DE102009006228A1 - Liposomal composition, useful to treat e.g. brain metastases, comprises liposomal vesicle, where the vesicles consist of a base lipid, a membrane stabilizer, a helper lipid and a charge carrier, and contain a cytostatic agent and a ligand - Google Patents

Abstract

Liposomal composition comprises liposomal vesicles, where the vesicles: consist of a base lipid, a membrane stabilizer, at least one helper lipid and a charge carrier; contain a highly effective cytostatic agent and a covalently bound ligand; and exhibits a diameter of 50-200 nm with a narrow size distribution. ACTIVITY : Cytostatic. No biological data given. MECHANISM OF ACTION : None given.

Description

The The invention relates to a liposomal composition for treatment of brain metastases in lung and breast cancer. application areas are the medicine and the pharmaceutical industry.

State of the art

• 1. Metastasis of primary tumors is despite all successes in the classical therapy and diagnostics still the biggest problem for a successful one Tumor therapy.

Especially problematic and with little chance of success is a therapy for tumors and metastases in the brain. While primary brain tumors (gliomas) have a relatively low incidence of 1-4% in adults, in particular, occur Bronchial (49%) and breast cancers (11%) very common brain metastases On top of that, they usually grow very aggressively [1].

• 2. Die Blut-Hirn-Schranke (BHS) ist eine der effektivsten Barrieren im Körper und sorgt auch unter kritischen Bedingungen dafür, dass im Gehirn ein stabiles physiologisches Milieu aufrechterhalten wird. Die physiologische Schranke soll die Zufuhr und Versorgung von Nährstoffen gewährleisten und das Eindringen von potentiellen Schadstoffen verhindern. Gleichzeitig blockiert sie jedoch auch einen effektiven Wirkstofftransport in das Gehirn, um Hirntumore und -metastasen zu therapieren, denn auch Zytostatika werden als toxische Fremdstoffe erkannt. Um einen therapeutischen Effekt zu erzielen, muss daher oft auf invasiv-operative Maßnahmen zurückgegriffen werden [2, 3] oder die BHS durch geeignete Techniken, wie Ultraschallbehandlung [4] oder hyperosmotische Zuckerbehandlung [5], temporär geöffnet werden.

So far, there are only a few ways to intervene therapeutically successful in a tumor or metastasis in the brain. Mostly surgical-invasive methods are used today, but they are only partially successful. Non-invasive therapeutic procedures are also used. However, the physiological activity of the blood-brain barrier impedes or prevents effective delivery of therapeutic agents into the brain. Thus, these systemic agents are only limitedly applicable for the treatment of brain metastases.

• 2. The Blood-Brain Barrier (BBB) is one of the most effective barriers in the body and, even under critical conditions, maintains a stable physiological environment in the brain. The physiological barrier is intended to ensure the supply and supply of nutrients and prevent the penetration of potential pollutants. At the same time, it also blocks effective drug delivery into the brain to treat brain tumors and metastases, as cytotoxic agents are also recognized as toxic foreign substances. In order to achieve a therapeutic effect, invasive surgical measures often have to be resorted to [2, 3] or the BBB should be temporarily opened by suitable techniques, such as ultrasound treatment [4] or hyperosmotic sugar treatment [5].

The special function of the BBB as an anatomical demarcation and transport barrier results from the metabolic and morphological features of the cerebral capillaries, which are evident in several ways different from peripheral capillaries.

in the Unlike cerebral capillaries, the endothelium possesses the peripheral Capillaries fenestrations or cellular fissures, which gives a nearly free Exchange of substrates between the blood and the extracellular Allow fluidity of the tissue [6].

• 3. Liposomen sind Lipidvesikel und bestehen aus einer oder mehreren konzentrisch angeordneten Lipiddoppelmembranen, die ein wässriges Kompartiment umschließen. Liposomen können über verschiedene Verfahren hergestellt werden, wodurch sich sowohl ihre Größe im Bereich von 40 nm (SUV – small unilamellar vesicles) bis 50 μm (MLV – multilamellar vesicles), als auch ein Teil der physiologischen Eigenschaften bestimmt.

