WO2003028736A2 - Liposomes a base d'alkylphosphocholine sterilisables a chaud - Google Patents

Liposomes a base d'alkylphosphocholine sterilisables a chaud Download PDF

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WO2003028736A2
WO2003028736A2 PCT/EP2002/010882 EP0210882W WO03028736A2 WO 2003028736 A2 WO2003028736 A2 WO 2003028736A2 EP 0210882 W EP0210882 W EP 0210882W WO 03028736 A2 WO03028736 A2 WO 03028736A2
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group
mol
cholesterol
alkylphosphopropanediols
cycloalkyl group
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PCT/EP2002/010882
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German (de)
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WO2003028736A3 (fr
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Jörg EIBL
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MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
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Priority to AU2002342770A priority Critical patent/AU2002342770A1/en
Publication of WO2003028736A2 publication Critical patent/WO2003028736A2/fr
Publication of WO2003028736A3 publication Critical patent/WO2003028736A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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
    • A61P33/04—Amoebicides
    • 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
    • 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 which contains phospholipid or alkylphosphocholine compounds in sterile-filterable and / or heat-sterilizable liposomes.
  • the pharmaceutical formulation is particularly for the stimulation of leukopoiesis and for the treatment and / or prophylaxis of tumor diseases and protozoan diseases, in particular leishmaniasis and amoeba diseases, of akarinosis and diseases caused by arthropods and of bacterial diseases such as e.g. Ehrlichiosis, suitable.
  • Alkylphosphocholine compounds have an antiproliferative effect and 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
  • the compounds are often poorly or not at all absorbed when administered orally.
  • 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 of toxicity are largely due to the hemolytic effects of the compounds.
  • Protozoa are unicellular organisms, some of which are pathogenic parasites.
  • the most common representatives that affect humans include plasmodia (malaria), trypanosomes (sleeping sickness), amoebas, e.g. Entamöben and acanthamöben (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.
  • Three types of Leishmania are currently known, which cause very different clinical pictures: "Kala-Azar” with affection of the spleen and liver, the "Orient bump” with inflammatory reactions on the skin and “Espundia” with symptoms also on the mucous membranes of the upper breath - and digestive tract.
  • the course of all three diseases is less characteristic than that of other protozoan diseases and is often gradual.
  • the incubation period can be weeks or even months. Very high mortality rates are often observed in untreated cases.
  • 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 histolytica causes dysenteries and liver abscesses in humans.
  • the pathogen is in many countries very common in this world, it causes about 36 to 50 million cases of illness per year with between 40,000 and 1 1 0,000 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. In the rectum, 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. This can result in small mucosal lesions, but also massive bleeding ulcers. The result is bloody diarrhea, the full picture of amoebic dysentery.
  • Another common manifestation of amebiasis is the amebic liver abscess. Here the 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.
  • Acanthamoeben e.g. Acanthamoeba castellanii, Acanthamoeba culbertsoni
  • Naegleria fowleri is a free-living amoeba flagellate. It typically lives in fresh water and can infect bathers. The parasite penetrates the nose and the
  • Olfactory nerve enters the brain and causes peracute
  • Meningoencephalitis The cases of encephalitis caused by Acanthamoeben or Naeglerien are extremely rare, but so far they have been extremely bad
  • Chemotherapy drugs at E. are currently nitroimidazoles, primarily metronidazole.
  • E. histolytica has no oxidative phosphorylation but gains its energy through glycolysis.
  • the pyruvate is oxidized to acetyl-CoA, 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. So far there are no reliable reports on the distribution of metronidazole - resistant E. histolytica strains.
  • Acanthamoeben Unlike £. histolytica have Acanthamoeben and Naeglerien 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 amoeba.
  • DE application P 41 32 344.0-41 discloses methods for producing a medicament which is suitable for oral or topical administration in the treatment of protozoan diseases, in particular leishmaniasis, and which as an active ingredient has one or more compounds of the general formula: 0 R 2
  • R 1 is a saturated or unsaturated hydrocarbon radical having 1 2 to 20 C atoms
  • R 2 , R 3 and R 4 are each independently H, a C ⁇ -Cg alkyl group, a C 3 -C 6 cycloalkyl group or a C T -Cg hydroxyalkyl group, with 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 an -O-, -S- or NR 5 group, wherein R 5 is H, a C r C 5 alkyl group, a C 3 -C 6 -CycIoalkyl distr or CC 5 -Hydroxyalkyl distr 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 moreover the finished product has the disadvantage that it is very difficult to sterile filter.
