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WO2006024675A1 - Utilisation d'alkylphospholipides pour traiter des tumeurs solides - Google Patents

Utilisation d'alkylphospholipides pour traiter des tumeurs solides Download PDF

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Publication number
WO2006024675A1
WO2006024675A1 PCT/EP2005/054537 EP2005054537W WO2006024675A1 WO 2006024675 A1 WO2006024675 A1 WO 2006024675A1 EP 2005054537 W EP2005054537 W EP 2005054537W WO 2006024675 A1 WO2006024675 A1 WO 2006024675A1
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Prior art keywords
formula
alkyl
pharmaceutical preparation
use according
treatment
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.)
Ceased
Application number
PCT/EP2005/054537
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German (de)
English (en)
Inventor
Harald Krug
Ulrich Massing
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KTB Tumorforschungs GmbH
Karlsruher Institut fuer Technologie KIT
Original Assignee
Forschungszentrum Karlsruhe GmbH
KTB Tumorforschungs GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Forschungszentrum Karlsruhe GmbH, KTB Tumorforschungs GmbH filed Critical Forschungszentrum Karlsruhe GmbH
Publication of WO2006024675A1 publication Critical patent/WO2006024675A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • 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
    • 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

Definitions

  • the invention relates to the use of a pharmaceutical preparation comprising alkylphospholipids (APL) of the general formula (I) for the treatment of solid tumors, said pharmaceutical preparation as novel liposomal formulation and novel alkylphospholipids (APL) of the formulas (II), (IIa) and ( IIb) as active ingredients for the treatment of tumors.
  • APL alkylphospholipids
  • compositions containing certain alkylphospholipids (APL) of the general formula (I) which have an inhibitory effect on the enzymatic activity of the phospholipase A2 are known from DE 42 34 130 A1.
  • the preparation and the use of some alkylphospholipids (APL) of the general formula (I) is furthermore also described in Massing et al. (Chem. Phys. Lipids, 1994, 69, 105-120).
  • APL alkyl phospholipids
  • hexadecylphosphocholine HePC
  • edelfosine Et-18-OCH3, rac-2-methyl-1-octadecyl-glycero (3) -phosphocholine
  • ilmofosine thio analogs of edelfosine
  • brain p-Gp is particularly highly expressed (i.e., also without induction by the drug).
  • An example of this problem is the poor reception of the
  • APL have not been successful in the treatment of solid tumors and brain tumors.
  • the main reason for this is that, for the treatment of solid tumors, significantly higher drug levels are needed than would be necessary for the killing of leukemic cells, since leukemic cells are much more sensitive to APL. It is an object of the present invention to provide pharmaceutical compositions which overcome the above problems and can be used to treat solid tumors.
  • Another object is to provide new APLs for the treatment of tumors which have a high antitumor action potential.
  • An inventive approach is the use of a pharmaceutical preparation containing at least one alkylphospholipid of the general formula (I)
  • A is O or NR 4 , wherein R 4 is H, C 1 -C 20 alkyl; R 1 is H, C 1 -C 20 alkyl or COR 5 , wherein R 5 is H or C 1 -C 20 alkyl;
  • R 2 is a C 10 -C 22 alkyl
  • R 3 for choline, carbachol, serine, inositol, H, ethanolamine or glycerol stands for the treatment of solid tumors.
  • the pharmaceutical preparation preferably contains compounds of the formula I in which A is NR 4 and R 1 is H.
  • A is O or NR 4 , wherein R 4 is H, C 1 -C 20 alkyl;
  • R 1 is H, C 1 -C 20 -alkyl or COR 5 , wherein R 5 is H or C 1 -C 20 -alkyl; and R 3 is choline, carbachol, serine, inositol, H, ethanolamine or glycerol.
  • A is O or NR 4 , wherein R 4 is H, C 1 -C 20 alkyl; R 1 is H, C 1 -C 20 alkyl, or COR 5 , wherein R 5 is H or C 1 -C 20 alkyl; stands.
  • the compounds can be present in the pharmaceutical preparation of the invention in the chemical R or S configuration or else racemically.
  • the specification of the configuration is part of the abbreviated name.
  • compositions comprising the following compounds of the formula (Ib): S-NH 2, S-OH, S-OCl, S-NC 2, rac-OMe, S-OMe, R-NH 2, R-OH, R-OCl 2, R-NC2, R-OMe, especially rac-OMe.
  • the use of the APL according to the invention has shown that there are cells of certain solid tumors in which significantly lower APL concentrations are sufficient to kill them than was previously known for cells of solid tumors. Some of these compounds are generally more effective than HePC, the only APL approved for tumor therapy (see above).
  • compositions containing APL according to the invention have the following advantages over classical cytostatic agents: APLs are not substrates for p-Gp (P-glycoprotein, causative for the multi-drug resistance MDRI of tumor cells), therefore detoxification of cells via up-regulation of MDRI is not possible.
  • p-Gp P-glycoprotein, causative for the multi-drug resistance MDRI of tumor cells
  • the groups of APL described as antitumoral can be readily transported in the blood (e.g., albumin, micelles, in vitro)
  • Lipoproteins etc.
  • These lysolipid-analogue APLs can penetrate cell membranes through flip-flop and so quickly enter tissue and cells. In addition, they can
