CN102961323B - Promote liquid preparation of the active closed loop rate of camptothecine compounds and its preparation method and application - Google Patents

Abstract

The invention relates to a preparation for improving the active ring-closing rate of camptothecin compounds by simply adding polyethylene glycol. Polyethylene glycol is used as an additive, camptothecin derivatives are used as drug molecules, and the dispersion medium mainly composed of water is used as a solvent. Composed of three. The main additive is polyethylene glycol, and the drug molecules are camptothecin, 10-hydroxycamptothecin, 9-nitrocamptothecin, 9-aminocamptothecin, 7-ethyl-10-hydroxycamptothecin, One or more of topotecan, irinotecan, rubitecan, exitecan, berotecan, karenitecin, gemitecan, gemotecan, etc. By simply adding polyethylene glycol, the active loop closure rate of camptothecin drugs can be significantly improved, the efficacy of the drug can be enhanced, and the systemic reaction of the drug can be effectively reduced. It is expected to be used in the treatment of tumors at different stages.

Description

Liquid preparation for improving active ring-closing rate of camptothecin compounds and its preparation method and application

technical field

The invention belongs to the technical field of medicines, and in particular relates to a liquid preparation for increasing the active ring-closing rate of camptothecin compounds and its preparation method and application.

Background technique

Camptothecin is an active molecule of anticancer drugs, which was isolated from camptotheca in our country in the 1960s, hence the name. Due to its poor water solubility and high toxicity and side effects, some functional groups are usually modified on active non-sensitive sites to improve drug efficacy and water solubility. At present, two camptothecin derivatives, irinotecan (CPT-11) and topotecan (Topotecan) have been approved by the State Food and Drug Administration for clinical use, and have been widely used in gastric cancer, esophageal cancer, and pancreatic cancer. and colon cancer treatment. But almost all camptothecin drugs face the problem of unstable structure, as shown in Figure 1.

There is a lactone ring in the structure of camptothecin drugs, and it is easy to undergo ring-opening hydrolysis under neutral and alkaline conditions. It has been clearly pointed out in the literature that only the closed-ring form of camptothecin-based anticancer drugs can It is effective, but once the ring is opened, the original anti-tumor activity will be lost, and some unavoidable toxic side effects will be caused. Under physiological conditions, the ring closure rate of camptothecin compounds only accounts for about 10%, so how to improve the active ring closure rate of camptothecin drugs is a key issue for their successful application.

Polyethylene glycol is a pharmaceutical excipient that has been approved by the FDA. It has been widely used as a solubilizer and modifier in pharmaceutical preparations. Some insoluble drugs are compatibilized by PEG, but PEG is used to change drug molecules (philic Aqueous drugs and hydrophobic drugs) the proportion of active ingredients has not been reported.

The patent of the present invention aims at the problem of low active loop closure rate of camptothecin derivatives, and the equilibrium loop closure rate can be significantly improved by simply adding PEG. The method is simple to operate, has good reproducibility, low cost, can effectively reduce the systemic reaction of drugs, and is expected to be used in the treatment of tumors at different stages.

Contents of the invention

The object of the present invention is to provide a liquid preparation capable of increasing the active ring closure rate of camptothecin derivatives, its preparation method and application.

The present invention proposes a liquid preparation, with polyethylene glycol as an additive, drug camptothecin derivatives as an active ingredient, and water as a main dispersion medium as a solvent, and the three together form together; the content of polyethylene glycol accounts for 30% of the total liquid preparation 10%-90wt%, and the drug contained accounts for 0.001-10wt% of the total liquid preparation. The addition of polyethylene glycol can significantly increase the active ring closure rate of the contained camptothecin and its derivatives, and improve the activity of the drug.

Additives of the present invention include:

(1) The molecular weight of polyethylene glycol is between 200-20000, and it can be a mixture of one or more of them;

(2) The end of polyethylene glycol can be capped with methoxy;

(3) The end of polyethylene glycol can be connected with a functional end group, and the end group can be any of hydrophilic hydroxyl, amino, carboxyl, imidazole, aldehyde, cyano, nitro; it can also be hydrophobic Any one of alkyl group, sterol, alkoxy group, aromatic group, aromatic heterocyclic group, amide ester group, halogen atom, trichloromethyl group, ester group, mercapto group and allyl group;

(4) The additive may be any one of the above-mentioned polymers, or a mixture of two or more of the above-mentioned polymers, including a mixture of polymers with different terminal groups.