  • PCT / EP01 / O3609 describes a pharmaceutical formulation which is 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 CC 5 alkyl group, a C 3 -C 6 cycloalkyl group or one , where 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 an -O-, -S- or NR 5 group, in which R 5 is H, is 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%, b) cholesterol and / or a cholesterol derivative of 25 to 65 mol% and c) a phosphatidyl monoglycerol or phosphatidyl oligoglycerol containing at least one oleyl
  • One object of the invention was, in particular, to provide a heat-sterilizable pharmaceutical preparation.
  • a pharmaceutical preparation containing a) 30 to 60 mol% of a phospholipid compound of the formula as active ingredient
  • R 1 is a saturated or unsaturated, in particular a mono- or polyunsaturated hydrocarbon radical having 15 to 24 carbon atoms, in particular having 16 to 24 carbon atoms, which optionally contain one or more heteroatoms selected from O, N or S.
  • R 2 , R 3 and R 4 each independently represent H, a C, -C 5 alkyl group, a C 3 -C 6 -
  • C 5 is a hydroxyalkyl group
  • n is an integer from 2 to 6
  • a), b) and c) together preferably give 100 mol%.
  • the components are preferably present as a complex dispersed in water.
  • Liposomes generally only form under the influence of an ultrasound or similar treatment, while the liposome-like complex according to the invention forms without any external influence and is stable. This means that other active ingredients such as Amphotericin B of the formulation can be incorporated.
  • the packaging of the active ingredients in the liposomes according to the invention provides considerable advantages over the free alkylphosphocholines.
  • the packaging in the liposomes can in particular increase the desired effectiveness and at the same time reduce undesirable side effects.
  • the hemolytic activity when administered in liposomal form is markedly reduced, it being assumed that the cholesterol present in the liposomes suppresses the hemolytic activity of the active compound.
  • a significant increase in absorption was observed when liposomal alkylphosphocholines were administered in oral form.
  • the invention is based on the fact that the active ingredients alkylphosphochoiines can be simply introduced into liposomes as substantial constituents and used as liposomal formulations.
  • Another essential advantage of the liposomes according to the invention is that they are heat-stable and can therefore be heat-sterilized.
  • the pharmaceutical preparations according to the invention contain a phospholipid, in particular an alkylphosphocholine compound as active ingredient.
  • the hydrocarbon radical R 1 can contain 1 to 5 to 26 carbon atoms, in particular 16 to 24 and more preferably 18 to 22 carbon atoms are preferred.
  • R 1 is particularly preferably an aikyi radical or a mono- or polyunsaturated alkenyl radical and in particular a hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, hexadecenyl,
  • the hydrocarbon residue can be saturated or single or multiple, in particular double or triple unsaturated, the double bond (s) of the unsaturated residues preferably being ice. Alkadienyl and alkatrienyl radicals are preferred, for example.
  • the hydrocarbon residue can be branched or linear and is preferably linear.
  • Compounds with an unsaturated radical R 1 have the advantage that they have a wide therapeutic range and at the same time a very low toxicity.
  • 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 3 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.
  • the polar component of the compounds of formula I preferably consists of phosphocholine (PC), i.e. n is preferably equal to 2. n can also be 3 or 4. Surprisingly, especially for compounds with n equal to 3, there was a stimulating effect on leucopoiesis.
  • PC phosphocholine
  • Suitable and usable alkyl phosphocholines as component a) are e.g. the compounds described in EP 0 507 337 or WP 00/08031.
  • the mixing ratio is preferably 30 to 45 mol% of component a), 30 to 60 Mol% of component b) (cholesterol) and 3 to 30 mol% of component c) (especially cholesterol phosphoglycerol, alkyl phosphoglycerol or alkyl phosphoglycol).
  • the mixing ratio of the individual components is preferably 30 to 55 mol% of component a), 10 to 40 mol% of component b ) (Cholesterol) and 3 to 30 mol% of component c) (in particular cholesterol phosphoglycerin, alkylphosphoglycerol or alkylphosphoglycol).
  • the conditions for good antineoplastic activity in particular half-lives in organs and tissues of 50 or more hours, can be achieved by the active substances specified above.
  • the amount of active ingredient of the formula I in the pharmaceutical preparations according to the invention is 30 to 60 mol%, preferably at least 40 mol% to 50 mol%.
