EP1267943A2 - Medicament pour stimuler la leucopoese, pour traiter des affections tumorales et des protozooses, l'acarinose, l'arthropodiase et procedes permettant de le produire - Google Patents

Medicament pour stimuler la leucopoese, pour traiter des affections tumorales et des protozooses, l'acarinose, l'arthropodiase et procedes permettant de le produire

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Publication number
EP1267943A2
EP1267943A2 EP01938070A EP01938070A EP1267943A2 EP 1267943 A2 EP1267943 A2 EP 1267943A2 EP 01938070 A EP01938070 A EP 01938070A EP 01938070 A EP01938070 A EP 01938070A EP 1267943 A2 EP1267943 A2 EP 1267943A2
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EP
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Prior art keywords
pharmaceutical formulation
mol
formulation according
cholesterol
group
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EP01938070A
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German (de)
English (en)
Inventor
Hansjörg EIBL
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Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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Publication of EP1267943A2 publication Critical patent/EP1267943A2/fr
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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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a new pharmaceutical formulation for stimulating leukopoiesis, for the treatment of tumor diseases and protozoan diseases, in particular leishmaniasis and amoeba diseases, of akarinosis and diseases caused by arthropods, and methods for their production.
  • phospholipid compounds with an alkyl chain have a good activity against tumor and protozoan diseases.
  • a major disadvantage of these compounds is, on the one hand, that especially the compounds with longer-chain hydrocarbon residues have poor solubility in aqueous solutions, which makes them unsuitable for intravenous (IV) administration and also for oral administration in the form of drinking solutions.
  • IV intravenous
  • many of these effective compounds are associated with considerable side effects, so that they cannot be administered in high doses for a prolonged period. The side effects are largely due to the hemolytic effect of phospholipid compounds, such as alkylphosphocholines with 1 6 to 21 carbon atoms.
  • Protozoa are unicellular organisms, some of which are pathogenic parasites.
  • the most common representatives that affect humans include plasmodia (malaria), trypanosomes (sleeping sickness), amoebas, such as entamoebas and acanthamoebas (amoebic dysentery, encephalitis), and leishmania (leishmaniasis).
  • Leishmaniases are various tropical diseases that are caused by protozoa of the genus Leishmania and transmitted by blood-sucking insects.
  • the therapy of leishmaniasis is essentially based on well-known antimony preparations, especially stibogluconate sodium (pentostam).
  • the treatment is usually carried out over two to three weeks, but then has to be interrupted for one or two weeks, because common side effects could otherwise reach a threatening extent and become irreversible.
  • the side effects include gastrointestinal irritation, circulatory disorders up to shock and liver parenchymal damage.
  • Another disadvantage has turned out to be that Leishmania strains already exist which are antimony-resistant.
  • Aromatic diamidines, pentamidine and amphothericin B are used as further pharmaceuticals. However, these agents are mostly only used in combination with antimony compounds, and they also have considerable side effects.
  • Entamoeba isto / ytica causes dysenteries and liver abscesses in humans.
  • the pathogen is very common in many countries around the world, causing around 36 to 50 million cases of illness each year with between 40,000 and 1 10,000 deaths.
  • the life cycle is simple, infection occurs through cysts that are ingested with contaminated water or food.
  • the cysts pass through the stomach unchanged and excise in the large intestine, with four trophozoites, the actual amoebas, arising from each cyst.
  • part of the trophozoites decysts again, thus forming the permanent forms that can survive outside of humans.
  • the trophozoites can live in the large intestine without causing much damage, but they can also attack the intestinal wall.