The medicine of the present invention is selected from hydrophobic camptothecin, 10-hydroxycamptothecin, 9-nitrocamptothecin, 9-aminocamptothecin, 7-ethyl-10-hydroxycamptothecin, Rubi Tecan, Exitecan, Berotecan, Karenitecin, Gemitecan, Gematecan, or one or a combination of hydrophilic topotecan and irinotecan.

The camptothecin derivatives contained in the present invention have an effective ring-closed form of 15%-80% when the pH of the solvent is between 6.5-8.

The solvent of the liquid preparation of the present invention can be pure water, buffer solution, body fluid, tissue culture fluid or other solvent media that do not mainly contain organic solvents.

The liquid preparation is characterized in that the pH value is between 4-8.

The preparation method of the liquid preparation of the present invention can be selected from one of the following:

(1) A certain amount of polyethylene glycol and the active dose of the drug are dissolved in the solvent together. After fully dissolving, store it at -20°C or below -20°C for later use, reconstitute before use, and inject in vivo;

(2) A certain amount of polyethylene glycol is first dissolved in the solvent, stored at -20°C or below for later use, redissolved before use, and the active dose of drug dry powder is added, fully dissolved, and used directly.

For the polyethylene glycol described in the above method, the polyethylene glycol content accounts for 10%-90% of the total liquid preparation.

Polyethylene glycol as described in the above method:

(1) The molecular weight of polyethylene glycol is between 200-20000, and it can be a mixture of one or more of them;

(2) The end of polyethylene glycol can be capped with methoxy;

(3) The end of polyethylene glycol can be connected with a functional end group, and the end group can be any of hydrophilic hydroxyl, amino, carboxyl, imidazole, aldehyde, cyano, nitro; it can also be hydrophobic Any one of alkyl group, sterol, alkoxy group, aromatic group, aromatic heterocyclic group, amide ester group, halogen atom, trichloromethyl group, ester group, mercapto group and allyl group;

(4) The additive may be any one of the above-mentioned polymers, or a mixture of two or more of the above-mentioned polymers, including a mixture of polymers with different terminal groups.

The drug contained in the above method is selected from hydrophobic camptothecin, 10-hydroxycamptothecin, 9-nitrocamptothecin, 9-aminocamptothecin, 7-ethyl-10-hydroxycamptothecin, Bitecan, Exitecan, Berotecan, Karenitecin, Gemitecan, Gematecan, or one or a combination of hydrophilic topotecan and irinotecan.

The camptothecin derivatives contained in the above method are characterized in that the effective ring-closed form is 15%-80% when the pH of the solvent is between 6.5-8.

The solvent described in the above method is characterized in that it can be pure water, buffer solution, body fluid, tissue culture fluid or other solvent media that do not mainly contain organic solvents.

The liquid preparation described in the above method is characterized in that the pH value is between 4-8.

The liquid preparation of the present invention can be used to prepare pharmaceutical preparations for treating tumors. The types of tumors can be brain tumors, liver cancer, lung cancer, esophageal cancer, gastric cancer, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, ovarian cancer, endometrial cancer, kidney cancer, prostate cancer, bladder cancer, colon cancer , rectal cancer, testicular cancer, head and neck cancer and other primary or secondary cancer, sarcoma or carcinosarcoma.

The pharmaceutical preparation of the present invention can be administered through oral administration, intravenous injection, subcutaneous injection, intramuscular injection and intratumoral injection.

The pharmacodynamic characteristics of different preparations in the S180 sarcoma model in vivo are shown in Table 1.

Description of drawings

Figure 1 Opening and closing ring transitions of camptothecin-like drugs.

Figure 2 The equilibrium ring closure rate of topotecan in PEG solution.

Fig. 3 Equilibrium ring closure rate of hydroxycamptothecin in PEG solution.

Fig. 4 The equilibrium ring closure rate of topotecan in different molecular weight PEG.

Fig. 5 Pharmacodynamic evaluation of S180 sarcoma model. In the figure, the Saline group is the negative control saline group; A0 is the blank MPEG5000 group; B1 is the PEG+drug group; C1 is the drug alone group; D is the positive control 5-fluorouracil group.

detailed description

The present invention is further described by examples below, but not limited to these examples.

Examples 1-9: Different end groups of polyethylene glycol

Example 1

Take 15g of polyethylene glycol 1500 (PEG1500), add 5g of succinic anhydride, 2ml of pyridine, dissolve in 200ml of dichloromethane, and reflux for 48 hours. After removing part of the organic solvent and pyridine by suspension evaporation, unreacted succinic anhydride was precipitated by cooling, and the filtrate was filtered off. Rotary evaporation again to remove most of the organic solvent, precipitation with 10 times excess diethyl ether, filtration to obtain the product, vacuum drying to obtain a carrier material with carboxyl groups at both ends.