  • the liposomes according to the invention contain cholesterol as a further constituent.
  • Cholesterol as used herein, means cholesterol itself and cholesterol derivatives.
  • Component b ie the cholesterol or cholesterol derivative, also serves to improve the solubility in aqueous solutions of Improve alkylphosphocholine compounds as defined above.
  • Cholesterol-like compounds such as cholesterol oligoglycerols or cholesterol phosphocholine, are also suitable, for example. Cholesterol derivatives with a hydrophilic group are preferred.
  • the amount of cholesterol is preferably 25 to 60 mol%, in particular 30 to 60 mol%.
  • Component c) of the liposomes according to the invention is a negative charge carrier and is particularly selected from cholesterol phosphoglycerols, cholesterol phosphooligoglycerols, alkylphosphoglycerols, alkyl phosphooligoglycerols, alkylphosphoglycols, alkylphosphopropanediols (1, 3) or alkylphosphopropanediols (1,2).
  • Component c) is in particular mono-, di- or triglycerol compounds.
  • the Aikyirest of component c) preferably has 15 to 24 carbon atoms and is saturated or mono- or polyunsaturated.
  • a component is preferably used as component c) whose aikyirest is identical to R 1 of the component a) used in each case.
  • liposomes which are heat-stable and can therefore be heat-sterilized can be obtained using the above-mentioned negative charge carriers. This represents a considerable advantage over other liposome formulations, particularly with regard to possible intravenous or subcutaneous administration of the liposomes. Such liposomes are therefore preferably heat-sterilized after their formation and before administration.
  • the pharmaceutical formulation contains the ingredients in such an amount that they are positive or negative overall Has excess charge.
  • This is particularly advantageous when using (ether) -lysolecithins with longer hydrocarbon chains.
  • the problem of poorer water solubility with longer chain compounds plays a role, particularly with intravenous administration, and to a lesser extent with oral administration.
  • the amount of component c) is preferably 5 to 15 mol%, in particular 7 to 10 mol%.
  • the molar ratio of the individual components of the liposomes according to the invention can vary, so that e.g. the alkylphosphocholine compound of the formula I is present in a slight excess. However, a ratio which does not deviate too far from 1: 1 is generally preferred, e.g. a molar ratio of active ingredient of the formula I to cholesterol of 1.2: 1 to 0.8: 1, in particular 1.1: 1 to 0.9: 1.
  • the cholesterol is preferably present in the liposome at 45 to 55 mol%.
  • the liposome-like complex formed from the components a), b) and c) can be sterile filtered without any problems through membranes with pore diameters 0.8 //, 0.45 ⁇ and even 0.2 ⁇ . This is a significant advantage over conventional liposomes, which are not easy to sterile filter. In addition, it has surprisingly been found that liposomes according to the invention are extremely stable in storage.
  • Components a, b and c together preferably represent 100% of the liposomes according to the invention.
  • liposomes which contain further shell components and / or encapsulated substances.
  • Liposomes are preferred which comprise further active substances in encapsulated form.
  • Additional active ingredients which can advantageously be contained in the liposomes according to the invention are, for example, oxytetracycline, doxycycline or minocycline, which have a bactericidal action are; Amphotericin B or griseofulvin, which are fungicidally active, and cyclosporin, which has an immunosuppressive effect.
  • the alcohol is preferably a water-miscible, physiologically acceptable 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) 30 to 60 mol% of a phospholipid compound of the formula I
  • R 1 is a saturated or unsaturated hydrocarbon radical having 15 to 24 carbon atoms, in particular having 16 to 24 carbon atoms
  • R 2 , R 3 and R 4 are each independently H
  • a are a C 3 -C 6 cycloalkyl group or 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 combined with an -O-, -S- or NR 5 group can be substituted
  • R 5 is H, a C, -C 5 alkyl group, a C 3 -C 6 cycloalkyl group or the C T -Cg hydroxyalkyl group
  • n is an integer is from 2 to 4, as active ingredient with b) 10 to 65 mol%, in particular with 25 to 65 mol% of cholesterol and c) 3 to 30 mol%, in particular -5 to 15 mol% of a cholesterol phosphomono
  • the phosholipid compound is preferably initially introduced in aqueous solution.
  • a water-miscible, physiologically acceptable alcohol having 2 to 4 carbon atoms can be added to the resulting mixture, so that the components form a complex which is dispersed or dispersible in water.