  • amebiasis Another common manifestation of amebiasis is the amebic liver abscess.
  • amoeba penetrate from the intestine through the mesenteric vessels into the liver and produce large abscesses there.
  • Both the amoeba liver abscess and the intestinal amebiasis are massively life-threatening if left untreated.
  • E. histolytica throphozoites cannot survive without the human host. In contrast, there are free-living amoeba, which in rare cases can cause more serious diseases in humans.
  • Acanthamoeben e.g. Acanthamoeba castellanü, Acanthamoeba culbertsoni
  • Näegleria fowleri is a free-living amoeba flagellate. It typically lives in fresh water and can infect bathers. The parasite penetrates the brain via the nose and olfactory nerves and causes peracute meningoencephalitis.
  • the cases of encephalitis caused by Acanthamoeben or Naeglerien are extremely rare, but have so far had an extremely poor prognosis.
  • Chemotherapy drugs for E. ⁇ / sfo / yf / ca infections are currently nitroimidazoles, primarily metronidazole.
  • E. histolytica has no oxidative phosphorylation but gains its energy through glycolysis.
  • reduced ferredoxin is produced in the amoeba, which is able to reduce the nitroimidazole to a nitrosoimidazole.
  • the biomolecules of the amoeba are damaged by this aggressive substance. Humans do not have such a strong reducing agent and do not convert the metronidazole into the more toxic form of nitrosoimidazole.
  • Acanthamoeben and Naeglerien have mitochondria and can live aerobically. They do not reduce nitroimidazoles and therefore these compounds are completely ineffective. Acanthamoeben are said to be sensitive to rifampicin and paromomycin, Naeglerien to amphotericin B, but only in a few individual cases has encephalitis been cured by open-air amoeba.
  • DE application P 41 32 344.0-41 discloses processes for the production of a medicament which is suitable for oral or topical administration in the treatment of protozoan diseases, in particular leishmaniasis, and which has one or more compounds of the general formula:
  • R 2 , R 3 and R 4 are each independently H, a C, -C 5 alkyl group, a C 3 -C 6 cycloalkyl group or a Ci-Cg-hydroxyalkyl group, two of R 2 , R 3 and R 4 can form a C 2 -C 5 alkylene group with one another, which may optionally be substituted by a -0-, -S- or NR 5 group, in which R 5 is H, a C T -C 8 alkyl group, a C 3 - C 6 cycloalkyl group or C r C 5 hydroxyalkyl group contains.
  • alkylphosphocholine-containing agents for intravenous administration have been packaged in liposomes.
  • the liposomes consisted of hexadecylphosphocholine, cholesterol and phosphatidylglycerol or of hexadecylphosphocholine, cholesterol and phosphatidylpolyethylene glycols.
  • the production of these liposomes is very complex and expensive, since they require high pressure or similar processes, and the finished product also has the disadvantage that it is very difficult to sterile filter.
  • a pharmaceutical formulation that contains as an active ingredient a phospholipid compound in a form that makes intravenous administration possible even in high doses and additionally enables any form of administration with little side effects, i.e. oral, topical, im-, ip -, sc and iv application allowed.
  • a pharmaceutical formulation which is characterized in that it comprises a mixture of a) a phospholipid compound of the formula I:
  • R 1 is a saturated or unsaturated hydrocarbon radical having 16 to 24 carbon atoms
  • R 2 , R 3 and R 4 are each independently H, a C, -C 5 alkyl group, a C 3 -C 6 cycloalkyl group or one C r C 5 hydroxyalkyl group, where two of R 2 , R 3 and R 4 together can form a C 2 -C 5 alkylene group which may optionally be substituted with an -O-, -S- or NR 5 group
  • R 5 is H, a C, -C 5 alkyl group, a C 3 -C 6 cycloalkyl group or C., C 5 hydroxyalkyl group
  • n is an integer from 2 to 6 as active ingredient to 30 to 60 Mol%
  • the molar mixing ratio can vary, so that either the phospholipid compound of the formula I (a), in particular in the case of phospholipids with chain lengths of 22 to 24 C atoms, or the cholesterol and / or cholesterol derivative (b), in particular in the case of phospholipids with chain lengths of 16 to 21 C atoms are present in a slight excess, but the ratio should generally not deviate too far from 1: 1.
  • the cholesterol derivative is preferably present in a mixture of a), b) and c) in an amount of 30 to 60 mol%.