Example 2

Take 20g of monomethoxypolyethylene glycol 2000 (PEG2000), add 5g of succinic anhydride, 2ml of pyridine, dissolve in 200ml of dichloromethane, and reflux for 48 hours. After removing part of the organic solvent and pyridine by suspension evaporation, unreacted succinic anhydride was precipitated by cooling, and the filtrate was filtered off. Rotary evaporation again to remove most of the organic solvent, precipitation with 10 times excess ether, filtration to obtain the product, and vacuum drying to obtain a carrier material with a single terminal group of carboxyl group.

Example 3

Take 15g of polyethylene glycol 1500 (PEG1500), remove water under vacuum at 130°C for 4 hours, add 50ml of acetonitrile to form a solution, slowly drop into the CDI acetonitrile solution with 4 times excess polymer hydroxyl groups, and react overnight. Afterwards, the reaction solution was transferred out and slowly dropped into ethylenediamine, and reacted for 4 hours to obtain polyethylene glycol with amino groups at both ends.

Example 4

Take 20g of monomethoxypolyethylene glycol 2000 (PEG2000), remove water under vacuum at 130°C for 4 hours, add 50ml of acetonitrile to form a solution, slowly drop into the CDI acetonitrile solution with 4 times excess polymer hydroxyl group, and react overnight. Afterwards, the reaction solution was transferred out and slowly dropped into ethylenediamine, and reacted for 4 hours to obtain polyethylene glycol with a single terminal group of amino group.

Example 5

Take 15g of polyethylene glycol 1500 (PEG1500), add 3.0g of N -Boc-histidine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) 3.5 g, 2.6 g of 4-dimethylaminopyrimidine (DMAP), 150 ml of dichloromethane, reacted at room temperature for 48 hours. Part of the solvent was removed by suspension evaporation, precipitated with ether, further washed at 80°C to remove residual unreacted substances and catalyst, and freeze-dried. Polyethylene glycol with double-terminal amino acid (histidine) was obtained.

Example 6

Take 20g of monomethoxypolyethylene glycol 2000 (PEG2000), add 3.0g of N -Boc-histidine, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl) 3.5g, 4-dimethylaminopyrimidine (DMAP) 2.6g, dichloromethane 150ml, react at room temperature for 48 hours. Part of the solvent was removed by suspension evaporation, precipitated with ether, further washed at 80°C to remove residual unreacted substances and catalyst, and freeze-dried. A polyethylene glycol with a single terminal amino acid (histidine) was obtained.

Example 7

Dissolve 15g of polyethylene glycol 1500 (PEG1500) in dichloromethane, slowly add acryloyl chloride (4mL) in dichloromethane solution (50mL) dropwise, and use triethylamine (4mL) as an acid-binding agent. Added dropwise for 8 hours, then stirred at room temperature for 48 hours. Precipitate with glacial ether and dry in vacuo to obtain polyethylene glycol modified with allyl groups at both ends.

Example 8

Dissolve 20g of monomethoxypolyethylene glycol 2000 (PEG2000) in dichloromethane, slowly add acryloyl chloride (4mL) in dichloromethane solution (50mL) dropwise, using triethylamine (4mL) as an acid-binding agent, Add dropwise under ice bath for 8 hours, then stir and react at room temperature for 48h. Precipitate with glacial ether and dry in vacuo to obtain polyethylene glycol modified with allyl group at one end.

Example 9

Take the polymer material synthesized in Examples 7-8, dissolve it in phosphate buffer, add cross-linking agents APS and TEMED, and obtain end-group cross-linked polyethylene glycol material.

Embodiment 10-12: the weight percent in the additive polyethylene glycol preparation

Example 10

Take 100 mg of topotecan and 10 g of polyethylene glycol 20000, add them together into 90 ml of phosphate buffer solution, and after fully dissolving, a liquid drug-loaded preparation with an additive of 10 wt % is obtained.

Example 11

Take 100 mg of topotecan and 40 g of polyethylene glycol 2000, and add them together into 60 ml of phosphate buffer solution. After fully dissolving, a liquid drug-loaded preparation with 40 wt% of the additive is obtained.

Example 12

Take 100 mg of topotecan and 90 g of polyethylene glycol 200, and add them together into 10 ml of phosphate buffer solution. After fully dissolving, a liquid drug-loaded preparation with an additive of 90 wt % is obtained.