  • components a), b) and c), as defined above can be mixed in a simple manner in the molar ratios mentioned.
  • an additional active ingredient is to be incorporated into the formulation according to the invention, it is preferably added to the mixture of a), b) and c).
  • a water-miscible alcohol is then added, which is a physiologically harmless alcohol with 2 to 4 carbon atoms, in particular ethanol, 2-propanol, 1, 2-propanediol or 2-butanol. Since a certain amount of the alcohol can remain in the finished pharmaceutical formulation, the alcohol is preferably selected so that it is suitable for both oral and intravenous administration.
  • Ethanol, 1, 2-propanediol or 2- Propanol used.
  • Ethanol is characterized by low toxicity and therefore relatively good physiological tolerance, but is not so well suited for the production of liposomes or complexes according to the invention which contain a relatively large amount of cholesterol, since cholesterol only dissolves to a limited extent in ethanol.
  • 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 is, ie. the (ether) -lysolecithin compound preferably contained in an amount of 0.1 to 200 // mol / g.
  • the compound of the formula I with the other constituents is present as a complex which is dispersed or dispersible in water.
  • component c) with an excess charge is preferably added 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.
  • Aqueous liquids are understood to mean in particular liquids with a water content> 60% by weight, in particular> 90% by weight and especially 95% by weight of water.
  • a major advantage of the method according to the invention is that liposomes, if appropriate with active substances included therein, can be obtained in a simple manner by simply combining the constituents and e.g. Dispersion in water, optionally in the presence of an alcohol can be obtained.
  • Another advantage of the mixture obtained by the process according to the invention is that it can be sterile filtered without problems. Filters with pore sizes of 0.8 ⁇ , 0.45 ⁇ and even 0.2 ⁇ can be used. If cholesterol phosphomono- or oligoglycerols are used, the preparation can also be heat sterilized, e.g. at temperatures> 80 ° C, in particular> 90 ° C and preferably> 95 ° C. In addition, the compositions are stable over a wide pH range (e.g. from pH 2 to pH 10).
  • the formulation according to the invention can be prepared galenically in liquid or solid form.
  • a formulation for intravenous, subcutaneous or oral administration is particularly preferred.
  • a topical O 03/028736 is particularly preferred.
  • administration is also possible.
  • oral administration it is advantageous to dilute the active mixture with water or another physiological liquid, a 5 to 1 50-fold dilution having proven particularly suitable.
  • it can also be diluted more, because even at dilutions of 1: 1,000 to 1: 10,000, the complex remains soluble 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 1% by weight.
  • the alcohol concentration does not have to be taken into account at all, ie the alcohol concentration can also be more than 3% by weight.
  • Dilutions with water or physiological aqueous solutions of 1: 5 to 1: 150, preferably 1: 10 to 1: 20, are particularly suitable.
  • the daily dose of an effective amount of a compound of the formula I is 0.1 to 100 / y mol / kg Body weight, preferably 1 to 5 / mol / kg.
  • sterile conditions can be easily met by storing in appropriately concentrated alcoholic solutions.
  • 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 100 is preferred here. If appropriate, the alcohol can 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, for example, poured out into hollow cells of the appropriate size or filled into granules of the appropriate size or granulated and then optionally compressed into tablets with the addition of other customary auxiliaries ,
  • the formulation can, for example, be mixed with one or more of the following auxiliaries: starch, cellulose, lactose, formalin, casein, modified starch, magnesium stearate, calcium hydrogen phosphate, highly disperse silica, talc and phenoxyethanol.
  • the mixture obtained can optionally be granulated with an aqueous solution of, for example, gelatin, starch, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and / or polyoxyethylene sorbitol monooleate and then compressed to tablets or filled into capsules.
  • an aqueous solution of, for example, gelatin, starch, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and / or polyoxyethylene sorbitol monooleate
  • the pharmaceutical preparations according to the invention can be used in particular for the treatment and / or prophylaxis of protozoan diseases. It has been shown that the liposomal preparations have excellent efficacy against protozoan diseases and diseases caused by them and are particularly suitable against plasmodia and thus the treatment of malaria, trypanosomes and thus the treatment of. Sleeping sickness, amoebas, eg endamoebas and acanthamoebas, and thus the treatment of amoebic dysentery and encephalitis and leishmanias and thus the treatment of leishmaniasis.
