EA041894B1 - LIPOSOMAL PHARMACEUTICAL COMPOSITION FOR USE FOR THE TREATMENT OF MALIGNANT NEOPLASMS - Google Patents

Description

Prerequisites for the creation of the invention

The invention relates to a pharmaceutical liposomal composition containing 2-{[5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2 ,3Hpyrimidin-4yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, referred to in the present invention as Compound A, or a pharmaceutically acceptable salt thereof. More specifically, the invention relates to a liposome carrier, an organic concentrate composition for the manufacture of a pharmaceutical composition containing Compound A, and a parenteral pharmaceutical composition containing liposomes and Compound A. The invention further relates to the use of such compositions for the treatment of cancer. compound A in the context of the present invention includes all of its enantiomers, diastereoisomers and atropisomers, or mixtures thereof, and optionally includes its pharmaceutically acceptable salts.

The structure of compound A is

2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3d]pyrimidine-4 -yl]oxu}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.

In a preferred embodiment of the invention, compound A is

(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl) thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid. In another embodiment of the invention, the compound A used in the composition described in the present invention is a free molecule (not its salt).

The preparation of Compound A, its use as a Mcl-1 inhibitor for the treatment of cancer, and its pharmaceutical formulations are described in WO 2015/097123, the contents of which are incorporated by reference. The preparation is in particular described in example 30 in WO 2015/097123.

Compound A is optically active, has one chiral center and a chiral axis. It has limited aqueous solubility for all pH values, including physiologically relevant pH values. To ensure safe and effective administration of Compound A, and to obtain the desired therapeutic effects, Compound A must be solubilized.

There are various ways to solubilize poorly soluble compounds for parenteral administration. Typical approaches are pH optimization or the use of a co-solvent (eg PEG300, PEG400, propylene glycol or ethanol). If these approaches, for whatever reason, are not feasible, then the use of surfactants (eg Tween® 80 or Cremophor EL®) may be considered. However, these types of surfactants are often associated with side effects. Cyclodextrins have shown themselves to be safe solubilizing agents, but with

- 1 041894 restrictions that they are not effective solubilizers for all compounds. In addition, compounds with high solubility in natural oils (eg Propofol) can be solubilized in parenteral fat emulsions.

Another possibility for the solubilization of poorly soluble compounds is the use of phospholipids (van Hoogevest P., Xiangli L., and Alfred F. Drug delivery strategies for poorly water-soluble drugs: the industrial perspective Expert Opinion on Drug Delivery 2011, 8(11), 1481- 1500). Thus, phospholipids themselves represent one of the additional means for the solubilization of poorly soluble compounds, in addition to the usual approaches. However, the solubilization of a particular poorly soluble compound by phospholipids cannot be predicted.

It is an object of the present invention to provide a composition that can be successfully used for the solubilization and parenteral delivery of Compound A. In particular, there is a need to provide a safe and effective pharmaceutical composition for Compound A. Other objectives are to provide a composition that is stable under relevant conditions and containers, and which makes it possible to administer a suitable dose of Compound A within reasonable time frames. According to another object, the composition must be able to be prepared in a reliable and functional manner.

The essence of the invention

The present invention provides a pharmaceutical liposomal composition containing Compound A suitable for parenteral administration to patients. In particular, such administration is by intravenous injection or infusion. The invention further provides two separate compositions that can be mixed together shortly before administration to a patient to provide a composition suitable for administration. One of the mixing compositions is an organic concentrate composition containing Compound A, and the second mixing composition is a liposomal carrier. When two separate compositions are mixed together, Compound A is loaded onto liposomes in a liposomal vehicle allowing Compound A to be solubilized, resulting in a pharmaceutical liposomal composition suitable for clinical use.

Preferably, the invention provides a composition containing Compound A that maintains the chemical stability of Compound A. For example, the formation of undesirable atropisomer and/or oxidation products and/or degradation products is limited.

Preferably, the invention provides a composition containing Compound A that has optimum chemical stability, eg gel formation is avoided and/or precipitation of the components is avoided. Surprisingly, compositions containing Compound A have been found to be resistant to gelling, in which the composition forms a gel. Such gelation may be reversible or irreversible. Gelation complicates or interferes with the manipulation of the composition containing Compound A for its intended use and should be avoided.

An organic concentrate composition intended for the manufacture of a pharmaceutical composition containing Compound A should allow Compound A to be loaded efficiently and optimally into liposomes in a liposomal vehicle by simply mixing the 2 compositions together shortly before administration to a patient.

Preferably, the invention provides a pharmaceutical liposomal composition which allows rapid release of Compound A from liposomes after intravenous administration.

Thus, the invention disclosed in the present invention allows effective administration of Compound A to patients despite the complex chemical characteristics of Compound A and the complex physical characteristics of formulations containing Compound A.

Brief description of the figures

In FIG. 1 shows the efficacy and tolerability of liposomal formulated Compound A after once weekly administration at a dose of 10 mg/kg to female nude rats bearing MV4;11 AML xenografts.

In FIG. 2 shows the efficacy and tolerability of liposomal formulated Compound A after once weekly administration at a dose of 30 mg/kg to female nude rats bearing MV4;11 AML xenografts.

In FIG. 3 is a schematic representation of the principles of an MLV-based release assay that provides the ability to monitor the release of Compound A from liposomes in MLV.

In FIG. 4 shows the release profile of compound A from SUV in 100% ePL (egg phospholipids) at a variety of different SUV:MLV ratios (v/v).

Detailed description of the invention

A liposome is a spherical vesicle having at least one lipid bilayer. The liposome can be used as a carrier for the delivery of nutrients and drugs. Liposomes are most often composed of phospholipids, in particular phosphatidylcholine, but may also include other lipids such as egg phosphatidylethanolamine, provided they are compatible with the lipid bilayer structure.

'Liposomal carrier' in the context of the present invention means a liquid containing liposomes, said liposomes containing phospholipids. Said liposomal carrier is suitable for solubilizing Compound A in an aqueous environment after mixing with Compound A, especially if Compound A is provided as an organic concentrate as described in the present invention. Said liposome carrier is suitable for loading with Compound A prior to administration to a patient.

Liposomal size, as disclosed in the present invention, refers to the size, as determined using photon correlation spectroscopy (PCS). The mean size, expressed as mean diameter Z and polydispersity coefficient, is determined using photon correlation spectroscopy in accordance with ISO 13321.

The pharmaceutical composition described in the present invention, in particular, is a pharmaceutical liposomal composition. Pharmaceutical liposomal composition means a composition containing liposomes that are suitable for pharmaceutical administration.

Gelation, in the context of the present invention, means the formation of a gel. As the gel forms, the composition becomes more viscous, less free-flowing. This greatly complicates or makes it impossible to process the composition for its intended purpose.

The phospholipid used in the liposomal carrier in the present invention contains at least one phospholipid of the formula

Where

R ₁ is C ₁₀ -C ₂₄ acyl;

R ₂ is C ₁₀ -C ₂₄ acyl, or alternatively R 2 is hydrogen or C ₁ o C ₂₀ acyl;

R ₃ is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C ₁ -C ₄ alkyl, C ₁ -C ₅ alkyl substituted with carboxy, C ₂ -C ₅ alkyl substituted with carboxy and hydroxy , C ₂ -C ₅ alkyl substituted with carboxy and amino, inositol group or glyceryl group;

or a salt of such a compound.

The term acyl previously used in the present invention is the following group:

ABOUT

where * represents the point of attachment of R ₁ or R 2 to the rest of the molecule, and, for example, R is a straight chain alkyl chain, which may be saturated or partially saturated.

The phospholipid may be neutral or may be charged. It can be double-stranded or single-stranded amphiphilic. Examples of neutral double chain phospholipids are phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin. Examples of charged phospholipids are phosphatidic acid (PA), phosphatidylinositol (PI), and phosphatidylserine (PS) and phosphatidylglycerol (PG). The hydrocarbon chain may be either unsaturated or saturated. In one embodiment, it has 14 to 18 carbon atoms.

For parenteral preparations, the phospholipid may be double-chain and may contain a fraction of less than 20% single-chain amphiphilic. For parenteral preparations, the phospholipid may be phosphatidylcholine (PC) and may contain a fraction of less than 40% charged phospholipid.

The single chain lipid may be a monoacyl derivative of a neutral or charged phospholipid, but it may also be a monoacyl derivative(s) of glycolipids and sphingolipids. However, for parenteral use, the monoacyl derivative is not preferred. Deacylation can be carried out by enzymatic hydrolysis with phospholipase A2 or by chemical means. The hydrocarbon chain may be either unsaturated or saturated and may especially have 14 to 18 or 14 to 24 carbon atoms. The lipids may be derived from natural plant or animal or microbiological sources, synthesized or partially synthesized, including polyethylene glycol (PEG) derivatives, monoacyl phospholipids, for example, pegylated monoacyl phosphatidyl ethanolamine.

In a preferred embodiment, R2 is not hydrogen.

In particular, the phospholipid used in the liposomal carrier described in the present invention is selected from egg lecithin, soy lecithin or synthetic phospholipids. Examples of synthetic phospholipids for use in the present invention are POPC (palmitoyl oleoyl phosphatidylcholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), DMPC (1,2 dimyristoyl-sn-glycero-3-phosphocholine), and DPPC ( 1,2-dipalmitoyl-sn-glycero-3-phosphocholine), in particular the synthetic phospholipids POPC (palmitoyl oleoyl phosphatidylcholine), DOPC (1,2-dioleoylsn-glycero-3-phosphocholine), and DMPC (1,2-dimyristoyl- sn-glycero-3-phosphocholine), especially POPC. More preferably, the phospholipid used in the liposomal vehicle is selected from egg lecithin or soy lecithin containing at least 75% phosphatidylcholine or at least 70% phosphatidylcholine. In another embodiment, you can use egg lecithin with 71.5% wt./wt. (±7.5% wt./wt.) egg PC (phosphatidylcholine) and 15% wt./wt. (±3% w/w) egg PE (phosphatidylethanolamine). In a preferred embodiment, said phospholipid is selected from Lipoid E 80 S and Lipoid E 80. In a preferred embodiment, said phospholipid is Lipoid E 80 S. If E 80 is used, then sodium oleate is optionally included in the preparation as a colloidal stability stabilizer .