  • the liposome-like complex formed from the constituents a), b) and c) and the alcohol with water can be sterile filtered without problems through membranes with pore diameters of 0.8 ⁇ , 0.45 ⁇ and even 0.2 ⁇ . This is a significant advantage over conventional liposomes, which are not easy to sterile filter.
  • complexes according to the invention are extremely stable on storage.
  • Component b) ie the cholesterol or cholesterol derivative, also serves to improve the solubility in aqueous solutions of phospholipid compounds as defined above.
  • Cholesterol-like compounds such as cholesterol oligoglycerols, are also suitable, for example.
  • Component c) of the complex according to the invention are phosphatidylglycerol, phosphatidyloligoglycerols. Phosphatidyl oligoglycerols with 1 to 4 glycerol residues are preferred, especially those with fatty acid residues which have a cis double bond.
  • Preferred such compounds include dioleyl compounds, such as dioleyl-SN-glycero-3-phospho-glycerol, dioleyl-SN-glycero-3-phospho-diglycerol, dioleyl-SN-glycero-3-phospho-triglycerol, dioleyl-SN- glycero-3-phosphotetraglycerin, which are preferably used as Na + salts.
  • dioleyl compounds with an oleyl radical and another radical, preferably palmitoyl can also be used. It is believed that these compounds facilitate the incorporation of membrane components into bilayer structures and stabilize emulsions and the complex of the invention. They preferably have a positive or negative excess charge of ⁇ 0.2 to ⁇ 0.05.
  • the pharmaceutical formulation preferably contains the constituents in such an amount that the complex as a whole has a positive or negative excess charge. This is particularly advantageous when using phospholipids with longer hydrocarbon chains. However, the problem of poorer water solubility with longer chain compounds only plays a role in intravenous administration, not in oral administration.
  • the amount of component c) is preferably 8 to 10 mol%.
  • the hydrocarbon radical R 1 can contain 1 6 to 26 C atoms, 1 8 to 24 and more preferably 1 8 to 22 C atoms are preferred.
  • R 1 is particularly preferably a hexadecyl, octadecyl, oleyl, elaidyl, eicosyl, eicosenyl-cis- (-9) -, heneicosyl, heneicosenyl, docosyl or docosenyl radical.
  • the hydrocarbon radical can be either saturated or unsaturated, the double bond (s) of the unsaturated radicals preferably being ice are.
  • cis double bond is present, these are preferably not in conjugation.
  • the higher-membered odd-numbered carbon hydrogen residues have also proven to be particularly effective.
  • Nonadecenyl and heneicosenyl are particularly preferred.
  • the polar component preferably consists of phosphocholine (PC), ie n is preferably equal to 2.
  • R 2 , R 3 and R 4 are preferably each methyl.
  • suitable radicals are ethyl, propyl, butyl and pentyl radicals, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, hydroxymethyl, hydroethyl and hydroxypropyl radicals.
  • Two of the radicals R 2 , R 3 and R 4 can form, for example, a pyrrolidine, a piperidine or a morpholine group.
  • At least one of the radicals R 2 , R 3 and R 4 is preferably different from hydrogen, particularly preferably all three radicals are different from hydrogen.
  • n can also be 3 or 4. Surprisingly, especially for compounds with n equal to 3, there was a stimulating effect on leucopoiesis.
  • the phospholipid compounds with short hydrocarbon chains often have a deleterious hemolytic effect in conventional formulations. This is significantly reduced by the combination according to the invention.
  • cholesterol or cholesterol derivatives in the above-mentioned quantitative range are therefore preferred. It is therefore preferred to have a small excess of cholesterol or its derivative in the complex, so that the molar ratio between phospholipid compound of formula I and cholesterol / derivative is then 1: 1 -1, 2.
  • phospholipid compounds with longer hydrocarbon chains with 22 to 24 carbon atoms there is less the problem of hemolysis than that of lower water solubility. For this reason, a molar ratio of phospholipid compound: cholesterol / derivative of 1: 0.5-1 is sufficient.
  • a mixture of phopholipid compound of formula I, cholesterol / derivative and phosphatidyloiigo or monoglycerol in the stated molar ratio can easily be dissolved in a water-miscible alcohol, preferably a physiologically acceptable alcohol.