The most important characteristic of the endothelial cells of the BBB are the very dense cell-cell contacts, the so-called tight junctions. They are part of a highly dynamic system that severely restricts the paracellular permeability of brain endothelial cells to larger molecules [7, 8]. Nevertheless, the BBB has a high metabolic activity, indicating that it not only functions as a physical barrier, but also exerts a metabolic or enzymatic barrier function. In the membrane of the brain capillaries are specific transporters (secretory export proteins, receptor and carrier systems) and metabolizing enzymes, which are responsible for the intracellular transport of many essential substances (amino acids, glucose and ions). Alternatively, gaseous or lipophilic substances such as oxygen, CO ₂ , alcohol or steroid hormones, and small, water-soluble molecules (peptides) can overcome BHS by cell migration or modulation of tight junctions.

• 3. Liposomes are lipid vesicles and consist of one or more concentrically arranged lipid double membranes enclosing an aqueous compartment. Liposomes can be produced by a variety of methods, ranging from 40 nm (small unilamellar vesicles) to 50 μm (MLV - multilamellar vesicles) as well as some physiological properties.

liposomes are excellent drug delivery vehicles that contribute to an improvement the pharmacokinetic and -dynamic properties of the active substances lead to therapeutic and analytical approaches. They have their effectiveness since the discovery before 40 Many times proven, compare z. B. Review article [9, 10]. The encapsulation disguises the active ingredients ("Trojan Horse ") and can have an active targeting using specific transport mechanisms into the brain become.

liposomes can be hydrophilic compounds in their aqueous Phase (core) and lipophilic compounds in integrate their lipid double membrane. Also a simultaneous inclusion two different in their solubility of active ingredients possible through a combination of both principles.

Presentation of the patent situation

There are already some property rights that the Claiming use of liposomal compositions for the transport of drugs through the blood-brain barrier. The developments formulated there are liposomes that have encapsulated drugs that are sterically stabilized and that realize an active targeting to overcome the BBB via ligands [P1-P5].

The Peptide angiopep-2 and other analogs of the aprotinin sequence are as a carrier for cytostatics to overcome the Blood-brain barrier and the therapy of various tumors or Metastases in the brain [P7] and as a carrier for transport secured in selected cell types [P8, P9]. The terms "liposome", "vesicle" or "nanoparticle" tau Do not get up, though.

In summary can be stated that so far still no convincing THL (Trojan Horse Liposomes) for intracerebral use were developed.

The The aim of the invention is to produce liposomes, the active substance transport via an active targeting system to and through the blood-brain barrier (BBB) and thus effectively to improve the treatment options of brain metastases to lead.

task The invention is the development of liposomes by the equipment selectively with the peptide angiopep-2 on the surface bind the LDL receptor of the endothelial cells of the blood-brain barrier. This is the transport of cytotoxic agents (Kanzerostatika like oxaliplatin or others) that are not otherwise from the endothelial cell be absorbed, or immediately discharged, effectively and the treatment of brain metastases and brain tumors and significantly improved. By an optimal composition The liposome membrane is said to facilitate cellular uptake Transcytosis is supported and by the packaging of the active ingredient in liposomes (Trojan Horse Liposomes = THL) at the same time the side effects be significantly reduced.

These The objective is achieved by the composition according to the invention according to the claims 1-21 and the use of these liposomes according to the claims 23-25 reached.

• – aus einem Basislipid, einem Membranstabilisator, einem oder mehreren Helferlipiden und einem Ladungsträger bestehen,
• – ein hochwirksames Cytostatikum enthalten,
• – einen kovalent gebunden Ligand und
• – einen Durchmesser von 50–200 nm bei einer engen Größenverteilung aufweisen.

This composition for the treatment of brain metastases contains liposomal vesicles, the

• Consist of a base lipid, a membrane stabilizer, one or more helper lipids and a charge carrier,
• - contain a highly effective cytostatic,
• A covalently bound ligand and
• Have a diameter of 50-200 nm with a narrow size distribution.

Further can also be used in addition a polyethylene conjugate which causes a steric stabilization, the one Elimination of vesicles from the bloodstream by the macrophage / monocyte system restricts or prevents.