  • the APL are particularly suitable as active ingredients, especially against solid tumors and brain tumors.
  • Another advantage is the location of the APL, which has been shown to be on the cell membrane, completely avoiding a mutagenic effect on healthy cells.
  • the use of the invention represents a way to use APL for the treatment of APL-sensitive solid tumors and thus circumvent the inherent disadvantages of classical cytostatics (high mutagenic potency, substrates for MDR).
  • the pharmaceutical preparation may be present as a tablet, ointment, suppository, granule, injection preparation or aerosol.
  • the pharmaceutical preparation contains further excipients such as carriers and stabilizers.
  • Excipients are to be understood as meaning, for example, the following substances: water-insoluble excipients or mixtures thereof, such as lipids, inter alia fatty alcohols, for example cetyl alcohol, stearyl alcohol and cetostearyl alcohol, glycerides, for example glycerol monostearate or mixtures of mono-, Di- and triglycerides of vegetable oils; hydrogenated oils, such as hydrogenated castor oil or hydrogenated cottonseed oil; waxes, eg beeswax or carnauba wax; solid hydrocarbons, for example paraffin or earth wax; fatty acids, for example stearic acid, certain cellulose derivatives, for example ethylcellulose or acetylcellulose, polymers or copolymers, such as polyalkylenes, for example polyethylene, polyvinyl compounds, for example polyvinyl chloride or polyvinyl acetate, and vinyl chloride-vinyl acetate copolymers and copolymers with
  • composition according to the invention may additionally contain fillers, binders, lubricants and carriers which have no decisive influence on the release of active ingredient.
  • fillers include bentonite (Alumina-silica hydrate), silica, cellulose (usually microcrystalline cellulose) or cellulose derivatives, for example methylcellulose, sodium carboxymethylcellulose, sugars, such as lactose, starches, for example maize starch or derivatives thereof, for example sodium carboxymethyl starch, starch liners, phosphoric acid salts, for example di- or tricalcium phosphate, Gelatin, stearic acid or suitable salts thereof, for example magnesium stearate or calcium stearate, talc, colloidal silica and similar auxiliaries.
  • bentonite Allumina-silica hydrate
  • silica cellulose (usually microcrystalline cellulose) or cellulose derivatives, for example methylcellulose, sodium carboxymethylcellulose
  • sugars such as lactose
  • starches for example maize starch or derivatives thereof, for example
  • auxiliaries preservatives, antioxidants, wetting agents, solubilizers, stabilizers, buffer substances and, if appropriate, flavorings and / or dyes must be taken into account.
  • a particular problem with an application of APL according to Fomel (I), (Ia) and (Ib) as well as (II), (IIa) and (IIb) for therapeutic purposes is the fact that (a) their therapeutic potential is not limited to their respective structure, but also depends on their biophysical properties and they are difficult to apply as lipids (b).
  • a special challenge in the development of modern drugs is also the requirement of so-called drug targeting (c), whereby the active ingredients should preferably be enriched in the diseased tissues / cells by the selected formulation.
  • the biophysical properties of the alkylphospholipids according to formulas (I), (Ia) and (Ib) and (II), (IIa) and (IIb) depend on the radicals R 1, R 2 and R 3 and may correspond to those of lyso-lipids (low CMC, (critical micelle concentration)) as well as those of two-chain phospholipids (high CMC, such as lecithin) correspond.
  • the biophysical properties are initially responsible for a good uptake (low CMC) or poor uptake (high CMC) in cells and thus promptly influence the therapeutic success.
  • the residence time of high CMC lipids in cellular systems is higher because they can not be rapidly removed from the membranes.
  • lipids with high CMC are transported via the lipoproteins and are thus not necessarily accumulated in the diseased tissue (on the other hand, this route can be used for a corresponding targeting, eg in the liver).
  • Gl-side effects especially with the inhibitors of PLA2 [phospholipase A2] by inhibition of pancreatic PLA2 also occur here.
  • the substances should be accumulated as selectively as possible at the site of action (drug targeting, enhancement of the effect and reduction of side effects).
  • Liposomes are spherical structures made up of amphipats. In aqueous solutions, liposomes are formed by self-aggregation of the amphipats, forming a lipid bilayer which encloses an aqueous interior. Depending on physical parameters such as mechanical influences, pressure, temperature and the ion concentration as well as the lipids and additives present, unilamellar, oligolamellar or multilamellar liposomes form. The liposomes may carry a positive or negative excess charge depending on their constituents.
  • Liposomes may also be loaded with drugs which, depending on the lipophilicity or hydrophilicity, are entrapped in the lipid layer or in the aqueous interior of the liposomes. Such liposomes are used in diagnostic detection methods or as therapeutic agents for the transport of active substances in the organism or as a drug depot.
  • the properties of the liposomes, such as their stability or shelf life, are substantially determined by the substances present in the lipid layer.