  • the mixing ratio of components a), b) and c) to alcohol is preferably in the range from 1: 0.1 to 500.
  • This resulting mixture can then simply be diluted with water or another aqueous liquid and thus brought to any desired concentration , It is thus possible to produce IV solutions in which the alcohol content is reduced to an acceptable concentration.
  • I.V. - Solutions should not contain more than 3% and oral solutions should not contain more than 10% ethanol.
  • Component d) the alcohol, for the purposes of the present invention is a water-miscible, physiologically compatible alcohol which has 2 to 4 carbon atoms.
  • Ethanol, 2-propanol, 1, 2-propanediol and 2-butanol or combinations thereof are particularly suitable. Most preferred, especially for iv preparations, is 1,2-propanediol.
  • Another aspect of the present invention is a process for the preparation of the pharmaceutical formulation according to the invention, wherein a phopholipid compound of formula I
  • R 1 is a saturated or unsaturated hydrocarbon radical with 1 6 to 24 carbon atoms
  • R 2 , R 3 and R 4 are each independently H, a C, -C 5 alkyl group, a C 3 -C 6 cycloalkyl group or are a CC 5 hydroxyalkyl group, where two of R 2 , R 3 and R 4 together can form a C 2 -C 5 alkylene group which may optionally be substituted by a -0-, -S- or NR 5 group
  • R 5 is H, a C 5 -C 5 -alkyl group, a C 3 -C 6 cycloalkyl group or C., - C 5 -hydroxyalkyl group
  • n is an integer from 2 to 4, as active ingredient in aqueous solution with b ) 25 to 65 mol% of cholesterol and / or a cholesterol derivative and c) 5 to 1 5 mol% of a phosphatidyl mono- or oli
  • components a), b) and c), as defined above are first mixed in the molar ratio mentioned. If an additional active ingredient is incorporated into the formulation according to the invention, it is preferably added to the mixture of a), b) and c). Subsequently, a water-miscible alcohol is added, which is a physiologically harmless alcohol with 2 to 4 carbon atoms, in particular ethanol, 2-propanol or 2-buntanol, since a certain amount of the alcohol remains in the finished pharmaceutical formulation, both for the oral and should also be suitable for intravenous administration. Ethanol, 1, 2-propanediol or 2-propanol are particularly preferably used.
  • ethanol is characterized by low toxicity and thus relatively good physiological tolerance, it is not so well suited for the production of complexes according to the invention which contain a relatively large amount of cholesterol, since cholesterol can only be found in ethanol limited extent solves. For this reason, 1,2-propanediol, which is also very little toxic, is preferably used in such cases.
  • the lipid components can first be dissolved in propanediol plus, if appropriate, chloroform and water. The solvent (mixture) can then be stripped off and the complexes formed can be dissolved in 1,2-propanediol.
  • Another possibility to improve the solubility is to use cholesterol derivatives instead of cholesterol, in particular cholesterol-phosphocholine (PC), which has good solubility properties in ethanol.
  • PC cholesterol-phosphocholine
  • the alcohol can be added to the mixture of components a), b) and c) at normal temperature (20 ° C.) or at an elevated temperature. It is preferably heated to 20 to 85 ° C, more preferably to 60 to 80 ° C.
  • the molar ratio of phospholipid compound: alcohol is 1: 0.1 to 500.
  • the amount of alcohol added can thus be varied over a wide range. The optimum amount of alcohol added can be readily determined by those skilled in the art within the range disclosed herein. Ratios of 1:50 to 200 are particularly preferred.
  • the final concentrations of the alcohol present in the pharmaceutical formulation according to the invention are advantageously not more than 10% for oral administration and not more than 3% for intravenous administration.
  • the active ingredient i.e. the phospholipid compound preferably contained in an amount of 0.1 to 200 ⁇ mol / g.
  • the phospholipid compound of the formula I is present as a complex with the other constituents, which is dispersed or dispersible in water.
  • the component is particularly preferred in the presence of less readily water-soluble phospholipid compounds (such as those with longer hydrocarbon chains) c) added with an excess charge in such an amount that the complex as a whole has a positive or negative excess charge.