In preferred embodiments of the invention, the phospholipids are chosen so as to facilitate more rapid release of Compound A into the circulation.

Organic concentrate in the context of the present invention means a composition which is a solution containing an organic, water-miscible solvent containing compound A, which is suitable for mixing with a liposomal carrier to allow loading into liposomes. In particular, said organic concentrate is suitable for mixing with and loading with a liposome carrier as described in the present invention. The resulting mixture is suitable for administration to a patient.

Loading refers to the incorporation or transfer of Compound A into liposomes from the organic concentrate.

Negatively charged or polar phospholipid stabilizer means a phospholipid containing at least some negatively charged lipid or polar lipid. In particular, the negatively charged or polar phospholipid stabilizer is selected from sodium or ammonium salt of DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol or dimyristoyl phosphatidylglycerol), sodium salt of POPG (1-palmitoyl-2-oleoyl -sn-glycero-3[phospho-rac-(1glycerol)]), DOPS sodium salt (1,2-dioleoyl-sn-glycero-3-phosphoserine), DOPG sodium salt (1,2dioleoyl-sn-glycero-3[ phospho-rac-(1-glycerol)]), sodium or ammonium salt of DPPG (1,2diπpalmitoyl-sn-glycero-3[phospho-rac-(1-glycerol)]), sodium or ammonium salt of DSPG (1,2distearoyl- sn-glycero-3[phospho-rac-(1-glycerol)]), soya phosphatidic acid sodium (PA), egg phosphatidic acid sodium (PA), soya phosphatidylserine sodium (PS), egg phosphatidylglycerol sodium (PG ), sodium salt of soy phosphatidylglycerol (PG), sodium salt of phosphatidylinositol (PI), Lipoid S 75, Lipoid E 80 S and sodium oleate. In particular, the negatively charged or polar phospholipid stabilizer is 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol, sodium or ammonium salt, or Lipoid E 80 S, preferably 1,2-dimyristoyl-sn-glycero-3 -phospho-rac-glycerol, sodium salt. Said negatively charged or polar phospholipid stabilizer facilitates the loading of Compound A into liposomes.

The negatively charged or polar phospholipid stabilizer may be egg lecithin or soy lecithin.

Tonicity correcting agent refers to a pharmaceutically acceptable compound that can be added to a formulation to make it isotonic with human plasma. Tonicity correcting agents include, for example, dextrose, glucose, mannitol, sucrose, lactose, trehalose, glycerol and NaCl, especially sucrose or glycerol, more preferably sucrose. Tonicity is the effective osmolality and is equal to the sum of the concentrations of solutes that have the ability to exhibit an osmotic potential within the membrane. Parenteral preparations must be isotonic with blood plasma. Tonicity correcting agents are well known to those skilled in the art.

A suitable diluent may be selected by a skilled formulation worker. In the organic concentrate of the present invention, the solvent or solvents may be selected from propylene glycol, ethanol, PEG300, Super-Refined® PEG300, PEG400 and Super-Refined® PEG400, especially propylene glycol and ethanol.

Super-Refined® refers to ultra-pure PEG300 or PEG400.

- 4 041894

A buffer is used to prevent changes in the pH of the solution, and suitable examples are well known to the skilled formulator.

Container means an ampoule or vial with a rubber stopper and a cap, a single or dual chamber syringe, an infusion bag, or a vessel made of polymeric materials or glass suitable for containing compositions for parenteral administration. It also includes any vessel for holding liquids.

Free molecule in the context of the present invention means a compound that is not used in the form of a salt formed by external counterions. Compound A may be present in zwitterionic form, and the term 'free molecule' in the context of the present invention includes the zwitterionic form.

In the context of the present invention, the term containing means including and is not intended to exclude the presence of any additional component, unless the context implies otherwise, for example, when the components together add up to 100%.

In the context of the present invention, the term to treat, treat, or treat any disease or disorder refers, in one embodiment, to alleviating the disease or disorder (i.e., slowing or stopping or lessening the development of the disease or at least one of its clinical symptoms). In another embodiment, treating, treating, or therapy refers to alleviating or improving at least one physical parameter, including those that may not yet be felt by the patient. In yet another embodiment, treating, treating, or therapy refers to modulating a disease or disorder, either physically (eg, stabilizing a recognizable symptom), physiologically (eg, stabilizing a physical parameter), or both.

An anti-gel stabilizer in the context of the present invention means an anti-gel stabilizer of a composition containing Compound A. This definition of stabilizers includes, for example, electrolytes or polymers. Examples of suitable electrolytes are sodium chloride, potassium chloride, dibasic and monobasic sodium phosphate, ammonium sulfate and arginine, preferably sodium chloride. If necessary, water with electrolyte can be added to the preparation. Examples of suitable polymers are PEG300 and PEG400, in particular PEG300. Gel stability can be tested using techniques well known to those skilled in the art, and in particular the techniques described in the present invention can be used. Example 12 of the present invention provides methods that can be used to test gelation. Once the gelation propensity of a selected composition is understood, the skilled person in the art of formulating can use the information to select the optimal storage conditions for compositions containing Compound A.

In one optional embodiment, the PEG300 is Super-Refined® PEG300, which is an ultra-pure PEG300.

In one preferred embodiment, a stabilizer is selected which prevents the composition containing Compound A from gelling and which also reduces or prevents the components of the composition containing Compound A from settling. For example, PEG300 is of particular interest in this regard. In one optional embodiment, the PEG300 is Super-Refined® PEG300, and which can also maintain Compound A's chemical stability.

Mixing shortly before administration to a patient means up to three days prior to administration, in particular up to 24 hours prior to administration, and for example up to 6 hours prior to administration to a patient.

Tistidine, in the context of the present invention, means in particular L-histidine.

Advantageously, in certain embodiments of the invention, due to the very small particle size of the liposomes, the preparation is transparent, which allows visual control of the complete dissolution of compound A before administration. In a preferred embodiment of the invention, the composition is administered to patients intravenously.

Embodiments of the invention

Various embodiments of the invention E1-E61 are described below.

E1. Composition of an organic concentrate intended for the manufacture of a pharmaceutical composition, containing:

a) compound A, which is 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2 ,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)-propanoic acid or a pharmaceutically acceptable salt thereof,

b) a negatively charged or polar phospholipid stabilizer, where this negatively charged or polar phospholipid stabilizer is selected from sodium or ammonium salt of DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol or dimyristoyl phosphatidylglycerol), sodium salt of POPG (1-palmitoyl-2-oleoyl-sn-glycero-3[phospho-rac-(1-glycerol)]), DOPS sodium salt (1,2-dioleoyl-sn-glycero-3-phosphoserine), DOPG sodium salt ( 1,2-dioleoyl-sn-glycero-

- 5 041894

3[phospho-rac-(1-glycerol)]), sodium or ammonium salt of DPPG (1,2-dipalmitoyl-sn-glycero3[phospho-rac-(1-glycerol)]), sodium or ammonium salt of DSPG (1, 2-distearoyl-sn-glycero-3[phosphorac-(1-glycerol)]), soya phosphatidic acid sodium (PA), egg phosphatidic acid sodium (PA), soya phosphatidylserine sodium (PS), egg phosphatidylglycerol sodium (PG), soy phosphatidylglycerol sodium (PG), phosphatidylinositol sodium (PI), Lipoid E 80 S and sodium oleate, and

c) an anti-gel stabilizer, wherein the anti-gel stabilizer is a polymer selected from PEG300 and PEG400 or an electrolyte selected from sodium chloride.

E2. Organic concentrate composition according to embodiment E1 containing compound A, which is (2R)-2-{[(5S _α )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazine -1 -yl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy} -3 -(2-{[2-(2methoxyphenyl)-pyrimidin-4 -yl]methoxy}phenyl)propanoic acid or a pharmaceutically acceptable salt thereof and a negatively charged or polar phospholipid stabilizer.

E3. An organic concentrate composition according to embodiments E1 or E2, wherein Compound A is a free molecule.

E4. An organic concentrate composition according to any one of embodiments E1-E3, wherein the negatively charged or polar phospholipid stabilizer is 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol, sodium or ammonium salt, egg lecithin, such such as Lipoid E 80 S, soy lecithin such as Lipoid S 75, preferably 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol, sodium salt.

E5. The organic concentrate composition according to any one of embodiments E1-E4, wherein the anti-gelling stabilizer is sodium chloride.

E6. An organic concentrate composition according to any one of embodiments E1-E5, wherein the anti-gelling stabilizer is PEG300.

E7. An organic concentrate composition according to any one of embodiments E1-E6 further comprising one or more solvents.

E8. An organic concentrate composition according to any one of embodiments E1-E7 further comprising a solvent selected from propylene glycol and ethanol.

E9. An organic concentrate composition according to any one of embodiments E1-E8 containing both propylene glycol and ethanol.

E10. An organic concentrate composition according to any one of embodiments E1-E9 further comprising water.

E11. A pharmaceutical composition obtained by mixing an organic concentrate composition according to any one of embodiments E1-E10 and a liposomal carrier, wherein said liposomal carrier contains a phospholipid and a tonicity correcting agent selected from dextrose, glucose, mannitol, sucrose, lactose, trehalose, glycerol and NaCl.