  • the pharmaceutical formulations are particularly preferably used for the treatment of leishmaniasis and / or for the treatment of diseases caused by amoebas. In the treatment of Leishmaniasis formulations are preferably used which contain amphotericin B as an additional active ingredient.
  • the pharmaceutical formulations according to the invention are excellent anti-tumor agents. They can thus be used for the treatment and / or prophylaxis of cancer, in particular leukemia and solid tumors.
  • the pharmaceutical formulation according to the invention also has a good activity against acarinosis, in particular mange and against diseases caused by arthropods and by ascarids, such as mites or ticks.
  • amphotericin B in particular showed a synergistic increase in effectiveness against protozoan diseases and an expansion to systemic fungal diseases.
  • the pharmaceutical formulations according to the invention also show excellent activity against bacterial diseases. They can therefore also be used for the treatment and / or prophylaxis of bacterial diseases, in particular for the treatment or / and prophylaxis of Ehrlichiosis.
  • Ehrlichiosis is a bacterial disease that is transmitted by ticks. In the treatment of dogs with pharmaceutical formulations according to the invention, a clear reduction in the Ehrlichios titer was found. Ehrlichiosis can be treated in combination with tetracyclines.
  • Eye diseases associated with cellular proliferation such as proliferative vitreoretinopathy or retinal detachments on the eye, which are difficult to surgically treat and also often involve very proliferating cells, can be successfully treated or avoided with the pharmaceutical preparations according to the invention.
  • the preparations can also be used for immunosuppression.
  • the liposomes according to the invention are preferably used for the treatment of mammals and most preferably for the treatment of dogs or humans.
  • the invention relates to the cholesterol phosphoglycerol and cholesterol phosphooligoglycerol compounds used as component c) as negative charge carriers.
  • These compounds are not described in the prior art and make it possible to provide liposomes which are heat-stable and thus also heat-sterilizable.
  • the cholesterol phosphoglycerol and cholesterol phosphooligoglycerol compounds are stable in particular at temperatures> 50 ° C, more preferably> 70 ° C, even more preferably> 80 ° C and especially at temperatures> 90 ° C, even more preferably> 95 ° C. In this way it is possible to use these compounds to provide liposomes in which all constituents are stable over a wide temperature range, for example from 0 to 100.degree. Such liposomes can then be sterilized using heat.
  • the cholesterol phosphoglycerols according to the invention comprise in particular the following structures: Chpfeste ⁇ ntheticenunqa ⁇ as negative Ladu ⁇ g ⁇ r ⁇
  • Lipid content 100 // mol / ml C total lipid: 0.1 M
  • Residual solvent is in the drying cabinet in the
  • the suspension is uniform. It can be easily filtered through a glass filter and then through a 0.8 ⁇ filter.
  • the liposomes thus obtained are stable at 4 ° C for at least 1 2 months.
  • the lipid mixture is treated as in Example 1 and brought into a liposomal formulation.
  • Example 4 (Z) -IO-NonadecenvH-PC: volume 250 ml
  • the lipid mixture is treated as in Example 1 and brought into a liposomal formulation.
  • Example 6 (Z) -1Q-heneicosenyl-1-PC: volume 250 ml
  • the lipid mixture is treated as in Example 1 and brought into a liposomal formulation.
  • Lipid content 100 // mol / ml
  • the lipid mixture 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 is treated as in Example 1 and brought into a liposomal formulation.
  • the dispersion is filtered through a glass fiber filter.
  • the filtrate can then be sterile filtered without problems (filter 0.45 ⁇ m, 0.20 ⁇ m) and / or heat sterilized.
  • the dispersion is filtered through a glass fiber filter.
  • the filtrate can then be sterile filtered without problems (filter 0.45 ⁇ m, 0.20 ⁇ m) and / or heat sterilized.
  • Content Amphotericin B, 9 mg / ml
  • Erucyl-PC H3 is a phosphocholine with a phospho-trimethylammonium distance extended to 3 carbon atoms:
  • the dispersion is filtered through a glass fiber filter.
  • the filtrate can then be easily sterile filtered (filter 0.45 ⁇ m, 0.20 ⁇ m) and / or heat sterilized.
  • Erucyl-PC H3 45 ⁇ mol / ml * Erucyl-PC H3 is a phosphocholine with a phospho-trimethylammonium distance extended to 3 carbon atoms.