  • the mixture can thus be easily diluted with water or other aqueous liquids, in particular aqueous liquids which are physiologically compatible are preferred.
  • Another advantage of the mixture obtained by the process according to the invention is that it can be sterilized without problems. Filters with pore sizes of 0.8 ⁇ , 0.45 ⁇ and even 0.2 ⁇ can be used.
  • the formulation according to the invention can be prepared galenically in liquid or solid form.
  • a formulation for intravenous or oral administration is particularly preferred.
  • topical administration is also possible.
  • oral administration it is advantageous to dilute the effective mixture with water or another physiological liquid, a 5 to 150-fold dilution having proven particularly suitable.
  • it can also be diluted more, since the complex remains soluble even at dilutions of 1: 1000 to 1: 10,000, and no deposition of components in the form of crystals or precipitates was observed.
  • an injection or infusion in a volume of 50 to 100 ml is advantageous, since in this way the alcohol concentration in ethanol can easily be brought below a value of 1%.
  • the alcohol concentration does not have to be taken into account at all.
  • the daily dose of an effective amount of the phospholipid compound, for example alkylphosphocholine of the formula I is 0.1 to 100 mmol /. kg body weight, preferably 1 to 5 / mol / kg. Due to the simple solubility, no overpressure is required for the preparation of the solutions from the phospholipid compound and the other components, as is required for the production of liposomes. As a rule, simple sound reinforcement is sufficient, in some circumstances even stirring is sufficient. This greatly simplifies and cheapens the manufacturing process. In addition, sterile conditions can easily be maintained by storing them in appropriately concentrated alcoholic solutions. These advantages also apply if an additional active ingredient is also incorporated into the formulation.
  • the pharmaceutical formulation according to the invention in another form, for example as a powder, tablets, capsules or as an ointment.
  • the alcohol is preferably added in a smaller amount than in the preparation of the formulation for use in liquid form.
  • a molar mixing ratio of phospholipid compound: alcohol of 1: 5 to 1 00 is preferred here.
  • the alcohol can also be removed from the mixture at least in part in order to obtain a concentrated formulation.
  • the pharmaceutical formulation can be mixed with customary physiologically compatible fillers, carriers, diluents and / or auxiliaries and poured out into hollow cells of appropriate size or filled or granulated in capsules of appropriate size and then optionally compressed into tablets with the addition of other customary auxiliaries.
  • the formulation can be mixed, for example, with one or more of the following auxiliaries: starch, cellulose, lactose, form in, casein, modified starch, magnesium stearate, calcium hydrogen phosphate, highly disperse silicic acid, talc and phenoxyethanol.
  • the mixture obtained can optionally be mixed with an aqueous solution of, for example, gelatin, starch, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and / or polyoxyethylene sorbitate. monooleat granulated and then compressed into tablets or filled into capsules.
  • the pharmaceutical formulation according to the invention also has a good activity against acarinosis, in particular mange and against diseases caused by arthropods. If required, additional active ingredients can promote, supplement or expand these indications.
  • amphotericin B in particular showed a synergistic increase in effectiveness against protozoan diseases and an expansion to systemic fungal diseases.
  • Lipid content 100 / mol / ml
  • the sample of 1 1, 1 7 g is mixed with 1 00 ml 2-propanol, 50 ml CHCl 3 and 1 ml H 2 O in a 1 l round-bottom flask and brought into solution at 50 ° C. After everything is dissolved, the solvent is removed in vacuo at 30 to 35 ° C. Residual solvent is removed in a drying cabinet in a vacuum at 30 ° C over a period of 30 minutes. The dry residue is mixed with 225 ml of a 0.25 M solution of 1,2-propanediol (MH 76, 10) and heated to 50 ° C. on a rotary evaporator while rotating. It is sonicated while rotating at 50 ° C.
  • the lipid mixture 11.99 g, is treated as in Example 1 and brought into a liposomal formulation.