E12. Pharmaceutical composition in accordance with embodiment E11, containing from 5% wt./wt. up to 20% w/w phospholipid, in particular from 7% wt./wt. up to 13% w/w phospholipid.

E13. The pharmaceutical composition according to embodiments E11 or E12, wherein the phospholipid is selected from egg lecithin, soy lecithin, or synthetic phospholipids.

E14. A pharmaceutical composition according to any one of embodiments E11-E13, wherein the phospholipid is represented by the formula:

Where

R1 is C ₁₀ -C ₂₄ acyl;

R2 is C ₁₀ -C ₂₄ acyl, or alternatively R2 is hydrogen or C ₁₀ C ₂₀ acyl;

R3 is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C1- _C4 alkyl,

C ₁ -C ₅ alkyl substituted with carboxy, C ₂ -C ₅ alkyl substituted with carboxy and hydroxy, C ₂ -C ₅ alkyl substituted with carboxy and amino, inositol group or glyceryl group;

or a salt of such a compound.

E15. A pharmaceutical composition according to any one of embodiments E11-E14, wherein the phospholipid is selected from egg lecithin, soy lecithin, POPC (palmitoyl oleoyl phosphatidylcholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and DMPC (1 ,2-dimyristoyl-sn-glycero-3phosphocholine), preferably POPC (palmitoyl oleoyl phosphatidylcholine), DOPC (1,2-dioleoyl-sn-

- 6 041894 glycero-3-phosphocholine) and DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine), particularly preferably POPC.

E16. A pharmaceutical composition according to any one of embodiments E11, E13 or E15, wherein the phospholipid is selected from egg lecithin or soy lecithin containing at least 75% phosphatidylcholine, or at least 70% phosphatidylcholine.

E17. The pharmaceutical composition according to any of the embodiments E11, E13, E15 or E16, wherein the phospholipid is Lipoid E 80 S.

E18. The pharmaceutical composition according to any one of embodiments E11-E17, wherein the tonicity correcting agent is sucrose or glycerol, especially sucrose.

E19. The pharmaceutical composition according to any of the embodiments E11-E18 further comprising a buffer.

E20. Pharmaceutical composition according to embodiment E19, wherein the buffer is histidine.

E21. A pharmaceutical composition according to any one of embodiments E11-E20 further comprising water.

E22. A pharmaceutical composition according to any one of embodiments E11-E21, wherein the liposomes present in the liposomal carrier have an average size of 20 nm to 300 nm, preferably 20 nm to 100 nm.

E23. Pharmaceutical composition according to embodiment E22, wherein the liposomes have an average size of 20 nm to 80 nm, preferably 40 nm to 70 nm.

E24. Pharmaceutical composition containing liposomes and additionally:

a) compound A, which is 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2 ,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)propanoic acid or a pharmaceutically acceptable salt thereof; And

b) an anti-gel stabilizer which is a polymer selected from PEG300 and PEG400 or an electrolyte selected from sodium chloride.

E25. The pharmaceutical composition according to embodiment E24, wherein Compound A is (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazine-1- yl)ethoxy]phenyl}6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy} -phenyl)propanoic acid or a salt thereof, preferably the free molecule.

E26. Pharmaceutical composition according to embodiment E24 or E25 for infusion or intravenous injection.

E27. Pharmaceutical composition in accordance with any of the embodiments of E24-E26, containing from 5% wt./wt. up to 20% w/w phospholipid, in particular from 7% wt./wt. up to 13% w/w phospholipid.

E28. A pharmaceutical composition according to any one of embodiments E24-E27 comprising a phospholipid selected from egg lecithin, soy lecithin, or synthetic phospholipids.

E29. The pharmaceutical composition according to any one of embodiments E24-E28, wherein the phospholipid is represented by the formula

Where

R ₁ is C ₁₀ -C ₂₄ acyl;

R ₂ is C ₁₀ -C ₂₄ acyl;

R ₃ is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C1- _C4 alkyl, _C1 - _C5 αkyl substituted with carboxy, _C2 - _C5 alkyl substituted with carboxy and hydroxy, C ₂ -C ₅ alkyl substituted with carboxy and amino, inositol group or glyceryl group;

or a salt of such a compound.

E30. A pharmaceutical composition according to any one of embodiments E24-E29 further comprising a negatively charged or polar phospholipid stabilizer.

E31. Pharmaceutical composition according to embodiment E30, wherein the negatively charged or polar phospholipid stabilizer is selected from sodium or ammonium salt of DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol or dimyristoyl phosphatidylglycerol), sodium salt of POPG ( 1-palmitoyl-2-oleoyl-sn-glycero-3[phospho-rac-(1-glycerol)]), DOPS sodium salt (1,2-dioleoyl-sn-glycero-3-phosphoserine), DOPG sodium salt (1 ,2-dioleoyl-sn

- 7 041894 glycero-3[phospho-rac-(1-glycerol)]), sodium or ammonium salt of DPPG (1,2-dunalmutoul-snglycero-3[phospho-rac-(1-glycerol)]), sodium or ammonium DSPG salts (1,2-distearoyl-sn-glycero3[phospho-rac-(1-glycerol)]), soy phosphatidic acid sodium salt (PA), egg phosphatidic acid sodium salt (PA), soy phosphatidylserine sodium salt (PS) , egg phosphatidylglycerol sodium (PG), soy phosphatidylglycerol sodium (PG), phosphatidylinositol sodium (PI), Lipoid E 80 S and sodium oleate, especially dimyristoyl phosphatidylglycerol sodium (DMPG), 1,2-dimyristoyl-sodium salt sn-glycero-3-phospho-rac-glycerol and Lipoid E80 S.

E32. A pharmaceutical composition according to any one of embodiments E24-E32 further comprising one or more solvents.

E33. A pharmaceutical composition according to embodiment E32, wherein said solvent is selected from propylene glycol and ethanol, or preferably containing both propylene glycol and ethanol.

E34. The pharmaceutical composition according to any one of embodiments E24-E33, wherein the anti-gelling agent is sodium chloride.

E35. The pharmaceutical composition according to any one of embodiments E24-E33, wherein the anti-gelling stabilizer is PEG300.

E36. The pharmaceutical composition according to any one of embodiments E24-E36 further comprising a tonicity correcting agent.

E37. The pharmaceutical composition according to embodiment E36 wherein the tonicity correcting agent is selected from dextrose, glucose, mannitol, sucrose, lactose, trehalose, glycerol and NaCl, especially sucrose and/or glycerol, more preferably sucrose.

E38. A pharmaceutical composition according to any one of embodiments E24-E38 further comprising a buffer, especially histidine.

E39. The pharmaceutical composition according to any one of embodiments E24-E39, wherein the ratio of the phospholipid from the liposomal carrier to compound A as a free molecule is from 100:1 to 4.5:1 parts by weight.

E40. The pharmaceutical composition according to embodiment E39, wherein the ratio of the phospholipid from the liposomal carrier to the free molecule compound A is 50:1 to 6:1 parts by weight, especially 20:1 to 9:1 parts by weight.

E41. A pharmaceutical composition according to any one of embodiments E24-E40, wherein the loaded liposomes have an average size of 20 nm to 100 nm, in particular 50 nm to 90 nm, more preferably 50 nm to 80 nm.

E42. A pharmaceutical composition for infusion or intravenous injection containing a mixture of a liposomal carrier and an organic concentrate composition according to any one of embodiments E1-E10.

E43. Pharmaceutical composition for infusion according to embodiment E42, additionally containing glucose for infusion.

E44. Cancer treatment kit, comprising:

a) liposomal carrier,

b) an organic concentrate composition according to any one of embodiments E1-E10.

E45. A kit according to embodiment E44, wherein a) and b) are intended to be mixed with each other immediately prior to administration to a patient.

E46. A process for solubilizing Compound A as described in any of Embodiments E1, E2, or E3 in an aqueous environment, comprising mixing:

a) liposomal carrier,

b) organic concentrate compositions according to any one of embodiments E1-E10.

E47. A method for preparing a pharmaceutical composition of Compound A suitable for parenteral administration, comprising mixing:

a) liposomal carrier,

b) an organic concentrate composition according to any one of embodiments E1-E10.

E48. The method according to embodiment E46 or E47, wherein the mixing is carried out just prior to administration to the patient.

E49. The method according to any one of embodiments E46, E47 or E48, wherein the mixing and liposomal loading is carried out by repeated inversion, in particular by shaking the container vigorously by inversion.

E50. The method according to any of the embodiments E47-E49, wherein the mixing and liposomal loading is carried out by inverting the container containing both components a) and b), especially repeatedly, or by shaking vigorously by inversion, until the mixture contains

- 8 041894 visible particles.

E51. A method for modulating Mcl-1 receptor activity in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of E11-E23 or E24-E41 or E42-E43 embodiments.

E52. A method of treating cancer, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition according to any one of embodiments E11-E23 or E24-E41 or E42-E43.

E53. The method according to embodiment E52, wherein the cancer is selected from bladder, brain, breast, and uterus cancers, chronic lymphoid leukemias, colon, esophagus, and liver cancers, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, for example, non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant diseases of the blood, for example, myelodysplastic syndrome, myeloma, for example, multiple myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer.

E54. The method according to embodiment E53, wherein the malignancy is selected from non-Hodgkin B cell lymphoma, diffuse large B cell lymphoma, multiple myeloma, myelodysplastic syndrome, chronic lymphoid leukemias, and acute myeloid leukemia.

E55. The use of a pharmaceutical composition according to any of the embodiments E11-E23 or E24-E41 or E42-E43 as a drug for the treatment of cancer.

E56. Use of the pharmaceutical composition according to embodiment E55, wherein the cancer is selected from bladder, brain, breast, and uterus cancers, chronic lymphoid leukemias, colon, esophagus, and liver cancers, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, for example, non-Hodgkin B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, blood cancers, for example, myelodysplastic syndrome, myeloma, for example, multiple myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer .

