WO2006024675A1

WO2006024675A1 - Use of alkylphospholipids for the treatment of solid tumours

Info

Publication number: WO2006024675A1
Application number: PCT/EP2005/054537
Authority: WO
Inventors: Harald Krug; Ulrich Massing
Original assignee: Forschungszentrum Karlsruhe Gmbh; Ktb Tumorforschungsgesell- Schaft Mbh
Priority date: 2004-09-03
Filing date: 2005-08-29
Publication date: 2006-03-09

Abstract

The invention relates to the use of a pharmaceutical preparation, containing alkylphospholipids (APL) of general formula (I), for the treatment of solid tumours, said pharmaceutical preparation as a novel liposomal formulation and novel alkylphospholipids (APL) of formula (II), (IIa) and (IIb) as active agents for the treatment of tumours.

Description

USE OF ALKYL PHOSPHOLIPIDES FOR THE TREATMENT OF SOLID TUMORS

This application claims the priority of DE 10 2004 042 718.6-11.

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.

Pharmaceutical preparations 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).

Certain synthetic alkyl phospholipids (APL) are known to be effective as antitumoral agents. Synthetic APL are analogs of naturally occurring phospholipids in which the natural carboxylic acid ester bonds have been replaced or completely removed by ether linkages or by methylene groups. Also, modifications of the polar head of these lipids have been described. The APLs, which are effectively discussed today as antitumoral drugs, are mostly analogues of lyso-phosphatidylcholine. Examples of these are hexadecylphosphocholine (HePC), edelfosine (Et-18-OCH3, rac-2-methyl-1-octadecyl-glycero (3) -phosphocholine) or ilmofosine (thio analogs of edelfosine). Clinical studies using APL (eg hexadecylphosphocholine) systemically (oral administration) for the treatment of mammary carcinoma have failed because the necessary amount to be administered (for a sufficient antitumor effect) has led to unacceptable gastrointestinal side effects. Accordingly, hexadecylphosphocholine has been approved only as a skin ointment for the treatment of skin metastases of breast carcinoma. A similar fate has befallen the APL Et ~ 18-OCH3 (Edelfosin®). Again, the clinical trials have not been successful, the substance is now used for extracorporeal purging of bone marrow.

Another APL, whose introduction into the clinic failed, is the Ilmofosin (Thioanaloga of Edelfosins).

Other analogous naturally occurring phospholipids are antitumorally active against leukemic cells from Bonjouklian et al. (J. Med. Chem., 1986, 29, 2472-2477) or Matzke et al. (Eur. J. Gell Biol., 2001, 80, 1-10).

In contrast to leukemic cancers, the chances of success in the treatment of solid tumors are still poor today. In particular, drug-based cancer therapy accounts for only about 4% of cures. An even bigger problem is especially the treatment of brain tumors, as drugs due to the blood-brain barrier can not reach the tumor in necessary amounts.

An additional problem is the prevention of drug accumulation in tumor tissues and cells by the so-called "multi-drug resistance." Here, p-glycoproteins (p-Gp) induced by the drug carry the

Active ingredients quickly out of the cell. This effect makes a special

Problem in the treatment of brain tumors, since the capillary endothelial cells of the

In principle, 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

Active substance pactitaxel in brain tumors (Fellner, S. et al., 2002: Clin Invest 110, 1309).

An additional problem with the use of most cytostatics is their mutagenic effect also on the healthy cells of patients, which is based on a direct interaction of the cytostatic with the DNA of these cells.

So far, 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.

It is another object of the present invention to provide pharmaceutical preparations and / or novel synthetic alkylphospholipids (APL) which exhibit improved activity over the prior art. Furthermore, it is an object to provide pharmaceutical preparations which have a high tumor-specific active potential.

An inventive approach is the use of a pharmaceutical preparation containing at least one alkylphospholipid of the general formula (I)

Formula I

wherein 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 and

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.

Also preferred are pharmaceutical preparations containing compounds of the formula I in which A is O and R ^{1 is} H, methyl or COR ⁵ where R ⁵ is methyl, more preferably R ^{1 is} methyl or COCH 3, in particular R ^{1 is} methyl.

Preference is furthermore given to using alkylphospholipids of the general formula (Ia):

Formula Ia

in which

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.

Particular preference is given to using compounds of the formula I in which R ^{3 is} choline.

Particular preference is given to the pharmaceutical preparation comprising compounds of the general formula (Ib):

Formula Ib

in which

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.