• – als Basislipid Phosphatidylcholin (PC), Phosphoethanolamin (PE), Phosphatiylserin (PS) oder hydrierte Formen dieser Lipide,
• – als Membranstabilisator Sterole wie Cholesterol (CH), Sitosterol oder analoge Verbindungen,
• – als Helferlipide Dioleylphosphoethanolamin (DOPE), Palmitoyl-oleyl-phosphoethanolamin (POPE), Myristoyl-oleyl-phosphoethanolamin (MOPS), oder Steroyl-oleyl-phosphoethanolamin (SOPE), bzw. deren Enantiomere oder Racemate,
• – als zusätzliches zweites Helferlipid ein Alkylphospholipid wie Octadecyl-1,1-dimethylpiperidin-1-ium-4-ylphosphat (OPP), Hexadecyl-1,1-dimethylpiperidin-1-ium-4- ylphosphat (HPP), Octadecylphosphocholin (OPC), Hexadecyl-phosphocholin (HPC) Tetradecylphosphocholin (TPC) oder Dodekanyl-phosphocholin (DPC),
• – als Ladungsträger Dicetylphosphat (DCP), Phosphatidsäure (PA), Phosphatidylglycerol (PG) oder ein Salz des Dioctadecyl-dimethylamins,
• – als Polyethylenkonjugat wird bevorzugt Polyethylenglykol eingesetzt, welches an ein lipophiles Ankermolekül wie Phosphoethanolamin, Ceramid oder Cholesterol gebunden ist.

In detail, the compositions according to the invention contain

• As base lipid phosphatidylcholine (PC), phosphoethanolamine (PE), phosphatiylserine (PS) or hydrogenated forms of these lipids,
• - as membrane stabilizer sterols such as cholesterol (CH), sitosterol or analogous compounds,
• As helper lipids dioleoylphosphoethanolamine (DOPE), palmitoyl-oleyl-phosphoethanolamine (POPE), myristoyl-oleyl-phosphoethanolamine (MOPS), or steroyl-oleyl-phosphoethanolamine (SOPE), or their enantiomers or racemates,
• As additional second helper lipid an alkyl phospholipid such as octadecyl-1,1-dimethylpiperidin-1-ium-4-yl phosphate (OPP), hexadecyl-1,1-dimethylpiperidin-1-ium-4-yl phosphate (HPP), octadecylphosphocholine (OPC) , Hexadecyl-phosphocholine (HPC), tetradecylphosphocholine (TPC) or dodecanyl-phosphocholine (DPC),
• Dicetyl phosphate (DCP), phosphatidic acid (PA), phosphatidylglycerol (PG) or a salt of dioctadecyl-dimethylamine as charge carrier,
• Polyethylene glycol used as the polyethylene conjugate is preferably bound to a lipophilic anchor molecule such as phosphoethanolamine, ceramide or cholesterol.

Preference is given to polyethylene conjugates having a molecular weight of 500-5000 g / mol (PEG ₅₀₀ -PEG ₅₀₀₀ ). The use of phosphatidylinositol instead of the polyethylene conjugate for steric stabilization is also possible.

When Active ingredients are mitoxantrone, doxorubicin, perifosin, Miltefosine, carboplatin, erlotinib or other modern cancer drugs, preferred are mitoxantrone or carboplatin.

The Ligands are preferably peptides from the angiopeptide family with aprotinin sequence, such as angiopep-1, angiopep-2, angiopep-3, angiopep-4a, angiopep-4b, Angiopep-5 and angiopep-6, with angiopep 2 being particularly preferred becomes.

The ligand is chemically coupled to an anchor molecule and thus anchored to the liposomal surface. Polyethylene glycol phosphatidylethanolamine having a molecular weight of 500-3000 g / mol (PEG ₅₀₀ -PEG ₃₀₀₀ ), to whose free end the ligand is chemically coupled, can also be used as the anchor molecule. As a result, the circulation time is extended at the same time, without the target Effect is lost.

The molar proportions of the liposomal composition vary, preferred is a composition with the molar proportions Basic lipid: 20-80; Membrane stabilizer 20-60, Helper lipid DOPE: 10-40, carrier: 3-20 and ligand: 1-20. In addition, up to to 40 molar proportions of helper lipid alkylphospholipid and bis to 15 parts of steric stabilizer find use.