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Abstract

La présente invention concerne une nouvelle formulation de médicament contenant des composés de phospholipide ou d'alkylphosphocholine dans des liposomes filtrables de façon stérile et/ou stérilisables à chaud. Cette formulation de médicament peut être utilisée en particulier pour stimuler la leucopoïèse ou pour traiter et/ou prévenir des maladies tumorales et des protozooses, en particulier des leishmanioses et des amibiases, ou des acarioses et des maladies dues à des arthropodes, ainsi que des maladies bactériennes, telles que l'ehrlichiose.
PCT/EP2002/010882 2001-09-28 2002-09-27 Liposomes a base d'alkylphosphocholine sterilisables a chaud WO2003028736A2 (fr)

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AU2002342770A AU2002342770A1 (en) 2001-09-28 2002-09-27 Pharmaceutical preparations comprising alkyl phosphocholine compounds in liposomes which may be sterile-filtered or heat-sterilised

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DE10148067A DE10148067A1 (de) 2001-09-28 2001-09-28 Hitzesterilisierbare Alkylphosphocholin-Liposome
DE10148067.9 2001-09-28

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WO2006024675A1 (fr) * 2004-09-03 2006-03-09 Forschungszentrum Karlsruhe Gmbh Utilisation d'alkylphospholipides pour traiter des tumeurs solides
WO2006042751A2 (fr) * 2004-10-19 2006-04-27 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Formulations contenant des alkylphosphocholines faisant intervenir de nouveaux porteurs de charge negatifs
WO2007071658A3 (fr) * 2005-12-19 2007-10-04 Aeterna Zentaris Gmbh Nouveaux derives d'alkylphospholipide ayant une cytotoxicite reduite et utilisations de ceux-ci
WO2007133261A1 (fr) * 2006-05-11 2007-11-22 Kimberly-Clark Worldwide, Inc. Formulation pour muqueuses
US20120027812A1 (en) * 2009-02-06 2012-02-02 Kirsten Eibl-Lindner Intraocular lenses treated with alkylphosphocholines for pharmacological aftercataract prophylaxis
US8541399B2 (en) 2002-02-19 2013-09-24 Resolution Chemicals Limited Solvent-based sterilisation of pharmaceuticals

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8541399B2 (en) 2002-02-19 2013-09-24 Resolution Chemicals Limited Solvent-based sterilisation of pharmaceuticals
WO2006024675A1 (fr) * 2004-09-03 2006-03-09 Forschungszentrum Karlsruhe Gmbh Utilisation d'alkylphospholipides pour traiter des tumeurs solides
WO2006042751A2 (fr) * 2004-10-19 2006-04-27 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Formulations contenant des alkylphosphocholines faisant intervenir de nouveaux porteurs de charge negatifs
WO2006042751A3 (fr) * 2004-10-19 2007-07-19 Max Planck Gesellschaft Formulations contenant des alkylphosphocholines faisant intervenir de nouveaux porteurs de charge negatifs
JP2008517023A (ja) * 2004-10-19 2008-05-22 マックス−プランク−ゲゼルシャフト・ツア・フェルデルング・デア・ヴィッセンシャフテン・エー・ファオ アルキルホスホコリンを含有する新規の負電荷担体を使用した配合物
US8828972B2 (en) 2004-10-19 2014-09-09 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Formulations containing alkylphosphocholines using novel negative charge carriers
WO2007071658A3 (fr) * 2005-12-19 2007-10-04 Aeterna Zentaris Gmbh Nouveaux derives d'alkylphospholipide ayant une cytotoxicite reduite et utilisations de ceux-ci
JP2009519999A (ja) * 2005-12-19 2009-05-21 エテルナ ツェンタリス ゲゼルシャフト ミット ベシュレンクテル ハフツング 低減された細胞毒性を有するアルキルリン脂質誘導体並びにそれらの使用
RU2469727C2 (ru) * 2005-12-19 2012-12-20 Этерна Центарис ГмбХ Способ лечения или профилактики заболеваний и/или патофизиологических состояний, вызванных микроорганизмами, посредством производных алкилфосфолипидов
WO2007133261A1 (fr) * 2006-05-11 2007-11-22 Kimberly-Clark Worldwide, Inc. Formulation pour muqueuses
US8703179B2 (en) 2006-05-11 2014-04-22 Kimberly-Clark Worldwide, Inc. Mucosal formulation
US20120027812A1 (en) * 2009-02-06 2012-02-02 Kirsten Eibl-Lindner Intraocular lenses treated with alkylphosphocholines for pharmacological aftercataract prophylaxis

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