  • Example 4 (Z) -10-Nonadecenvi-1-PC: volume 250 ml
  • the lipid mixture 12.091 g, is treated as in Example 1 and brought into a liposomal formulation.
  • Example 6 (Z) -10-heneicosenyl-1-PC: volume 250 ml
  • the lipid mixture, 11,316 g, is treated as in Example 1 and brought into a liposomal formulation.
  • Lipid content 100 ⁇ mol / ml
  • the lipid mixture 9.63 g, is treated as in Example 1 and brought into a liposomal formulation.
  • Example 9 (ZZ) -6.1 5-tetracosadienyl-t-PC: volume 250 ml
  • the lipid mixture, 8,016 g, is treated as in Example 1 and brought into a liposomal formulation.
  • the following table shows some combinations of a pharmaceutical formulation according to the invention.
  • Alkylphosphocholines and cholesterol were weighed in the molar ratios 1, 3 (1: 0.75, excess alkylphosphocholine) to 0.8 (1: 1, 25, excess cholesterol) and each dissolved in ethanol or 2-propanol.
  • the solutions were mixed at 60 to 80 ° C. with stirring with different amounts of H 2 O or physiologically compatible solutions, or the active ingredient concentrate was added to H 2 O or physiologically compatible solutions.
  • the emulsion that formed was sterile filtered through 0.8 ⁇ , 0.45 ⁇ and 0.2 filters.
  • Suitable daily doses and dilutions can be found in the table below.
  • Dogs are typical carriers of Leishmania, especially in the
  • Dog 1 "Leo" (Dachshund, male) body weight: 9 kg
  • Entamoeba histolytica SFL-3 and HM-1 IMSS (American Type Culture Collection, order number ATCC 30459), pathogenic amoebas of Zymodem II, were dissolved in TYI-S-33 medium (Diamond et al., Trans. Roy. Soc. Trop. Med. Hyg. 72: 431 -432 (1 978)) cultured with 10% bovine serum at 37 ° C.
  • the cultures of SFL-3 were kept in 100 ml glass bottles, the cultures of HM-1: IMSS in 50 ml tissue culture bottles.
  • the strains are deposited with the American Type Culture Collection.
  • the effect of the alkylphosphocholines was determined after 24 h and after 48 h.
  • three of the cultures were shaken up and transferred into three plastic centrifuge tubes.
  • the amoebas were centrifuged for 5 min at 2200 rpm and 4 ° C. and suspended in a final volume of 1 ml in a 1: 1 mixture of trypan blue (Sigma) and PBS.
  • Each of the samples was then counted in the hemocytometer and the number of live and dead amoeba stained blue by the dye uptake was recorded.
  • Table 4 ED 50 values in [/ M] of the alkylphosphocholines tested on two strains of Entamoeba histolyticya.
  • the tests were carried out as described above.
  • the E. histofytica strains SFL-3 and HM-1: IMSS were tested.
  • the ED 50 values were determined using the "Probit" program and are shown in Table 1.
  • alkylphosphocholines in pure and liposomal form represent a completely new form of therapy against amoebas. They are not dependent on the anaerobic metabolism of amoebas, but intervene in the relatively sensitive membrane structure of amoebas. Therefore, not only the classic E. histolytica but also free-living amoebas are a possible target for therapy with alkylphosphocholines in pure or liposomal form.
  • the treatment of dogs suffering from Sarcoptes mange with the medicament according to the invention by injection was carried out with the same dosage and the same medicament composition as described for Leishmaniasis in Example 1 2.
  • the diseased animals were treated according to the therapy plan given in the table below Depending on their body weight treated 1 0 days. After 4 to 6 days there was not only a strong clinical improvement but also an improved mental state. The dogs became lively, playful and communicated with the environment. So far in the 1st Decade not all symptoms disappeared was repeated after 8 weeks. In those treated dogs that still showed little signs of illness after the first decade of treatment, these were completely eliminated with the treatment in the second decade, whereby the physical and psychological condition of the treated animals improved significantly.
  • the dispersion is filtered through a glass fiber filter.
  • the filtrate can then be sterile filtered without any problems (filters 0.45 // m, 0.20 // m).
  • the dispersion is filtered through a glass fiber filter.
  • the filtrate can then be sterile filtered without any problems (0.45 ⁇ m, 0.20 // m filter).
  • Erucyl-PC H3 is a phosphocholine with a phospho-trimethylammonium distance extended to 3 carbon atoms.