Furthermore, particular preference is given to pharmaceutical preparations containing compounds of the formula (Ib) in which the remaining substituents A and R 1 have the following meanings and are designated according to these substituents as follows:

NH2:

OMe:

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.

Particular preference is given to pharmaceutical preparations 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 synthesis of the enantiomerically pure compounds of the formula (Ib) is described by Massing et al. in Chemistry, Physics of Lipids, 69, 105-120, 1994. The synthesis of the compounds of the formula (I) takes place by means of analogous processes known to the person skilled in the art.

Surprisingly, 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).

The pharmaceutical 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.

In addition, the groups of APL described as antitumoral, like lysolipids, 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

Albumin or bound to lipoprotein from tissue / cells. Thus, 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.

Thus, 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).

According to the invention, the pharmaceutical preparation may be present as a tablet, ointment, suppository, granule, injection preparation or aerosol. For this purpose, 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 crotonic acid, or polymers and copolymers of acrylates and methacrylates, for example copolymers of acrylic esters and methacrylates or ode Other solvents, emulsifiers or surfactants, such as polysorbate 80 or docusate. In addition to the auxiliaries and active ingredients mentioned, the composition according to the invention may additionally contain fillers, binders, lubricants and carriers which have no decisive influence on the release of active ingredient. Examples 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.

As further auxiliaries, preservatives, antioxidants, wetting agents, solubilizers, stabilizers, buffer substances and, if appropriate, flavorings and / or dyes must be taken into account.

Furthermore, other formulations are possible, as described, for example, in "Arzneiformenlehre", Ursula Schöffling, 4th ed., Deutscher Apotheker Verlag, Stuttgart 2003.

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.

(a) 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. On the other hand, the residence time of high CMC lipids in cellular systems is higher because they can not be rapidly removed from the membranes. Thus, in the development of drugs with lipidic drugs in particular pay attention to suitable biophysical properties.

(b) Another problem in the development of drugs with lipidic agents is that a direct application of the compounds described in all

Usually not possible. If they are lyso-lipid structures (low CMC), they are micellar-soluble. In IV injections, these compounds cause hemolytic effects. Upon oral administration, the rapid uptake of low CMC lipids by the cells of the gastrointestinal tract (GI) poses a problem that causes serious GI side effects. In principle, this is a local application of lipids in the gastrointestinal tract, which of course can also be used therapeutically. In the case of lecithin-like lipids (high CMC), iv administration (intravenously) is not possible because the compounds are in no way water-soluble and tend to form large aggregates (risk of thrombosis / embolism) and are biologically limited Are available. Oral application of lipids with high CMC is possible, but the lipids 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. (C) In order to ensure the best possible response of the respective active substance to certain diseases, 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).

These problems could be solved by the formulation of the compounds according to Fomel (I), (Ia) and (Ib) as well as (II), (IIa) and (IIb) as liposomes. 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. For the preparation of liposomes are 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.

It is also possible to use other lipids in which the problems described above in the application, selection of suitable lipids for specific indications and drug targeting are circumvented.

Thus, by incorporating the APL, 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. Furthermore, by introducing the APL according to formula (I), (Ia) and (Ib) and (II), (IIa) and (IIb) into so-called VPG (Vesicular Phospholipid Gels), their tumor targeting and an improved antitumoral action be achieved. In addition, by introducing the APL according to formulas (I), (Ia) and (Ib) as well as (II), (IIa) and (IIb) into liposomes with positive excess charge (net charge) their tumor endothelial cell targeting and thus an improved specific antitumoral Impact be achieved. Furthermore, by introducing the APL according to formula (I), (Ia) and (Ib) as well as (II), (IIa) and (IIb) into negative net charge liposomes (with or without stealth components) their tumor targeting and an improved antitumor effect can be achieved.

In a preferred embodiment of the present invention, in addition to the alkylphospholipids of the formula I, Ia or Ib, the pharmaceutical preparation contains further lipids.

Preferably, the pharmaceutical preparation provides a lipid mixture with neutral

Net charge. In another preferred embodiment, 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.

Particularly preferably, the pharmaceutical preparation contains a composition of the additional lipids, which is based on the lipid composition of the surfactant.

Here is meant the lung surfactant. This lipid composition is characterized (biophysically) by drastically reducing the surface tension of the water film in the lungs (aveoli). 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%. Typical features of the 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%).