A concrete composition according to the invention from 10 μmol PC, 4 μmol CH, 4 μmol DOPE, 2 μmol DCP, 4 μmol OPP, 1 μmol Chol-Angiopep2 conjugate per ml batch and contains approx. 830-840 μg Mitoxantrone / ml encapsulated. Instead of DCP as charge carrier can it also contain 2 μmol of dioctadecyldimethylamine bromide (DDAB) contain. Another concrete composition according to the invention is characterized in that it consists of 14 .mu.mol PC, 6 .mu.mol CH, 4 μmol DOPE, 2 μmol DDAB, 4 μmol Chol-angiopep2 conjugate per ml batch and encapsulated mitoxantrone contains. Likewise, it can also be used instead of mitoxantrone contained as a cytostatic carboplatin encapsulated. The liposomal Composition preferably has a diameter of 50 to 200 nm, preferably, however, a diameter of about 100-200 nm. The liposomal composition according to the invention will be beneficial for the treatment of brain metastases and gliomas used. These are in particular metastases of breast cancer, Colon carcinomas, lung carcinomas, melanomas and other tumors, which metastasize to the brain. Gliomas can be an ependymoma, Be oligodendroglioma or astrocytoma.

• – Durch den Durchmesser von – 50–200 nm bei einer engen Größenverteilung wird erreicht, dass die Zirkulationszeit im Blut verlängert wird und eine aktive Aufnahme mit transendothelialem Transport unterstützt wird.
• – In den Liposomen ist ein hoch wirksames Zytostatikum verkapselt, das in das Hirn transportiert wird, um dort nach Anreicherung eine effektive therapeutische Wirkung gegenüber Metastasen und Hirntumore zu erreichen.
• – Die sterische Stabilisierung verringert eine Eliminierung der Vesikel aus dem Blutsystem durch Zellen des Monozyten/Phagozytensystems. Durch die Verwendung von Konjugaten, an dessen Ende der Ligand gebunden ist, wird der Schutzeffekt noch mit dem Targeteffekt kombiniert, wodurch eine Anreicherung an der Blut-Hirn-Schranke als Voraussetzung für deren Überwindung gefördert wird.
• – Die erfindungsgemäßen Liposomen haben eine hohe Lagerstabilität und weisen eine geringe bzw. keine Freisetzung des Wirkstoffes im Blut auf. Das ist notwendig, um den Wirkstoff in hoher Konzentration zur BHS zu bringen.
• – Der auf der Oberfläche kovalent gebunden Ligand ist verantwortlich für das aktive Targeting (zielgerichtete Bindung) an einen spezifischen Rezeptor auf der Oberfläche der Endothelzellmembran im Gehirn. Eine Anreicherung des Wirkstofftransporters an der BHS begünstigt den transendothelialen Transport und damit die Anreicherung des Wirkstoffes im Hirn.
• – Die Liposomen binden selektiv und mit hoher Affinität an die BHS, was eine Voraussetzung für eine hohe Aufnahmerate ist.
• – Die Liposomen weisen eine hohe Durchtrittsrate durch die Endothelzellmembran der BHS auf (hoher transendothelialer Transport), was eine Voraussetzung für eine hohe Wirkstoffkonzentration am Tumor oder den Metastasen im Gehirn darstellt;
• – Die THL sind im Tiermodell gut verträglich, verringern deutlich die durch das freie Kanzerostatikum verursachten Nebenwirkungen (wie z. Bsp. gastrointestinale Beschwerden; und Dehydrierung beim Mitoxantron) und haben eine hohe therapeutische Wirkung (gemessen an der Hemmung des Tumorwachstums).

The compositions according to the invention have the following advantageous properties.

• - The diameter of - 50-200 nm with a narrow size distribution ensures that the circulation time is extended in the blood and an active uptake with transendothelial transport is supported.
• - In the liposomes, a highly effective cytostatic agent is encapsulated, which is transported into the brain, there to achieve an effective therapeutic effect on metastases and brain tumors after enrichment.
• Steric stabilization reduces elimination of vesicles from the blood system by cells of the monocyte / phagocyte system. By using conjugates, at the end of which the ligand is bound, the protective effect is combined with the target effect, which promotes accumulation at the blood-brain barrier as a prerequisite for overcoming them.
• The liposomes according to the invention have a high storage stability and have little or no release of the active substance in the blood. This is necessary to bring the active ingredient in high concentration to the BBB.
• The ligand covalently bound on the surface is responsible for the active targeting to a specific receptor on the surface of the endothelial cell membrane in the brain. An accumulation of the drug carrier at the BBB promotes the transendothelial transport and thus the accumulation of the drug in the brain.
• - The liposomes bind selectively and with high affinity to the BBB, which is a prerequisite for a high rate of uptake.
• - The liposomes have a high rate of penetration through the endothelial cell membrane of the BBB (high transendothelial transport), which is a prerequisite for high drug concentration on the tumor or metastases in the brain;
• - The THL are well tolerated in the animal model, significantly reduce the side effects caused by the free Kanzerostatikum (such as gastrointestinal complaints, and dehydration in mitoxantrone) and have a high therapeutic effect (as measured by the inhibition of tumor growth).