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
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Abstract

L'invention concerne des formulations de médicaments utilisées pour stimuler la leucopoèse et pour traiter des affections tumorales et des protozooses, l'acarinose et des affections induites par arthropodes. Ces formulations se caractérisent en ce qu'elles contiennent un mélange actif comprenant a) au moins un composé phospholipide de formule (I) dans laquelle R1 désigne un reste hydrocarbure saturé ou insaturé ayant entre 16 et 24 atomes de C, R?2, R3 et R4¿ désignent chacun indépendamment les uns des autres, H, un groupe alkyle C¿1?-C5, un groupe cycloalkyle C3-C6 ou un groupe hydroxyalkyle C1-C5, deux des restes R?2, R3 et R4¿ pouvant former conjointement un groupe alkylène C¿2?-C5, qui peut être éventuellement substitué par un groupe O-, -S- ou NR?5¿, dans lequel R5 désigne H, un groupe alkyle C¿1?-C5, un groupe cycloalkyle C3-C6 ou un groupe hydroxyalkyle C1-C5, n vaut un nombre entier compris entre 2 et 6, comme principe actif à raison de 30 et 60 % en mole, b) entre 25 et 65 % en mole de cholestérine et/ou d'un dérivé de cholestérine, c) entre 5 et 15 % en mole d'au moins une monoglycérine de phosphatidyl ou une oligoglycérine de phosphatidyl, a),b) et c) atteignant conjointement 100 % en mole, et d) un alcool miscible à l'eau physiologiquement tolérable ayant entre 2 et 4 atomes de C, qui contient éventuellement de l'eau, ainsi que le cas échéant des auxiliaires pharmaceutiques classiques, les constituants se trouvant sous forme de complexe dispersible dans l'eau. L'invention concerne en outre des procédés permettant de produire lesdites formulations.
EP01938070A 2000-03-30 2001-03-29 Medicament pour stimuler la leucopoese, pour traiter des affections tumorales et des protozooses, l'acarinose, l'arthropodiase et procedes permettant de le produire Withdrawn EP1267943A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10015814 2000-03-30
DE10015814A DE10015814A1 (de) 2000-03-30 2000-03-30 Arzneimittel zur Stimulierung der Leukopoese, zur Behandlung von Tumor- und Protozoenerkrankungen und Verfahren zu seiner Herstellung
PCT/EP2001/003609 WO2001072289A2 (fr) 2000-03-30 2001-03-29 Medicament pour stimuler la leucopoese, pour traiter des affections tumorales et des protozooses, l'acarinose, l'arthropodiase et procedes permettant de le produire