E57. Use of a pharmaceutical composition according to embodiment E56, wherein said malignancy is selected from non-Hodgkin's B-cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, myelodysplastic syndrome, chronic lymphoid leukemias, and acute myeloid leukemia.

E58. The use of an organic concentrate composition according to any one of embodiments E1-E10 for the preparation of a medicament for the treatment of cancer.

E59. The use according to embodiment E58 for the preparation of a liposomal drug for the treatment of cancer.

E60. Use according to embodiment E58 or E59, wherein the cancer is selected from bladder, brain, breast, and uterus cancers, chronic lymphoid leukemias, colon, esophagus, and liver cancers, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, for example, non-Hodgkin B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, blood cancers, for example, myelodysplastic syndrome, myeloma, for example, multiple myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer , especially non-Hodgkin B-cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, myelodysplastic syndrome, chronic lymphoid leukemia and acute myeloid leukemia.

E61. A combination containing a pharmaceutical composition according to any of the embodiments E11-E23 or E24-E41 or E42-E43, one or more therapeutically active agents, for simultaneous, sequential or separate use.

In a preferred embodiment of the invention, patients were selected, for example, according to the following criteria.

Main inclusion criteria:

age >18 years.

For patients with multiple myeloma:

histologically confirmed lymphoma or confirmed multiple myeloma, in a preferred embodiment of the invention for patients with multiple myeloma, the multiple myeloma is recurrent and/or difficult to treat with standard treatment.

- 9 041894

It is characterized by chromosomal aberration.

Measurable manifestations of the disease:

Serum M-protein >0.5 g/dl,

Urinary M-protein >200 mg/24 h, or serum free light chain (FLC) level >100 mg/L of involved FLC.

For patients with histologically confirmed DLBCL:

documented positive MYC as determined by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC).

Measurable disease manifestations (as per Guidelines for Initial Evaluation, Staging, and Response Evaluation of Hodgkin's and Non-Hodgkin's Lymphoma).

Main exclusion criteria.

1. History of chronic kidney disease, including active hepatitis B or C infection, primary biliary cirrhosis, cirrhosis of the liver, or portal hypertension.

2. Chronic pancreatitis in history.

3. Patients at high risk for tumor lysis syndrome (TLS).

4. History or diagnosis of pneumonia, interstitial lung disease, or inflammatory bowel disease.

5. Cardiac dysfunction or clinically significant heart disease, including any of the following.

Left ventricular ejection fraction (LVEF) < 50% as determined by multiview radioisotope scanning (MUGA) or echocardiogram (ECHO).

Fredericia corrected QT (QTcF) > 450 ms (male patients), > 460 ms (female patients).

6. Severe and/or uncontrolled medical conditions that, in the opinion of the investigator, may affect the safety of the individual or interfere with the evaluation of study results.

7. Prior treatment with a Mcl-1 inhibitor.

8. Prior treatment with a Bcl-2 inhibitor (for patients enrolled in the study using the maximum tolerated dose determined during the dose escalation phase).

9. Patients with a primary CNS tumor or an involved CNS tumor.

The liposomal carrier described in the present invention can be obtained using any method of obtaining, which leads to the production of liposomes with an average particle size of up to 1000 nm, preferably up to 300 nm, in particular up to 100 nm. The size of the liposome, as described in the present invention, refers to the average diameter Z using photon correlation spectroscopy in accordance with ISO 13321, which describes the obtained average particle size and polydispersity coefficient. A typical preparation method involves dispersion, high shear mixing and subsequent high pressure homogenization, and such methods are well known to those skilled in the art.

An organic concentrate is formed by mixing the components until a homogeneous solution is formed in which Compound A is dissolved.

To form a composition for administration, the concentrate is added to the liposomal carrier, then immediately mixed, for example, by repeated inversion, or vigorous shaking. Alternatively, the concentrate may be added to the carrier during rotation.

Advantageously, in a preferred embodiment of the invention, a liposomal carrier is provided that can be mixed with compound A shortly before administration to obtain a clear composition. In particular, this is achieved by mixing the liposomal carrier with an organic concentrate containing compound A, as described in the present invention. Clarity is desirable to verify that Compound A has solubilized prior to administration. This can be assessed by visual inspection or transparency is determined at the most appropriate wavelength depending on the lipid concentration, e.g. 660 nm or using a transmission cell or a 1 cm cuvette. In an aspect of the invention, the pharmaceutical composition for administration (liposomes loaded with ) should not reduce transmission compared to the liposome carrier by no more than 30%, preferably no more than 20%, most preferably no more than 10%.

In a preferred embodiment of the invention, the liposome carrier, when mixed with Compound A, allows maximum loading of Compound A onto liposomes, especially when Compound A is presented as an organic concentrate as described in the present invention.

In the examples in the present invention, Compound A' is (2R)-2-{[(5S _a )-5-{3-chloro-2-10 041894 methyl-4-[2-(4-methylpiperazin-1-yl) ethoxy]phenyl}-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]oxy}3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy }phenyl)propanoic acid (without salt).

Example 1 Organic concentrate containing compound A and sodium chloride.

Compound Composition per ml [mg] filler function Compound A 61.75 DMPG-Na (1,2 Dimyristoyl-swglycero-3-phospho-/?w/glycerol, sodium salt) 3.83 stabilizer Ethanol, anhydrous 94.39 solvent Sodium chloride 4.00 stabilizer Water for injections 9.58 solvent propylene glycol 851.41 solvent

Preparation of bulk solvent.

Water for injection, then anhydrous ethanol, then DMPG-Na was loaded into a vessel and stirred until the DMPG-Na powder was moistened. After that, about a quarter of propylene glycol was added and the mixture was stirred and heated. Stirring was continued and the temperature was maintained for 90 minutes or until complete dissolution of DMPG-Na. After dissolution was complete, the mixture was subsequently cooled to room temperature, the remaining propylene glycol was added and the mixture was stirred until it became homogeneous. After that, sodium chloride was added and the mixture was heated for 90 minutes or until complete dissolution of sodium chloride. The resulting solution was cooled to room temperature.

Preparation of organic drug concentrate.

The bulk solvent prepared as described above was loaded into a vial, Compound A was added and the mixture was stirred until Compound A powder was wet. Stirring was continued for 60 minutes or until Compound A was completely dissolved. The concentrate was filtered through sterile 0.2 µm Pall Fluorodyne® II DFL membrane in Kleenpak™ capsules KA3DFLP1G or KA3DFLP1. After filtration, the resulting organic drug product concentrate (61.75 mg/mL) was transferred into sterile, pyrogen-free vials.

Example 2 Liposomal Reconstituting Vehicle.

Filler Composition per ml [mg] filler function sucrose 90 tonicity correcting agent ePL, Lipoid E 80 S (Egg phospholipids) 100 solubilizer L-Histidine 1.5 buffer Hydrochloric acid If necessary, up to pH 6.5 pH adjusting agent Sodium hydroxide If necessary, up to pH 6.5 pH adjusting agent Water for injections Qs up to 1 ml solvent

Preparation of the liposomal carrier for dilution.

Since lecithin (ePL) is susceptible to oxidation, oxygen was removed whenever technically possible and the materials were preferably protected by a layer of nitrogen.

Water for injection, then L-histidine, was loaded into a vessel and stirred until L-histidine was completely dissolved. The sucrose was charged and the mixture was stirred until the sucrose was completely dissolved. The pH value was checked and adjusted to 6.5 ± 0.2 by adding a solution of 1 N. hydrochloric acid or 1 N. sodium hydroxide, after which the solution was stirred until it became homogeneous. Lipoid E 80 S was then added to the vessel. The mixture was stirred until a homogeneous dispersion was obtained.

Linear mixing.

The dispersion obtained above was mixed and transferred to another vessel using a linear homogenizer (Kinematica MEGATRON MT-SV 1-45 M) controlled at a flow of 2-5 l/min. Linear mixing was continued until the source vessel was placed empty. High pressure homogenization

The vessel containing the lecithin dispersion as described above was connected to a high pressure homogenizer (Avestin Emulsiflex C160) in a recirculation loop and the dispersion was cooled to 2-8° C. while stirring at 300 rpm. After pressurizing the vessel to 0.5 bar, the pump was set to maximum speed and the high pressure homogenizer was pumped using an open

- 11 041894 valves for removing air in the system. After that, the high pressure homogenizer was set to 60 Hz, flow to 130-140 l/h and pressure to 950-1050 bar, and high pressure homogenization was carried out for 19 passes (about 7.5-8 h), then for 20- m passage, the contents of the vessel were transferred to another vessel using a high pressure homogenizer.

Pre-filtration was carried out with a PVDF (polyvinylidene difluoride membrane) 0.2 μm filter, and the filtered solution was stored at room temperature. Thereafter, the solution was sterile filtered through a PVDF sterilizing filter and then transferred to sterile vials depyrogenated by dry heat treatment.

This aqueous preparation may be injected or infused as such or diluted with infusion solutions (eg 5% glucose) prior to infusion.

Example 3A. Infusion drug.

The organic concentrate from Example 1 was mixed with the liposome carrier from Example 2 as follows. The liposome carrier of Example 2 was allowed to warm to room temperature (ie, 20-25° C.) by removing from the refrigerator at least 30 minutes prior to mixing. The total amount of active liposomal carrier that will be administered to the patient can be determined as shown in Table. 3A.1 below. The liposomal carrier contains small liposomes and is used as a solubilizing carrier capable of dissolving Compound A in an aqueous environment after mixing with an organic concentrate containing Compound A.