The surfactant-like APL liposomes according to the invention contain (mol%):

(a) up to 20% APL, preferably 2-18%, 5-15%, more preferably 8 to 12%, especially 10%

(b) 40-90% saturated phosphatidylcholine (DPPC or hydrogenated egg / soy PC), preferably 50-60%, more preferably 70-80%

(c) 5-15% saturated phosphatidylglycerol (neg. charged phospholipid, preferably DPPG), preferably 8-12%, especially 10% (d) to 20% cholesterol,

(e) up to 30% non-hydrogenated egg or soy PC

(f) to 10% other phospholipids (PI, PE, PS)

(g) optionally, surfactant proteins (especially SP-B and SP-C) to natural concentration.

Furthermore, it is essential that the liposomes according to the invention do not contain sphingomyelin.

Preferably, the administration of the liposomes takes place as a micellar solution in buffer / medium as an isotonic mixture. In one variant, a phosphate-buffered isotonic saline solution is used for this purpose. Further, 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.

There is also the possibility of inhalation, i. the gift as an aerosol. This can be done with liposomes in an aqueous medium or by administering the (freeze) dried lipids. With a lipid composition that does not increase the surface tension several applications a day would be possible.

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:

In one study, the IC50 and LD50 values of various lysolipid-type APLs were expressed on HL-60 cells (leukemic) and on MDA-MB-468 cells

(Breast cancer) among themselves and compared with HePC. It turned out that the

IC50 and LD50 values of a particular APL, S-OC2, were significantly better than HePC in both cell lines. In addition, a specific effect of the compounds was shown

S-OH / R-OH on the metabolic activity especially in MDA cells. The metabolic activity of these mammary carcinoma cells was more inhibited by a factor of 3-9 than when using HePC and about 10 times more potent than in the leukemic HLA.

60 cells.

Example 2: Colony assays with solid human tumors:

In another study, the effect of different APL on various human tumors in the so-called colony assay was investigated. In this assay, cells of human tumor material are seeded into an agar layer where, when untreated, they form countable colonies. Antitumor agents can reduce the colony count. The effectiveness is mostly expressed in IC70 values. Of the Colony assay is to be located in terms of its prognostic properties between the pure cell culture experiment and the animal experiment. The test included various human, solid tumors (bladder, head-neck, 2 x lung, ovarian and renal cell carcinomas). It was found that some of the APL have significantly better antitumoral effects than HePC (mean IC70: 28 μM): S-OC2: 6.7 μM; S-NC2: 4.7 μM; R-NH2: 9.7 μM; S-NH 2: 4.3 μM; R-NC2: 7.3 μM and racOMe: 8.1 μM

In particular, it was found that the tumors did not react evenly to APL. Thus, KB (head-neck tumors) and a lung tumor were extremely sensitive to APL.

A comparison of the IC70 values of APL between the various tumor cells surprisingly revealed that certain APLs apparently kill highly selectively certain cells (i.e., the ratio of the highest and lowest IC70 values of a particular APL to the different tumors is greater than 100). 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.

In summary, these experiments suggest that APL with good to high antitumoral potency (low IC70 values) in combination with high selectivity may be candidates for successful treatment of certain tumors. Such compounds could be: racOMe, S-NH2; S-OC2, S-OH.

Example 3 Confirmation of the Discoveries In Vivo Described Above:

To verify the in vivo assay in vivo, the effect of racOMe and S-NC2 was compared to a human tumor xenograft on the nude mouse (tumor: APL-susceptible head-neck tumor "KB"), which was highly selective against KB tumors, but S-NC2 not (see above) The animals were treated with the two APL on day 1 and 8 (orally) at 100 mg / kg at this dose, no toxic effects were observed, which was the development of body weight The effect of racOMe with a reduction of tumor growth to 19.4% of control was evident. Example 4: Anti-angiogenic efficacy of APL

In the o.g. In vitro experiments with APL revealed that renal cell carcinoma cells had only an average sensitivity to APL. It was all the more surprising that in animal experiments with immunocompetent mice into which RencA renal cell tumor had been implanted, a significant decrease in the primary tumor weight to approximately 60% of the control in the treatment with racOMe (50 .mu.mol / kg / d, oral) was observed, and the number of metastases in the lung decreased to about 50% and in the lymph nodes to about 20% of the control. This suggests a surprising antiangiogenic effect, which could subsequently be confirmed by experiments on HUVEC cells: In an SRB assay with HUVEC cells, the growth inhibition under racOMe was compared with the growth inhibition under TNP470, a known and strong angiogenesis inhibitor , The IC50 value for racOMe was 0.5 μM, while the IC50 value of TNP470 was about 25-30 μM.