  • membrane-forming lipids such as phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidylethanolamine (PE), sphingomyelin, membrane-forming amphipats, such as block polymers, alkyl esters, ethers, amides of sugars, diols and polyols, amines, amino acids, peptides and sugars, cholesterol and other substances used.
  • PC phosphatidylcholine
  • PG phosphatidylglycerol
  • PS phosphatidylserine
  • PI phosphatidylinositol
  • PE phosphatidylethanolamine
  • sphingomyelin membrane-forming amphipats, such as block polymers, alkyl esters, ethers, amides of sugars, diols and polyols
  • alkyl phospholipids of formula (I), (Ia) and (Ib) and (II), (IIa) and (IIb) can be made into neutral liposomes (with net neutral charge, with or without stealth components
  • Stealth components are structures on the liposome surface, preferably coatings which prevent an immune reaction, for example polyethylene glycol chains, PEG 2000), to achieve their tumor targeting and an improved antitumoral effect.
  • VPG Vehicle Phospholipid Gels
  • the pharmaceutical preparation in addition to the alkylphospholipids of the formula I, Ia or Ib, contains further lipids.
  • the pharmaceutical preparation provides a lipid mixture with neutral
  • the pharmaceutical preparation is a positive net lipid lipid mixture. In another preferred embodiment, the pharmaceutical preparation is preferably a net negative charge lipid mixture.
  • the pharmaceutical preparation contains a composition of the additional lipids, which is based on the lipid composition of the surfactant.
  • Natural surfactant has the following composition: phospholipids: about 81%, surfactant proteins (SP-A, -B, -C, and -D): about 5.4%; Free fatty acids: about 1.6%, glycerides: about 0.6% and cholesterol about 5.6%.
  • composition of the surfactant are, in addition to the high biological content of saturated glycerophospholipids (in particular DPPC 1, 2-dipalmitoyl-sn-3-phosphatidylcholine, main constituent, and DPPG1, 2-dipalmitoyl-sn-3-phosphatidylglycerol, from the phospholipid side, 5-15%).
  • saturated glycerophospholipids in particular DPPC 1, 2-dipalmitoyl-sn-3-phosphatidylcholine, main constituent, and DPPG1, 2-dipalmitoyl-sn-3-phosphatidylglycerol, from the phospholipid side, 5-15%).
  • the surfactant-like APL liposomes according to the invention contain (mol%):
  • the liposomes according to the invention do not contain sphingomyelin.
  • the administration of the liposomes takes place as a micellar solution in buffer / medium as an isotonic mixture.
  • a phosphate-buffered isotonic saline solution is used for this purpose.
  • administration may be by bypassing an IV injection / infusion or the gastrointestinal tract, for example as injection / direct instillation (single dose) into the lung or infusion (continuous dose) into the lung. This can also be done on an outpatient basis, but it is easily possible, especially if the patient is ventilated.
  • the APL according to the invention of the formula (I), (Ia) and (Ib) and (II), (IIa) and (IIb) and the pharmaceutical preparations according to the invention can furthermore be employed as activators and mediators of cell, immune and gene therapies ,
  • Example 1 Comparison of the APL effect on a mammary carcinoma cell line and a leukemic cell line:
  • IC50 and LD50 values of various lysolipid-type APLs were expressed on HL-60 cells (leukemic) and on MDA-MB-468 cells
  • Example 2 Colony assays with solid human tumors:
  • KB head-neck tumors
  • a lung tumor were extremely sensitive to APL.
  • Highly selective APL are: S-OC2: 124; S-OH:> 100; S-NH2:> 100, and racOMe:> 150. This suggests a specific mechanism of action, which apparently only occurs in certain tumor cells.
  • HePC shows a selectivity of 50.
  • Example 5 Efficacy of APL against glioma blastomas.
  • Glioma blastomas are known as radio and chemoresistant cancer cells.
  • the efficacy of S-OC2 and of racOMe against three different glioma-blastoma cell lines was investigated.
  • the APLs tested were highly potent against two of the cell types (LNT-229 and LN18) with LD50 values of approximately ⁇ 10 ⁇ M for LNT229 and ⁇ 20 ⁇ M for LN-18.
  • LN-308 the effect was over 30 ⁇ M).
  • the APL according to formula (I), (Ia) and (Ib) and (II), (IIa) and (IIb) and the pharmaceutical preparations according to the invention thus represent a promising group of active ingredients for the selective treatment of certain tumors.
  • the APL and the lipids necessary for liposome formation are weighed in and mixed with a suitable organic solvent (eg ethanol, 2-propanol or eg chloroform / methanol (2: 1)). taken and placed in a round bottom flask transferred. The solvent is carefully removed under vacuum and rotation of the flask until a glassy film of LiPid is formed on the glass. Solvent residues are removed by applying high vacuum for 24 hours. Subsequently, the required amount of liquid (eg physiological saline or an isotonic buffer) is added, the flask to a temperature 5 0 C higher than the phase transition temperature of the lipid with the highest
  • phase transition temperature heated and the flask gently shaken (so-called hand-shake liposomes). Subsequently, the liposome dispersion is sonicated until small, unilamellar vesicles (SUV) are formed.
  • the liposome size may also be e.g. be adjusted by extrusion.
  • the liposomes can also be prepared by high pressure homogenization or by the injection method.