Table 3A.1

Need- number of vials, Overall volume Syringe size / Concentration May dose necessary for active scale Compounds A in Connections medicinal liposomal bag 250 ml, A product (Connection carrier ready for A concentrate for (concentration infusions infusion) and Compounds A 7.5 (Notes: liposomal mg/ml) to transfer to overflow carrier for glucose bag no bag breeding (LV) take into attention) MG No. ml mg/ml thirty 1 4.0 5 ml / 0.2 ml 0.12 45 1 6.0 10 ml / 0.5 ml 0.18 180 1 24.0 30 ml / 0.5 ml 0.72 360 2 48.0 30 ml / 0.5 ml 1.44 540 3 72.0 30 ml / 0.5 ml 2.16 720 4 96.0 30 ml / 0.5 ml 2.88 900 5 120.0 30 ml / 0.5 ml 3.60 1080 6 144.0 30 ml / 0.5 ml 4.32 1260 7 168.0 30 ml / 0.5 ml 5.04 1400 8 186.7 30 ml / 0.5 ml 5.60 X [mg] Determined on = X [mg] / 7.5 mg/ml See above. = X [mg] / 250 ml on the basis of the Chose size dose and nominal syringe / scale, content closest Compounds A to value 180 mg/vial total volume medicinal active product (concentrate liposomal Connections A for carrier, infusion) presented in table

One vial of compound A organic concentrate (185.25 mg (including overage) of compound A in 3 ml) was combined with one vial of liposomal vehicle (2.1 g Lipoid E 80 S in 21 ml) to give a recoverable volume of 24 ml of active liposomal vehicle containing compound A, containing a total of 180 mg of compound A). For one patient, it may be necessary to prepare more vials. Sufficient vials of the active liposomal carrier should be prepared to allow the dose to be administered to the patient.

Compound A organic concentrate (3 ml) was aseptically and accurately withdrawn quickly into one vial of liposomal vehicle and immediately mixed by inverting the vial >40 times. The initial turbidity disappears. The resulting formulation of the active liposomal vehicle will be slightly cloudier than the liposomal vehicle for reconstitution. It must not contain visible particles after mixing. If more than 180 mg of Compound A is to be administered to the patient, the addition and mixing steps are repeated as necessary.

The total volume of glucose solution to be removed from the infusion bag is then calculated (eg using Ecobag glucose 5%, or Ecoflac glucose 5%). This volume is identical to the volume of the active liposomal carrier, as presented in table. 3A.1. The calculated volume of glucose solution is aseptically and accurately withdrawn from the infusion bag (and discarded).

- 12 041894

A calculated volume of the active liposomal vehicle (containing Compound A) is aseptically and accurately withdrawn from one or more vials and injected into the glucose bag prepared above and mixed well by inverting the bag at least 10 times. If less than a multiple of 180 mg of compound A is needed, then the remainder of the vials should be discarded.

The prepared infusion bag, ready for infusion, should be examined visually for the presence of particles. The contents of the bag may show slight opalescence or slight haze depending on the concentration of Compound A. If particles are visible, discard the bag and prepare a fresh infusion bag.

Compound A is slightly sensitive to light, so the infusion bag is placed under a light-tight cover.

One example of the procedure is shown below. Freshly made infusion bags were stored for up to 5 hours at room temperature (ie, at 20-25°C) plus up to 8 hours under refrigerator conditions (2-8°C), which included the actual infusion time. If kept at room temperature 20-25°C, then you can prepare a diluted solution for infusion in an infusion bag and start infusion within 2 hours after preparation and enter at controlled room temperature. If the intravenous solution is not administered immediately, then the solution must be placed in a refrigerator at 2-8 ° C for no more than 8 hours. If the prepared solution is cooled in the refrigerator before administration, then the bag can be brought to room temperature before administration. An infusion formulation containing the desired concentration of Compound A drug product can be infused using an infusion set and an inline 1.2 µm filter after the infusion bag as close as possible to the catheter.

Example 3B. Infusion drug.

Using the same procedure as described in example 3A, the liposomal carrier from example 2 was mixed with an organic solution of the following composition.

Description Composition per ml [mg] filler function Compound A 100 Lipoid E 80 S 18.54 stabilizer propylene glycol 410.73 solvent ethanol 410.73 solvent

You can use the following mixing ratios.

Required Required Volume Lipo Concentration Volume Active Organic Somal

Compounds A liposomal solution (ml) carrier (mg/ml) drug (ml) (ml)

0.00 80 0.00 80.00 0.30 65 0.20 64.80 0.60 83.5 0.50 83.00 0.75 80 0.60 79.40 1.50 80 1.20 78.80 2.50 80 2.00 78.00 3.00 80 2.40 77.60 3.75 80 3.00 77.00 5.00 80 4.00 76.00 7.50 80 6.00 74.00

Example 4 Efficacy of Compound A Liposomal Preparation in the MV4;11 xenograft model of acute myeloid leukemia in nude rats using a weekly intravenous regimen.

Methods.

Table 4.1

Organic solvent composition used to prepare the dosage solution for the carrier group

Component Composition per ml [mg] Egg lecithin Lipoid E 80 S 20 propylene glycol 443.0 ethanol 443.0

- 13 041894

Table 4.2

Liposomal carrier composition used to prepare the dosage solution for the carrier group

Component Composition per ml [mg] Egg lecithin Lipoid E 80 S 100 sucrose 90 L-Histidine 1.552 Water for injections q.s up to 1.00 ml

Liposomal media was obtained using the components listed in table. 4.2, and the methods described in the present invention in example 2. The organic solution (Table 4.1) was mixed with the liposomal carrier in a ratio of 1:32.33 (v/v) and used to dose the group with the carrier at a dose of 10 ml / kg.

This study assessed the antitumor activity and tolerability of Compound A in a liposome formulation following iv infusion in athymic rats bearing an MV4;11 tumor. Experiments were performed on female athymic Crl:NIH-Foxnlrnu rats (Charles River).

The human acute myeloid leukemia (AML) MV4;11 luc cell line was derived from parental MV4;11 cells that originated from the patient. Parental MV4;11 cells were obtained from the DSMZ cell bank. MV4;11 luc cells were used for all in vivo studies and cultured in RPMI-1640 medium (BioConcept Ltd. Amimed, no. 1-41F01-I) supplemented with 10% FCS (GE health care life sciences, no. H30071.03) 4 mM L-glutamine (BioConcept Ltd. Amimed, no. 5-10K00-H), 0.6 mg/ml geneticin (Life Technologies, no. 10131-027) at 37° C. in 5% CO ₂ in air. Cells were maintained in the range of 0.2 to 1.1 x 10 ⁶ cells/ml. To obtain MV4;11 luc xenografts, cells were harvested and resuspended in HBSS (Gibco, no. 14175) and mixed with Matrigel (BD Bioscience, no. ⁷ cells, subcutaneously in the right hind paw of animals anesthetized with isoflurane. 24 hours before cell inoculation, all animals were irradiated with 5 Gy for 2 minutes using a γ-emitter.

Tumor growth was monitored regularly after cell inoculation and animals were randomized to treatment groups when their tumors reached an appropriate volume. Tumor size, in mm, was calculated using the formula: (LxW2xn/6) where W = width and L = length of the tumor.

Animals bearing tumors were divided into treated groups (n=5), with an average tumor volume of approximately 450 mm ³ . Thereafter, the animals were treated with vehicle or Compound A formulation at 10 and 30 mg/kg.

Compound A was formulated into a liposome formulation using an organic drug concentrate (described in Example 1) and a carrier (described in Example 2 of the present invention). Dosing solutions were prepared by mixing the product from examples 1 and 2 at a ratio of 1:7.236 (v/v), then diluting this mixture by adding 5% glucose at a ratio of 1:6.50 (v/v) for a dose of 10 mg/kg and 1:1.50 (v/v) for the 30 mg/kg dose.

Vehicle and Compound A were administered once a week (QW) by 15 min IV infusion into the lateral tail vein at a dose of 10 ml/kg. Animals were anesthetized with isoflurane/O ₂ for approximately 20 minutes for infusion. Tumor volumes were measured using calipers 2-3 times per week. Animals were weighed 2-3 times per week and frequently examined for signs of any side effects.

Tumor changes and body weight data were analyzed statistically using GraphPad Prism 7.00 (GraphPad software). If the fluctuations in the data were normally distributed, then the data were analyzed using one-way ANOVA with Dunnett's retrospective test to compare the treated group with respect to the control group. Tukey's post hoc test was used for intragroup comparison. In other cases, the Kruskal-Wallis test with Dunnett's retrospective test was used. Where applicable, the results were presented as the mean±SPS. As a criterion for determining the effectiveness, the %T/C value after the end of the experiment was calculated according to the following formula:

(Δtumor volume ^treated /Δtumor volume ^control )*100

Tumor regression was calculated according to the following formula:

(Δtumor volume ^treated /tumor volume ^{treated at start} )*100, where Δtumor volume is the mean tumor volume on the day of assessment minus the mean tumor volume at the start of the experiment.

Results: efficacy and tolerability.

The liposome formulation of Compound A exhibits a significant dose-dependent efficacy after infusion. At an infusion dose of 10 mg/kg QW, a maximal antitumor response was induced after the first dose (61% regression on day 3 post-treatment) and the response was attenuated with each subsequent dose, resulting in a gradual increase in volume.

- 14 041894 tumors in dynamics. On day 24 (the last day of tumor volume measurement in the vehicle group), the regression was 6% after a dose of 10 mg/kg QW (p < 0.05 compared with the vehicle group). After infusion of Compound A liposomal formulation at 30 mg/kg QW for 2 weeks, complete regression (CR) was achieved in all MV4;11 xenografts on day 13 post-treatment. Complete regression was maintained in all animals until day 21, after which tumor re-growth was observed in 3 animals and 2 animals showed no tumor growth for a further 60 days after reaching CR. On day 25 after the start of treatment with 30 mg/kg, the mean tumor volume showed a 92% regression (p < 0.05 compared with the vehicle group). Based on changes in body weight, both liposome dosing regimens were well tolerated. The results are shown in FIG. 1 and 2.