The Invention is intended below by embodiments and Results will be explained in more detail.

example 1

Production of liposomes with mitoxantrone (MTO)

defined Volumes of stock solutions of the lipids to be used in Solvent mixtures of dichloromethane / methanol (7/3, v / v), are pipetted in a round bottom flask so that the solution 150 μmol PC, 60 μmol CH, 60 μmol DOPE, 60 μmol OPP and 30 μmol DCP and 15 μmol Contains Chol-Angiopep2 conjugate. Subsequently the solvent is evaporated on a vacuum rotary evaporator, to get a lipid film. This will be followed by this in a high vacuum on the oil pump for at least during One hour last solvent residues removed. By Addition of 15 ml of ammonium citrate buffer (300 mM, pH 7.4) becomes Lipids with heating in an aqueous phase resuspended and there are obtained multilamellar vesicles Finally, shake for 12 hours.

in the next step will be from these MLVs through repeated Extrusion through polycarbonate filters with defined pore sizes of 400 nm and 200 nm small vesicles with a diameter of 100-200 nm produced. These vesicles then have a polydispersity index from below 0.25.

Of the Buffer is then purified by size exclusion chromatography exchanged with Sephadex G50 for PBS buffer (pH 7.4). It will the liposome concentration reduced by about a factor of 1.4.

To Warm the liposome solution to 60 ° C is used to encapsulate the MTO 10 ml of drug solution Concentration 2 mg / ml added to 10 ml liposome suspension, the mixture vortex and then for 30 minutes on the water at 60 ° C, with the solution in between always shaken again.

Finally is unencapsulated MTO by dialysis in the dialysis tube (cut-off Limit MWCO: 6-8,000), in which the buffer after each 1-2 hours is exchanged. This cycle will be 6 times repeated.

By this method gives you 20 ml liposome suspension, the have a total lipid content of 8.63 μmol / ml and Encapsulated 844 μg MTO / ml solution (84.4% encapsulation rate). The vesicles have a mean diameter of 139.7 nm, and the suspension has a polydispersity index of 0.20, which is a monodisperse distribution of vesicle size in the suspension corresponds.

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patents:

• P1 Collins, FD, Thomson R.C., Yarus M.J: Method of transporting compositions across the blood brain barrier. US 2025907 from 21.9.1990.
• P2 Micklus MJ, Greig NH, Rapaport SI: Targeting liposomes to the blood brain barrier. US 2141216 from 07/23/1993 ,
• P3 Pardridge, WM, Huwyler J: Transport of liposomes across the blood-brain barrier. US 9721352 from 20.11.1997 ,
• P4 Micklus MJ, Greig NH, Rapaport SI: Targeting liposomes to the blood-brain barrier. US 9306942 from 3.2.1994.
• P5 Collins, FD, Thomson R. C, Yarus M. J: Method of transporting compositions across the blood brain barrier. US 9005349 from 21.9.1990.
• P6 Chief T, Shan P, Fu J: Method for preparing brain targeting liposomes pharmaceutical. Canada 200310105969 from 27.11.2003.
• P7 Beliveau et al, Aprotinin and anglos as carriers across the blood brain barrier. WO 2004/060403 A3 from 22.7.2004.
• P8 Beliveau et al., Use of aprotinin polypeptides as carriers in pharmaceutical conjugates WO 2007/009229 A1 from 25.1.2007.
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QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• US 2025907 [0031]
• - US 2141216 [0031]
• US 2371993 [0031]
• US 9721352 [0031]
• US 20111997 [0031]
• - US 9306942 [0031]
• - US 9005349 [0031]
• WO 2004/060403 [0031]
• WO 2007/009229 A1 [0031]
• WO 2008/144919 A1 [0031]

Claims (25)