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. Surprisingly, the APLs tested were highly potent against two of the cell types (LNT-229 and LN18) with LD50 values of approximately <10 μM for LNT229 and <20 μM for LN-18. In the third cell type, LN-308, the effect was over 30 μM).

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.

Example 6: Preparation Protocol Liposomes

The APL and the lipids necessary for liposome formation (eg the lipid composition as described under "surfactant liposomes") 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.

Alternatively, the liposomes can also be prepared by high pressure homogenization or by the injection method.

Claims

Patentanprüche

1. Use of a pharmaceutical preparation containing at least one

Alkylphospholipid of the general formula (I)

Formula I

in which

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 and

R ^{3 is} choline, carbachol, serine, inositol, H, ethanolamine or glycerol,

for the treatment of solid tumors.

2. Use according to claim 1, characterized in that the pharmaceutical preparation contains at least one alkyl phospholipid of the general formula (Ia):

Formula Ia

wherein 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. Use according to one of claims 1 or 2, characterized in that the pharmaceutical preparation contains at least one alkyl phospholipid of the general formula (Ib):

Formula Ib

contains, where

4. Use according to any one of claims 1 to 3, characterized in that the alkyl phospholipid is the R enantiomer.

5. Use according to one of claims 1 to 3, characterized in that it is the S-enantiomer in the alkyl phospholipid.

6. Use according to one of claims 1 to 3, characterized in that it is a racemate in the alkylphospholipid.

Use according to one of Claims 1 to 6, characterized in that the pharmaceutical preparation contains, in addition to the alkylphospholipids of the formula I, Ia or Ib, further lipids.

8. Use according to claim 6, characterized in that the pharmaceutical preparation is a lipid mixture with neutral net charge.

9. Use according to claim 6, characterized in that the pharmaceutical preparation is a lipid mixture with a positive net charge. 10. Use according to claim 6, characterized in that the pharmaceutical preparation is a lipid mixture with negative net charge.

11. Use according to one of claims 6 to 10, characterized in that the composition of the additional lipids of the lipid composition of the surfactant is based.

12. Use according to one of claims 1 to 11, characterized in that the pharmaceutical preparation is present as a tablet, ointment, suppository, granules, injection preparation or aerosol.

13. Use according to one of claims 1 to 12, characterized in that the pharmaceutical preparation is present as a liposomal formulation.

14. Use according to one of claims 1 to 13 for the treatment of metastatic tumors.

15. Use according to one of claims 1 to 14 for the treatment of SCLC (small cell lung carcinoma) and / or nSCLC (non-small cell lung cancer) and / or lung cancer and / or bladder cancer and / or breast cancer and / or pancreatic cancer and / or brain tumors.

16. Alkylphospholipid (rac-OMe) of the formula (II):

Formula Il

17. Alkylphospholipid (R-OMe) of the formula (IIa):

Formula IIa

18. Alkylphospholipid (S-OMe) of the formula (IIb):

Formula IIb

19. Use of the alkylphospholipids according to formula (I), (Ia), (Ib), (II), (IIa) and / or (IIb) for the preparation of a pharmaceutical preparation for the therapy of solid tumors.

20. Use of the alkylphospholipids according to claim 19 for the treatment of metastatic tumors.

21. Pharmaceutical preparation containing alkylphospholipids of the formula (II), (IIa) and / or (IIb) according to claims 16 to 18.

22. Liposomes containing alkylphospholipids of the formula (I), (Ia) and (Ib) and (II), (IIa) and (IIb).

23. Liposomes according to claim 22 comprising (a) 0.1 to 20% of APL of the formula (I), (Ia) and (Ib) and (II), (IIa) and (IIb)

(more preferably up to 10%)

(b) 40-90% saturated phosphatidylcholine

(c) 5-15% saturated phosphatidylglycerol

(d) 0 to 20% cholesterol; (e) 0 to 30% unhydrogenated egg or soy PC

(T) 0 to 10% other phospholipids and (g) optionally surfactant proteins (especially SP-B and SP-C)

24. Liposomes according to claim 22 or 23, characterized in that they reduce the surface tension of the water film in the lungs (aveoli), preferably by 10%, 20%, 30%, 40%, 50%, particularly preferably by 60%, 70%. , 80%, especially around 85%, 90%, 95% or 99%. 25. Use of the liposomes according to claim 22, 23 or 24 for the treatment of tumors, in particular solid tumors.