Example 5 Stability Data for the Composition of Example 1

The stability of the composition of Example 1, Compound A 185.25 mg in 3.0 ml, was examined by testing storage times up to 3 months and light stability.

5.1. Testing at 5°C/RH ambient (relative humidity).

During 3 months storage in vials at 5°C/RH ambient, the formulation of Compound A Example 1 185.25 mg/3.0 ml was observed and was physically and chemically stable. No significant changes in chemical or physical properties were observed.

5.2. Testing at 25°C/60% RH.

During 3 months storage in vials at 25° C./60% RH, the formulation of Compound A Example 1 185.25 mg/3.0 ml was observed and was physically stable. No significant changes were observed within 3 months. Elevated levels of the unwanted atropisomer were observed. All results remained within acceptable limits.

5.3. Testing at 40°C/75% RH.

During 3 months of storage in vials at 40°C/75% RH, the composition of Example 1 of compound A 185.25 mg/3.0 ml was observed and was physically stable. No significant changes were observed within 3 months, except for increased levels of undesirable atropisomer over time. All results were within acceptable limits after 1.5 months.

5.4. Light stability.

During vial light stability testing, it was observed that the 185.25 mg/3.0 ml formulation of Compound A Example 1 was neither chemically nor physically stable. It was observed that all results for the sample protected from exposure to light were within acceptable limits.

Conclusions.

Satisfactory stability data were obtained for 3 months at 5°C/RH ambient and 25°C/60% RH and 1.5 months at 40°C/75% RH. The available stability data indicate satisfactory stability of the composition of Example 1 Compound A 185.25 mg/3.0 ml. Light protection required.

Example 6 Stability data for the composition of example 2.

The stability of the carrier composition of Example 2 (21.7 ml) was examined by testing storage times up to 3 months and light stability.

6.1. Testing at 5°C/RH ambient.

No change in container appearance, contents appearance, and phospholipid counts was observed up to 3 months at 5°C compared to baseline. No significant changes were observed in either the pH value or the particle size.

6.2. Testing at 25°C/60% RH.

No change was observed in the appearance of the container and the appearance of the contents up to 3 months of storage at 25°C, compared with the original results. The initial pH of 6.6 decreased to pH 6.3 within 3 months, respectively. No significant changes were observed for particle size according to photon correlation spectroscopy and quantitative indicators of phospholipids up to 3 months. Invisible to the naked eye solid particles increased, but the values remained in the acceptable range.

6.3. Testing at 40°C/75% RH.

No change was observed in the appearance of the container and the appearance of the contents up to 3 months of storage at 40°C, compared with the original results. Observed a slight change in pH, which decreased slightly from pH 6.6 initially, to 6.3 after storage for 3 months at 40°C.

No significant changes were observed during particle size according to photon correlation spectroscopy and quantitative indicators of phospholipids up to 3 months of storage at 40°C. Significant differences were observed when testing particles invisible to the naked eye. However, these conditions are considered stressful compared to long-term storage at 5°C.

6.4. Light stability.

Light stability testing was performed on the product in a glass vial and compared with

- 15 041894 bottle protected from light in a cardboard box. In the light stability study, no significant changes were observed for the parameters of the appearance of the container, the appearance of the contents, the pH of the solution, visible solids and quantitative indicators of phospholipids after storage.

Conclusions.

Satisfactory stability data have been demonstrated for long term storage conditions at 5°C and accelerated aging conditions at 25°C/60% RH up to 3 months. Satisfactory stability data have been demonstrated for accelerated aging conditions at 40°C/75% RH up to 1.5 months, limited by the results of invisible particulate matter. For container appearance, contents appearance and particle size, no change was observed for all storage conditions up to 3 months. The pH values were stable and within the regulatory limits for all storage conditions. Satisfactory stability data have been shown for long term storage at 5°C/RH ambient. The carrier is considered to be light stable.

Example 7 In vitro release study. Compound A: release of compound A from small liposomes to an acceptor containing an excess of lipids present as large multilamellar vesicles (MLV).

The aim of this experiment was to investigate the rate of release of compound A from small unilamellar vesicles (SUV; used in the present invention as a drug carrier system, see example 3A) into large multilamellar vesicles (MLV) composed of egg phospholipids and used as a lipophilic acceptor for the released drug (see Shabbits J. A., Chiu G. N. and Mayer L. D. Development of an in vitro drug release assay that accurately predicts in vivo drug retention for liposome-based delivery systems Journal of Controlled Release 2002, 84(3), 161- 170).

Preparation and implementation of a release study using multilamellar vesicles as an acceptor.

Preparation and characteristics of MLV.

Multilayer vesicles were prepared using the film hydration method. Briefly, egg phospholipids (Lipoid E 80 S) were weighed and completely dissolved in an organic solvent (EtOH/DCM at 4:1 v/v) to ensure a homogeneous mixture of all components.

Thereafter, the organic solvent was removed using rotary evaporation (first step: 200 mbar, 50° C., 2 h; second step: 30 mbar, 50° C., 45 min) to obtain a homogeneous lipid film. To ensure complete removal of the organic solvent, the flask was purged with nitrogen. Thereafter, the film was rehydrated using phosphate buffered saline (PBS, pH 7.4) to form MLV and after rehydration was complete, the MLV was sonicated for 15 minutes.

In order for MLV to be resuspended in the same buffer system as SUV, the suspension was centrifuged for 10 min at 14,000 g, the supernatant (PBS) was removed, and replaced with sucrose-histidine buffer. Finally, the mixture was thoroughly vortexed to ensure complete redispersion of the MLV in the new medium before starting the release experiment.

MLV preparations were characterized based on their size by laser diffraction using the HELOS KR system (SympaTec) after a 1:5000 dilution using PBS to give x ₁₀ , x ₅₀ , and x ₉₀ values.

Xy = particle size corresponding to 10% cumulative distribution less than nominal size, x ₅₀ = average particle size (i.e., 50% of particles are smaller and 50% of particles are large), and x ₉₀ = particle size corresponding to 90% cumulative distribution less nominal size.

Table 7.1 Size distribution MLV ,, Size (µm)

Drug ----------------------------------Hu X50 X90

PBS-loaded MLV (100% ePL) in PBS_____________________________2.98___________5.79__________11.56_______

Release study using MLV.

For a release study using MLV, the following setup was used for all experiments.

SUV (donor) was mixed with MLV (acceptor) in a 25 ml Erlenmeyer flask with stopper while stirring (500 rpm) at various ratios (1:40, 1:100, 1:200, 1:500; SUV: MLV v/v). 1 ml samples were taken at various time points and immediately centrifuged (14,000 rpm, 10 min) to separate the MLV from the SUV for further processing. In FIG. 3 of the present invention is a schematic representation of the principles of release analysis based on MLV.

Thereafter, the MLV portion was removed by aspiration and 50 μl of the SUV portion was mixed with 450 μl

- 16 041894

ACN:H2O for HPLC sample preparation. After that, the sample was centrifuged (14000 rpm, min), the supernatant was filtered using a 0.22 μl filter and injected into HPLC for analysis.

High performance liquid chromatography method for compound A.

A high performance liquid chromatography (HPLC) system with UV detection was used, including the following equipment and solvent system settings.

Shimadzu LC2010C NT instrument

Column Waters Symmetry Shield, RP18, 3.5 µm, 3 x 150 mm

Column conditions 45 °C

mobile phase A) ACN:H ₂ O:FA:NH ₄ OH (20:80:1:0.4) B) ACN:H ₂ O:FA:NH ₄ OH (80:20:1:0.4) Solvent Gradient multi-stage gradient Solvent flow 1.0 ml/min Pressure Max 270 bar Automatic, sampling Samples were injected using an autosampler UV detection HPLC-UV detector set to 210 nm and

245 nm

Solvent gradient for HPLC. Hold (min)_________ Flow (ml/min) % A % IN 0 1 40 60 0 1 40 60 1 1 40 60 4 1 100 0 4.1 1 40 60 5_________________ 1 40 60

Compound A release study using MLV.

Compound A release was determined using MLV as the acceptor compartment. In this case, compound A-loaded SUVs (7.5 mg/ml) were added to these MLVs at different ratios (v/v). In FIG. 4 shows the release profile of Compound A from SUV to 100% ePL at a variety of different SUV:MLV ratios (v/v).

Note. For all MLV release experiments, the maximum concentration (maxC=100%) was obtained by diluting 7.5 mg/mL loaded SUVs 1 in 40, 1 in 100, 1 in 200, or 1 in 500 (v/v) in sucrose. -histidine buffer instead of MLV.

Using this type of experimental model, a very rapid release of Compound A from SUV into the MLV acceptor was observed. In this case, for a 1 to 40 dilution, only about 44% of the starting amount of Compound A used was found in the SUV portion in the sample after only 2 minutes. Thus, ~60% was released or already transferred to the acceptor MLV portion at this time point. Moreover, increasing the dilution ratio (1:100, 1:200, 1:500 SUV:MLV v/v) only accelerates and enhances the release of the drug, since at t=2 min a dilution of 1 in 100 demonstrates a release of ~70 %, a 1:200 dilution ~80%, and for a 1:500 dilution, almost 90% of the total drug was not found anywhere in the SUV at t=2 min and, therefore, was released into the acceptor compartment.

Conclusion.

A fast release profile of Compound A was demonstrated with up to 90% release of the drug after only 2 minutes. The data show that liposomes do not physically retain Compound A encapsulated in the presence of excess lipids, but there is a rapid redistribution of Compound A between all lipids present during incubation. Under in vivo conditions, comparable behavior is expected. The formulation provides an extremely favorable balance of effective compound A solubilization, with the desirable fast release profile of compound A.