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

Abstract

L'invention concerne l'utilisation, pour le traitement de tumeurs solides, d'une préparation pharmaceutique contenant des alkylphospholipides de formule générale (I). L'invention concerne également cette préparation pharmaceutique en tant que nouvelle formulation liposomale, ainsi que de nouveaux alkylphospholipides de formules (II), (IIa) et (IIb) comme principe actif pour le traitement de tumeurs.
PCT/EP2005/054537 2004-09-03 2005-08-29 Utilisation d'alkylphospholipides pour traiter des tumeurs solides Ceased WO2006024675A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004042718 2004-09-03
DE102004042718.6 2004-09-03

Publications (1)

Publication Number Publication Date
WO2006024675A1 true WO2006024675A1 (fr) 2006-03-09

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PCT/EP2005/054537 Ceased WO2006024675A1 (fr) 2004-09-03 2005-08-29 Utilisation d'alkylphospholipides pour traiter des tumeurs solides

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007147875A2 (fr) 2006-06-21 2007-12-27 Staatliches Weinbauinstitut Freiburg Alkylphospholipides utilisés en tant que substance active pour lutter contre des agents phytopathogènes
WO2008101469A3 (fr) * 2007-02-19 2009-01-29 Epo Experimentelle Pharmakolog Préparation pharmaceutique pour lutter contre des métastases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4234130A1 (de) * 1992-10-09 1994-04-14 Max Planck Gesellschaft Phospholipase A¶2¶ inhibierende Phosphatidylcholinverbindungen
WO2003028736A2 (fr) * 2001-09-28 2003-04-10 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Liposomes a base d'alkylphosphocholine sterilisables a chaud

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4234130A1 (de) * 1992-10-09 1994-04-14 Max Planck Gesellschaft Phospholipase A¶2¶ inhibierende Phosphatidylcholinverbindungen
WO2003028736A2 (fr) * 2001-09-28 2003-04-10 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Liposomes a base d'alkylphosphocholine sterilisables a chaud

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BONJOUKLIAN R. ET AL.: "Studies of the Antitumor Activity of (2-Alkoxyalkyl)- and (2-Alkoxyalkenyl)phosphocholines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 12, 1986, pages 2472 - 2477, XP002353207 *
MASSING U ET AL: "Antitumoral effects of octadecylphosphocholine analogous", EUROPEAN JOURNAL OF CANCER, PERGAMON PRESS, OXFORD, GB, vol. 33, September 1997 (1997-09-01), pages S175, XP004283631, ISSN: 0959-8049 *
MASSING U ET AL: "SYNTHESIS OF ENANTIOMERICALLY PURE 1-O-PHOSPHOCHOLINE-2-O- ACYL-OCTADECANE AND 1-O-PHOSPHOCHOLINE-2-N-ACYL-OCTADECANE", CHEMISTRY AND PHYSICS OF LIPIDS, LIMERICK, IR, vol. 69, no. 2, 1994, pages 105 - 120, XP000980577, ISSN: 0009-3084 *
MATZKE A ET AL: "Killing tumour cells by alkylphosphocholines: Evidence for involvement of CD95", EUROPEAN JOURNAL OF CELL BIOLOGY, WISSENSCHAFLICHE VERLAGSGESELLSCHAFT, STUTTGART,, DE, vol. 80, no. 1, January 2001 (2001-01-01), pages 1 - 10, XP004954766, ISSN: 0171-9335 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007147875A2 (fr) 2006-06-21 2007-12-27 Staatliches Weinbauinstitut Freiburg Alkylphospholipides utilisés en tant que substance active pour lutter contre des agents phytopathogènes
WO2008101469A3 (fr) * 2007-02-19 2009-01-29 Epo Experimentelle Pharmakolog Préparation pharmaceutique pour lutter contre des métastases

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