Liposomal composition for the treatment of Brain metastases containing liposomal vesicles, the - out a base lipid, a membrane stabilizer, one or more Helper lipids and a charge carrier, - one contain highly effective cytostatic, - a covalent bound ligand and - a diameter of 50-200 nm at a narrow size distribution. Liposomal composition according to claim 1 by the additional use of a polyethylene conjugate for steric stabilization. Liposomal composition according to claims 1 and 2, characterized in that as base lipid phosphatidylcholine (PC), Phosphoethanolamine (PE), Phosphate Advently Serine (PS) or their hydrogenated Shapes are used. Liposomal composition according to claims 1-3, characterized in that as membrane stabilizer sterols such as Cholesterol, sitosterol or analogous compounds are used. Liposomal composition according to claims 1-4, characterized in that as assistant lipids Dioleylphosphoethanolamin (DOPE), palmitoyl-oleylphosphoethanolamine (POPE), myristoyl-oleyl-phosphoethanolamine (MOPS), or steroyl-oleyl-phosphoethanolamine (SOPE), or their enantiomers or racemates. Liposomal composition according to claims 1-5, characterized in that as additional second helper lipid an alkyl phospholipid such as octadecyl-1,1-dimethylpiperidin-1-ium-4-yl phosphate (OFF), hexadecyl-1,1-dimethylpiperidin-1-ium-4-yl phosphate (HPP), Octadecylphosphocholine (OPC), hexadecylphosphocholine (HPC) tetradecylphosphocholine (TPC) or dodecanyl-phosphocholine (DPC) is used. Liposomal composition according to claims 1-6, characterized in that as charge carrier dicetyl phosphate (DCP), phosphatidic acid (PA), phosphatidylglycerol (PG) or a salt of dioctadecyl-dimethylamine is used. Liposomal composition according to claim 2, characterized characterized in that polyethylene glycol is used, which to a lipophilic anchor molecule such as phosphatidylethanolamine, Ceramide or cholesterol is bound. Liposomal composition according to claim 8, characterized by the use of polyethylene conjugates having a molecular weight of 500-5000 g / mol (PEG ₅₀₀ -PEG ₅₀₀₀ ). Liposomal composition according to claims 1-7, characterized in that phosphatidylinositol instead of the polyethylene conjugate is used for steric stabilization. Liposomal composition after all preceded Claims, characterized in that it contains mitoxantrone, Doxorubicin, perifosine, miltefosine, carboplatin, erlotinib or Contains other modern cancer remedies. Liposomal composition according to claim 10 in that it contains carboplatin. Liposomal composition according to claims 1-12, characterized in that the ligand is a peptide having aprotinin sequence is used. Liposomal composition according to claim 13 in that this ligand is Angiopep 2. A liposomal composition according to claims 1, 13 and 14, characterized in that the ligand is chemically attached to an anchor molecule is coupled and thus anchored to the liposomal surface becomes. Liposomal composition according to claims 1-14, characterized by a composition with the molar proportions Basic lipid: 20-80; Membrane stabilizer: 20-60, Helper lipid DOPE: 10-40, carrier: 3-20 and ligand: 1-20. Liposomal composition according to claim 16 by the additional use of up to 40 molars Proportions of assistant lipid alkyl phospholipid and up to 15 parts steric Stabilizer. Liposomal composition, characterized from 10 μmol PC, 4 μmol CH, 4 μmol DOPE, 2 μmol DCP, 4 μmol OPP, 4 μmol Chol-Angiopep2 per ml batch and about 830-840 μg mitoxantrone / ml encapsulated contains. Liposomal composition according to claim 18, characterized characterized in that instead of DCP as a charge carrier 2 .mu.mol Dioctadecyl-dimethylamine bromide (DDAB). Liposomal composition, characterized in that it consists of 14 μmol PC, 6 μmol CH, 4 μmol DOPE, 2 μmol DDAB, 4 μmol Chol-Angiopep2 per ml batch and contains encapsulated mitoxantrone. Liposomal composition according to claims 18-20, characterized in that instead of mitoxantrone as a cytostatic Contains carboplatin encapsulated. Liposomal composition according to claims 1-21, characterized by a diameter of 50 to 200 nm, preferably however, with a diameter of about 100-200 nm. Use of the liposomal composition for treatment of brain metastases and gliomas. Use of the liposomal composition according to Claim 23 for the treatment of metastases of breast cancer, colon carcinomas, Lung carcinomas, melanomas and other tumors that metastasize to the brain. Use of the liposomes of claim 23, wherein Glioma can be an ependymoma, oligodendroglioma or astrocytoma.