Example 8 Organic concentrate composition containing compound A and PEG300, variant 1.

- 17 041894

Compound Composition per ml [mg] filler function Compound A 60 DMPG-Na (1,2- DiMIRISTOIL-57? glycero-3-phospho-/?sh/glycerin, sodium salt) 4 stabilizer ethanol 94 solvent PEG300 224 solvent, stabilizer propylene glycol 728 solvent

The composition may be prepared using a method similar to that described in Example 1 or using methods well known to those skilled in the art.

Example 9 Organic concentrate composition containing compound A and PEG300, variant 2.

Compound Composition per ml [mg] filler function Compound A 60 DMPG-Na (1,2 Dimyristoyl-5Lglycero-3-phospho-/?w/glycerol, sodium salt) 4 stabilizer ethanol 79 solvent PEG300 224 solvent, stabilizer propylene glycol 792 solvent

The composition may be prepared using a method similar to that described in Example 1 or using methods well known to those skilled in the art.

Example 10 Organic concentrate composition containing compound A and PEG300, variant 3.

Compound Composition per ml [mg] filler function Compound A 60 DMPG-Na (1,2- Dimyristoyl-5"glycero-3-phospho-/?sh/glycerol, sodium salt) 2 stabilizer ethanol 94 solvent PEG300 224 solvent, stabilizer propylene glycol 851 solvent

The composition may be prepared using a method similar to that described in Example 1 or using methods well known to those skilled in the art.

Comparative Example 11 Organic concentrate containing Compound A without anti-gelling agent.

Compound Composition per ml [mg] filler function Compound A 60 DMPG-Na (1,2 Dimyristoyl-5glycero-3-phospho-/?w/glycerol, sodium salt) 4 stabilizer ethanol 94 solvent propylene glycol 851 solvent

The composition may be prepared using a method similar to that described in Example 1 or using methods well known to those skilled in the art.

Example 12 Study of the physical stability of organic concentrates from examples 1, 8-10.

The study of physical stability was carried out using two separate methods: a) resistance to seeding and b) diagnostic stability with vigorous stirring at 250 rpm at 2°C.

a) The seeding experiment was carried out by adding ~1 μl of gelled preparation (compound A: 60 mg/ml, DMPG: 4.0 mg/ml, propylene glycol 851 mg/ml, ethanol: 94 mg/ml: this solution

- 18 041894 solidified on storage with stirring at 2°C) into clear concentrates from examples 1, 8 and 9.

Samples were vortexed for 10 s and stored in a refrigerator overnight at

2-8°C. Examples 1, 8 and 9 did not show compound A gel upon seeding.

b) Stirring diagnostic stability studies were carried out by placing 2 ml of each organic concentrate in a glass tube and mixing homogeneously at 250 rpm at 2°C. As shown in Table. below, gelation did not occur for the preparations described in examples 1, 8-10, within 10 days. After 13 days, the composition of example 1 solidified, while the preparations described in examples 8-10 remained stable, ie clear solutions.

Example 1 Example 8 Example 9 Example 10 Comparative Example 11 48 hours Clear solution Clear solution Clear solution Clear solution Irreversible white gel 1 Week Clear solution Clear solution Clear solution Clear solution Irreversible white gel 10 days Clear solution Clear solution Clear solution Clear solution - 13 days Reversible white gel Clear solution Clear solution Clear solution -

Advantageously, formulations containing PEG300 are resistant to gelation in the mixing experiment described above, in combination with seeding resistance. The gelation of Example 1 can be controlled by selecting an appropriate storage temperature, for example by storage at room temperature.

Example 13 Liposomal loading using the composition concentrate of Examples 1, 8-10.

Liposomal loading was tested at the 23.7 ml scale using the same approach as described in Example 3A.

The organic concentrate from Examples 8-10 exhibited comparable liposome loading characteristics compared to Example 1. Examples 8-10 resulted in liposome preparations with comparable turbidity compared to those prepared from Example 1.

Liposomal preparation from Example 1 concentrate Liposomal preparation from Example 8 concentrate Liposomal preparation from Example 9 concentrate Liposomal preparation from Example 10 concentrate Size, nm 54.3 58.3 54 62.6 PDI 0.287 0.298 0.283 0.282 Light transmission, % 71.2 72.9 72.2 70.7

Size, nm, calculated as described in the present invention;

PDI: polydispersity index

To facilitate liposomal loading of Example 8 and Example 9, loading using 19 G needles was examined and compared with a 21 G needle. Use of a 19 G needle resulted in slightly smaller particle size and slightly less turbidity compared to injection using a 21 G needle.

Example 14 Physical Stability of Placebo Organic Concentrate Preparations.

Placebo preparations (without Compound A) were tested at -20°C; an extreme condition that can accelerate the possible precipitation of drug components. The physical stability of the organic placebo concentrates described below was studied up to 17 days.

Composition mg/ml placebo from Example 1 placebo from Example 8 placebo from Example 10 propylene glycol 851 728 728 ethanol 94 94 94 DMPG-Na (1,2 Dimyristoyl-5glycero-3-phospho/?w/-glycerol, sodium salt) 4 4 2 PEG300 0 224 224 NaCl 4 0 0 Water 10 0 0 Observations placebo from Example 1 placebo from Example 8 placebo from Example 10 48 hours turbid transparent transparent 6 days precipitation transparent transparent 10 days precipitation transparent transparent 17 days precipitation transparent transparent

- 19 041894

Precipitation was observed in the placebo formulation of Example 1. The placebo formulation of Examples 8 both remained clear and no precipitation was observed during the experiment.

Example 15 Chemical Stability of the Active Organic Concentrates of Examples 1, 8 and 9

The chemical stability of the active compound was tested in the preparations of examples 1, 8 and 9, in particular to study the levels of impurities arising from oxidative degradation and the formation of an undesirable atropisomer.

Identification, investigation and degradation products by HPLC.

Principle Reverse phase HPLC method with ion pairing and UV detection

Reagents

Acetonitrile gradient purity, e.g. Merck LiChrosolv No. 100030 ethanol LC purity, e.g. Merck 1.00983 Formic acid LC purity, e.g. Prolabo No. 84865.260

Ammonium hydroxide 25% Analytical grade, e.g. Sigma No. 09860

H2O2 30% Analytical grade, e.g. Sigma No. 95313

MilliQ water or HPLC grade

Diluted ammonium hydroxide In a volumetric flask with a volume of 50.0 ml, 2.5 ml of ammonium hydroxide 25% was added and the volume was adjusted with purified water.

Thinner Ethanol

materials Glassware Can use amber glass labware

Equipment device HPLC system with gradient elution and UV detector, e.g. Agilent 1290 with UV detector or equivalent Column Acquity VEN C18 Length: 100mm, inner diameter: 2.1mm Particle size: 1.7 µm

- 20 041894

Additional equipment Ultrasonic bath, analytical balance, microbalance

Chromatographic Conditions Split mode Gradient Mobile Phase A Water + acetonitrile + formic acid, 95 + 5 + 0.02 (v/v/v) The pH value of the aqueous fraction = 4.9, adjusted with ammonium hydroxide. 200 μl of formic acid was added to 950 ml of water. The pH was adjusted to 4.9 using diluted ammonium hydroxide. 50 ml of acetonitrile was added. Mobile Phase B Water + acetonitrile + formic acid, 5 + 95 + 0.02 (v/v/v), aqueous fraction pH = 4.9 adjusted with ammonium hydroxide. 200 μl of formic acid was added to 50 ml of water. The pH was adjusted to 4.9 using diluted ammonium hydroxide. 950 ml of acetonitrile was added. You can use different volumes, provided that the volume ratio remains the same.

Gradient table.

Time [min] Phase A [%] Phase B [%]

0.0 100 0 2.0 100 0 h, o 60 40 and about 52 48 14.0 10 90 14.3 100 0 16.0 100 0 Flow rate 0.6 ml/min Detection UV 210 nm Column temperature 40°C

Temperature of automatic 2-8 °C sampler

Injection of flush solvent Ethanol using the flush port with a minimum of 10 seconds

Volume injected 5 μl of test and reference solutions, equivalent to approximately 1.0 μg of the drug substance listed in the reference solution

-

Claims (30)

