that works with micro titer 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 following hole, again mixed with 100 ⁇ l of medium, etc.
  • a geometric dilution series n 1 / s is formed.
  • the samples are incubated in the plaque assay for 3 to 5 days at 37 ° C with 3 ⁇ % 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 greatest cytotoxic dilution is determined. The quantitative evaluation can also be carried out by means of scanning and absorption measurement on the spectrophotomer.
  • CYTOTOXICITY TEST with Py6 cells virus transformed mouse fibroblasts
  • AOT Fluka 86139
  • AOT bis-2-ethylhexyl sulfosuccinate Na salt.
  • CYTOTOXICITY TEST with Py6 cells virus transformed mouse fibroblasts
  • 8'-APOCAROTIN-10- 1 640 * 000 32 million UNDECENOAT
  • AZAFRINYL-10- 1 256 * 000 25.6 million UNDECENOAT VITALITY TEST with human tumor cell lines A HL 60 promyeolytic LEUK ⁇ MIE 1 x 104 cells per well
  • the morphological differences between the transformed and the non-transformed cells can still be determined in the in-vitro test even at the end of the test on the surviving populations.
  • the transformed cells have longer filopodia and retain this characteristic.
  • the active substance peak appears after approx. 4 minutes. Resolution up to 0.5 ppm.
  • UV / VIS (Et2 ⁇ , tormented): sharp three-band spectrum with ⁇ m ax 375, 394.5, 419 nm; (Tormented benzene): 377, 402, 428 nm.
  • the apocarotenes esters used in accordance with the invention extinguish the fluorescence in the long-wave UV light range caused by the marker Uvitex CF conc, or Uvitex EBF, or Tinopal GS; a blue color develops on the thin-layer plate. UV scanning at 366 nm. Control using micellar capillary zone electrophoresis, (Beckman Instruments, P / ACE System 2100).
  • M monocytes (macrophages)
  • N neutrophil granulocytes
  • E eosinophilic granulocytes

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

Abstract

L'invention concerne des ultramicro-émulsions de concentrés à dispersion spontanée avec des esters d'apocarotinoles à effet pharmacologique, leur utilisation comme médicaments agissant sur les tumeurs, le psoriasis et l'eczéma, de nouveaux esters comportant ces apocarotinoles, ainsi que des procédés permettant de les préparer.
EP95902021A 1993-12-19 1994-12-07 Ultramicro-emulsions de concentres a dispersion spontanee avec des esters d'apocarotinoles a effet pharmacologique Withdrawn EP0689432A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH3783/93 1993-12-19
CH3783/93A CH685674A5 (de) 1993-12-19 1993-12-19 Ultramikroemulsionen aus spontan dispergierbaren Konzentraten mit pharmakologisch wirksamen Estern von Apocarotinolen.
PCT/CH1994/000234 WO1995016441A1 (fr) 1993-12-19 1994-12-07 Ultramicro-emulsions de concentres a dispersion spontanee avec des esters d'apocarotinoles a effet pharmacologique

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EP0689432A1 true EP0689432A1 (fr) 1996-01-03

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EP (1) EP0689432A1 (fr)
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WO (1) WO1995016441A1 (fr)

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WO1998013359A1 (fr) * 1996-09-24 1998-04-02 Marigen S.A. Ultramicroemulsions constituees de concentres pouvant etre disperses de façon spontanne, renfermant des esters de composes de baccatine-iii a effet antitumoral et antiviral
TWI241915B (en) 1998-05-11 2005-10-21 Ciba Sc Holding Ag A method of preparing a pharmaceutical end formulation using a nanodispersion

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US3316101A (en) * 1965-08-03 1967-04-25 Hoffmann La Roche Stabilizing carotenoid compositions
CH523024A (de) * 1967-09-20 1972-05-31 Basf Ag Verfahren zur Herstellung eines als Futter- bzw. Lebensmittelzusatz bestimmten Carotinoidpräparates
FR2187291A1 (en) * 1972-06-07 1974-01-18 Quatrar Sarl Water-sol carotenoid compsns - for poultry food additives or colouring human foodstuffs
US3886294A (en) * 1973-03-12 1975-05-27 Hoffmann La Roche Carotenoid coloring compositions and preparation thereof
GB1581744A (en) * 1976-03-22 1980-12-17 Unilever Ltd Edible composition
JPS58128141A (ja) * 1982-01-26 1983-07-30 Sumitomo Chem Co Ltd 自己乳化分散型カロチノイド類含有ソフトカプセル剤の製法
FR2664164A1 (fr) * 1990-07-04 1992-01-10 Texinfine Patrinove Composition dermatologique ou cosmetique.
CH683426A5 (de) * 1993-08-24 1994-03-15 Marigen Sa Biotenside Lösungsvermittler für Pharmazeutika und Kosmetika.

Non-Patent Citations (1)

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Title
See references of WO9516441A1 *

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CH685674A5 (de) 1995-09-15
WO1995016441A1 (fr) 1995-06-22

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