Publications (1)

Publication Number Publication Date
EP1267943A2 true EP1267943A2 (fr) 2003-01-02

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EP01938070A Withdrawn EP1267943A2 (fr) 2000-03-30 2001-03-29 Medicament pour stimuler la leucopoese, pour traiter des affections tumorales et des protozooses, l'acarinose, l'arthropodiase et procedes permettant de le produire

Country Status (11)

Country Link
US (1) US20030199476A1 (fr)
EP (1) EP1267943A2 (fr)
JP (1) JP2003528134A (fr)
CN (1) CN1426311A (fr)
AU (1) AU2001263828A1 (fr)
BR (1) BR0109799A (fr)
CA (1) CA2404322A1 (fr)
DE (1) DE10015814A1 (fr)
IL (1) IL151926A0 (fr)
MX (1) MXPA02009434A (fr)
WO (1) WO2001072289A2 (fr)

Families Citing this family (7)

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Publication number Priority date Publication date Assignee Title
DE10148066A1 (de) * 2001-09-28 2003-04-24 Max Planck Gesellschaft Liposome enthaltend (Ether)-Lysolecithine
DE10148067A1 (de) * 2001-09-28 2003-04-17 Max Planck Gesellschaft Hitzesterilisierbare Alkylphosphocholin-Liposome
ES2184650B1 (es) * 2001-10-10 2004-09-16 Farmaleis, S.L. Utilizacion de colesterol y fosfolipidos en medicamentos para el tratamiento de la leishmaniasis en los canidos.
BRPI0516937A (pt) * 2004-10-19 2008-09-23 Max Planck Gesellschaft formulações com alquilfosfocolinas na utilização de partìculas portadoras de carga negativa
EP1745788A1 (fr) 2005-07-22 2007-01-24 KTB Tumorforschungsgesellschaft mbH Acylglycerophospholipides pour le traitement du cancer et de la cachexie
EA029363B1 (ru) * 2012-08-13 2018-03-30 Адифарм Еад Фармацевтические составы, содержащие 3-(4-циннамил-1-пиперазинил)аминопроизводные 3-формил рифамицина sv и 3-формил рифамицина s, и способ их получения
EP3895709A1 (fr) 2020-04-17 2021-10-20 Andreas Hettich GmbH & Co. KG Phospholipide et métabolites de phospholipide destinés au traitement des viraux et des pneumonies bactériennes et de la septicémie

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FI874742A (fi) * 1987-10-28 1989-04-29 K & V Licencing Oy Foerfarande foer framstaellning av liposomer.
HU201567B (en) * 1988-07-21 1990-11-28 Gyogyszerkutato Intezet Process for production of intravenous medical compositions containing cyclosphorin
DE4111105A1 (de) * 1991-04-05 1992-10-08 Max Planck Gesellschaft Neue erucyl-, brassidyl- und nervonylderivate
DE4132344A1 (de) * 1991-09-27 1993-04-01 Max Planck Gesellschaft Verfahren zur herstellung eines arzneimittels zur oralen oder topischen verabreichung bei der behandlung von leishmaniasis
US6413543B1 (en) * 1996-02-16 2002-07-02 Max-Planck-Gesselschaft Zur Forderung Der Wissenschaften E.V. Phosphatidyl oligoglycerols
DE19835611A1 (de) * 1998-08-06 2000-02-10 Max Planck Gesellschaft Neuartige Phospholipide mit synthetischen, ungesättigten Alkyl- und Acylketten

Non-Patent Citations (1)

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See references of WO0172289A2 *

Also Published As

Publication number Publication date
DE10015814A1 (de) 2001-10-11
WO2001072289A3 (fr) 2002-04-18
MXPA02009434A (es) 2003-09-22
AU2001263828A1 (en) 2001-10-08
JP2003528134A (ja) 2003-09-24
WO2001072289A2 (fr) 2001-10-04
CA2404322A1 (fr) 2002-09-24
CN1426311A (zh) 2003-06-25
IL151926A0 (en) 2003-04-10
BR0109799A (pt) 2003-01-21
US20030199476A1 (en) 2003-10-23

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