Compound Time point (weeks) Temp °C Unwanted atropisomer,% 0x1% 0x2% SUM D.P. Example 8 6 5 <0.1 <0.1 <0.1 (0.06*) <0.1 40 3.78 <0.1 (0.04*) 0.13 0.13 Example 8 8 5 <0.1 <0.1 <0.1 (0.05*) <0.1 40 4.86 <0.1 0.18 0.28 Example 9 6 5 <0.1 <0.1 <0.1 (0.07*) <0.1 40 3.53 <0.1 (0.02*) 0.11 0.11 Example 9 8 5 <0.1 <0.1 <0.1 (0.04*) <0.1 40 4.42 <0.1 0.14 0.14 Example 1 6 5 1.54 <0.1 <0.1 (0.05*) <0.1 40 4.63 <0.1 <0.1 (0.04*) <0.1 Example 1 8 5 1.62 <0.1 <0.1 (0.04*) <0.1 40 6.06 <0.1 <0.1 (0.05*) <0.1 Example 1, fresh- 5 5 <0.1 <0.1 <0.1 (0.04*) <0.1 cooked 40 2.82 <0.1 <0.1 (0.06*) <0.1 Example 1, fresh- 7 5 <0.1 <0.1 <0.1 (0.03*) <0.1 cooked 40 3.58 <0.1 <0.1 (0.05*) <0.1 *below the determined level; % expressed as % peak area; Ox 1 and 0x2 are two products of oxidative degradation The sum of the DP is the sum of the degradation products, excluding atropisomers, above the determined level. The composition of example 1 was prepared 8 months before the study, stored at 25°C until the start of the study. The composition of example 1, freshly prepared immediately before the start of the study and immediately placed at 5°C and 40°C, respectively. Oxidative degradation products were low for all drug variants listed above. The observed increase in the undesired atropisomer was related to temperature and time, but did not change for the tested drug variants. By visual inspection, no change in the color of the concentrate was detected in any of the test preparations mentioned above. CLAIM 1. The composition of an organic concentrate intended for the manufacture of a pharmaceutical composition, containing: a) compound A, which is 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2 ,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)propanoic acid or a pharmaceutically acceptable salt thereof, b) a negatively charged or polar phospholipid stabilizer, where this negatively charged or polar phospholipid stabilizer is selected from sodium or ammonium salt of DMPG (1,2-dimyristoyl-sπ-glycero-3-phospho-rac-glycerol or dimyristoyl phosphatidylglycerol), sodium salt of POPG (1-palmitoyl-2-oleoyl-sπ-glycero-3[phospho-rac-(1-glycerol)]), DOPS sodium salt (1,2-dioleoyl-sπ-glycero-3-phosphoserine), DOPG sodium salt ( 1,2-dioleoyl-sπ-glycero3[phospho-rac-(1-glycerol)]), sodium or ammonium salt of DPPG (1,2-diπalmitoyl-sπ-glycero3[phospho-rac-(1-glycerol)]), sodium or ammonium salt of DSPG (1,2-distearoyl-sπ-glycero-3[phosphorac-(1-glycerol)]), sodium salt of soy phosphatidic acid (PA), sodium salt of egg phosphatidic acid (PA), sodium salt of soy phosphatidylserine (PS), egg phosphatidylglycerol sodium (PG), soy phosphatidylglycerol sodium (PG), phosphatidylinositol sodium (PI), egg lecithin, soy lecithin and sodium oleate, And c) an anti-gel stabilizer, wherein the anti-gel stabilizer is a polymer selected from PEG300 and PEG400 or an electrolyte selected from sodium chloride. - 22 041894 2. Organic concentrate composition according to claim 1, containing compound A, which is (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylninerazine -1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4- yl]methoxy}phenyl)propanoic acid or a pharmaceutically acceptable salt thereof. 3. Organic concentrate composition according to claim 1 or 2, wherein compound A is a free molecule. 4. Organic concentrate composition according to any one of claims 1 to 3, wherein the negatively charged or polar phospholipid stabilizer is 1,2-dimyristoyl-sn-glycero-3-phospho-racglycerol, sodium or ammonium salt, egg lecithin such as Lipoid E 80 S, soy lecithin such as Lipoid S 75, preferably 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol, sodium salt. 5. Organic concentrate composition according to any one of claims 1 to 4, wherein the anti-gelling stabilizer is sodium chloride. 6. An organic concentrate composition according to any one of claims 1 to 4, wherein the anti-gelling stabilizer is PEG300. 7. Organic concentrate composition according to any one of claims 1 to 6, additionally containing a solvent. 8. Organic concentrate composition according to any one of claims 1 to 7, additionally containing a solvent selected from propylene glycol and ethanol, or preferably containing both propylene glycol and ethanol. 9. A pharmaceutical composition obtained by mixing an organic concentrate composition according to any one of claims 1 to 8 and a liposomal carrier, wherein said liposomal carrier contains a phospholipid and a tonicity correcting agent selected from dextrose, glucose, mannitol, sucrose, lactose, trehalose, glycerin and NaCl. 10. The pharmaceutical composition of claim 9, wherein the phospholipid is selected from egg lecithin, soy lecithin, or synthetic phospholipids. 11. Pharmaceutical composition according to claim 9 or 10, where the phospholipid is represented by the formula Where R1 is C ₁₀ -C ₂₄ acyl; R ₂ is C ₁₀ -C ₂₄ acyl; R3 is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C1- _C4 alkyl, _C1 - _C5 alkyl substituted with carboxy, _C2 - _C5 alkyl, substituted with carboxy and hydroxy, C ₂ -C ₅ alkyl substituted with carboxy and amino, inositol group or glyceryl group; or a salt of such a compound. 12. Pharmaceutical composition according to any one of claims 9-11, wherein the phospholipid is selected from egg lecithin, soy lecithin, POPC (palmitoyl oleoyl phosphatidylcholine), DOPC (1,2-dioleoyl-snglycero-3-phosphocholine) and DMPC (1,2 -dimyristoyl-sn-glycero-3-phosphocholine), preferably POPC (palmitoyl oleoyl phosphatidylcholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) and DMPC (1,2 dimyristoyl-sn-glycero-3-phosphocholine ), preferably POPC. 13. A pharmaceutical composition according to any one of claims 9, 10 or 12, wherein the phospholipid is selected from egg lecithin or soy lecithin containing at least 70% phosphatidylcholine, preferably from Lipoid E 80 S. 14. A pharmaceutical composition according to any one of claims 9 to 13, wherein the tonicity correcting agent is selected from sucrose or glycerol. 15. Pharmaceutical composition containing liposomes and additionally: a) compound A, which is 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2 ,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)propanoic acid or a pharmaceutically acceptable salt thereof; And b) an anti-gel stabilizer which is a polymer selected from PEG300 and PEG400 or an electrolyte selected from sodium chloride. 16. The pharmaceutical composition according to claim 15, wherein compound A is a free molecule. 17. The pharmaceutical composition according to claim 15 or 16, wherein the anti-gelling agent is sodium chloride. 18. The pharmaceutical composition according to claim 15 or 16, where the anti-gelling stabilizer is - 23 041894 is PEG300. 19. Pharmaceutical composition according to any one of claims 15-18, additionally containing a negatively charged or polar phospholipid stabilizer, where the specified negatively charged or polar phospholipid stabilizer is selected from sodium or ammonium salt of DMPG (1,2 dimyristoyl-sn-glycero-3-phospho- rac-glycerol or dimyristoyl phosphatidylglycerol), POPG sodium salt (1-palmitoyl-2-oleoyl-sn-glycero-3[phospho-rac-(1-glycerol)]), DOPS sodium salt (1,2dioleoyl-sn-glycero- 3-phosphoserine), DOPG sodium salt (1,2-dioleoyl-sn-glycero-3[phospho-rac-(1glycerol)]), DPPG sodium or ammonium salt (1,2-duπpalmitoyl-sn-glycero-3[phospho -rac-(1glycerol)]), sodium or ammonium salt of DSPG (1,2-distearoyl-sn-glucero-3[phospho-rac-(1glycerol)]), sodium salt of soy phosphatidic acid (PA), sodium salt of egg phosphatide acid (PA), sodium soy phosphatidylserine (PS), sodium egg phosphatidylglycerol (PG), sodium salt of soy phosphatidylglycerol (PG), sodium co or phosphatidylinositol (PI), egg lecithin such as Lipoid E 80 S, soy lecithin such as Lipoid S 75, and sodium oleate. 20. Pharmaceutical composition according to claim 19, wherein the negatively charged or polar phospholipid stabilizer is 1,2-dimyristoyl-sn-glucero-3-phospho-rac-glycerin, sodium or ammonium salt, egg lecithin such as Lipoid E 80 S , soy lecithin such as Lipoid S 75, preferably 1,2-dimyristoyl-sn-glycero-3-phospho-rac-glycerol, sodium salt. 21. Pharmaceutical composition according to any one of claims 15-20, additionally containing a solvent. 22. A pharmaceutical composition according to claim 21, wherein said solvent is selected from propylene glycol and ethanol, or preferably containing both propylene glycol and ethanol. 23. Pharmaceutical composition according to any one of claims 15-22, containing a phospholipid selected from egg lecithin, soy lecithin or synthetic phospholipids. 24. Pharmaceutical composition according to claim 23, where the phospholipid is represented by the formula Ri----О r ₂ —О O' R ₃ (I) where R1 is C ₁₀ -C ₂₄ acyl; R2 is C ₁₀ -C ₂₄ acyl; R ₃ is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C1- _C4 alkyl, _C1 - _C5 alkyl substituted with carboxy, _C2 - _C5 alkyl substituted with carboxy and hydroxy, C ₂ -C ₅ alkyl substituted with carboxy and amino, inositol group or glyceryl group; or a salt of such a compound. 25. The pharmaceutical composition according to claim 23 or 24, wherein the phospholipid is selected from egg lecithin, soy lecithin, POPC (palmitoyl oleoyl phosphatidylcholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) and DMPC (1,2-dimurustoyl -sn-glycero-3-phosphocholine), preferably POPC (palmitoyl oleoyl phosphatidylcholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) and DMPC (1,2 dimyrustoyl-sn-glucero-3-phosphocholine), preferably RORS. 26. The pharmaceutical composition according to claim 23 or 25, wherein the phospholipid is selected from egg lecithin or soy lecithin containing at least 70% phosphatidylcholine, preferably from Lipoid E 80 S. 27. A pharmaceutical composition according to any one of claims 15 to 26, further comprising a tonicity correcting agent, which is preferably selected from dextrose, glucose, mannitol, sucrose, lactose, trehalose, glycerol and NaCl. 28. The use of a pharmaceutical composition according to any one of claims 9 to 14 or claims 15 to 27 as a drug for the treatment of cancer. 29. Use of the pharmaceutical composition of claim 28, wherein the cancer is preferably selected from bladder, brain, breast, and uterus cancers, chronic lymphoid leukemias, colon, esophagus, and liver cancers, lymphoblastic leukemias, acute myeloid leukemias, lymphomas , such as non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant blood diseases, such as myelodysplastic syndrome, myelomas, such as multiple myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer. 30. The use of the organic concentrate composition according to any one of claims 1 to 8 for the preparation -