Examples 13-25: Different PEG compositions

Example 13

Take 100 mg of topotecan and 10 g of polyethylene glycol 200 and add them together into 90 ml of phosphate buffer solution. After fully dissolving, a liquid drug-loaded preparation with PEG200 as the additive is obtained.

Example 14

Take 100 mg of topotecan and 10 g of polyethylene glycol 400 and add them together into 90 ml of phosphate buffer solution. After fully dissolving, a liquid drug-loaded preparation with PEG200 as the additive is obtained.

Example 15

Take 100 mg of topotecan and 10 g of polyethylene glycol 1000, add them together into 90 ml of phosphate buffer solution, and after fully dissolving, obtain a liquid drug-loaded preparation in which the additive is PEG1000.

Example 16

Take 100 mg of topotecan and 10 g of polyethylene glycol 5000, add them together into 90 ml of phosphate buffer solution, and after fully dissolving, obtain a liquid drug-loaded preparation in which the additive is PEG5000.

Example 17

Take 100 mg of topotecan and 10 g of polyethylene glycol 20000, add them together into 90 ml of phosphate buffer solution, and after fully dissolving, obtain a liquid drug-loaded preparation in which the additive is PEG20000.

Example 18

Take 100 mg of topotecan, 5 g of polyethylene glycol 200 and 5 g of polyethylene glycol 2000, and add them together into 90 ml of phosphate buffer solution. After fully dissolving, a liquid drug-loaded preparation whose additive is a mixture of PEG200 and PEG2000 is obtained.

Example 19

Take 100 mg of topotecan, 5 g of polyethylene glycol 5000 and 5 g of monomethoxy polyethylene glycol 5000, and add them together into 90 ml of phosphate buffer solution. After fully dissolving, a liquid drug-loaded preparation whose additive is a mixture of PEG5000 and MPEG2000 is obtained.

Example 20

Take 100 mg of topotecan, 3 g of polyethylene glycol 2000 and 7 g of carboxyl-terminated polyethylene glycol 2000, and add them together to 90 ml of phosphate buffer solution. After fully dissolving, a liquid drug-loaded preparation whose additive is a mixture of PEG2000 and carboxyl-terminated PEG2000 is obtained.

Example 21

Take 100 mg of topotecan, 1 g of polyethylene glycol 4000 and 9 g of amino-terminated polyethylene glycol 2000, and add them together to 90 ml of phosphate buffer solution. After fully dissolving, a liquid drug-loaded preparation whose additive is a mixture of PEG4000 and amino-terminated PEG2000 is obtained.

Example 22

Get 100mg of topotecan, 5g of polyethylene glycol 10000 and 5g of allyl-terminated polyethylene glycol 4000, and add them together in 90ml of phosphate buffer solution. After fully dissolving, the additive is a mixture of PEG10000 and allyl-terminated PEG4000. Liquid drug-loaded formulations.

Example 23

Take 100mg of topotecan, 4g of carboxyl-terminated polyethylene glycol 8000 and 6g of allyl-terminated polyethylene glycol 2000, and add them together into 90ml of phosphate buffer solution. After fully dissolving, the additives are carboxyl-terminated PEG8000 and Liquid drug-loaded formulation based on PEG2000 mixture.

Example 24

Take 100 mg of topotecan and 10 g of allyl polyethylene glycol 2000, add them together into 90 ml of phosphate buffer, and after fully dissolving, obtain a liquid drug-loading preparation in which the additive is allyl PEG2000.

Example 25

Take 100 mg of topotecan and 10 g of cross-linked polyethylene glycol 2000, add them together into 90 ml of phosphate buffer, and after fully dissolving, obtain a liquid drug-loaded preparation in which the additive is cross-linked PEG2000.

Examples 26-29: Different entrapped drugs

Example 26

Take 10 mg of camptothecin and 40 g of polyethylene glycol 2000, and add them together into 60 ml of phosphate buffer solution, and after fully dissolving, a liquid preparation containing camptothecin is obtained.

Example 27

Take 20 mg of hydroxycamptothecin and 40 g of polyethylene glycol 2000, and add them together into 60 ml of phosphate buffer solution, and after fully dissolving, a liquid preparation containing hydroxycamptothecin is obtained.

Example 28

Take 100 mg of topotecan and 40 g of polyethylene glycol 2000, and add them together into 60 ml of phosphate buffer solution, and after fully dissolving, a liquid preparation containing topotecan is obtained.

Example 29

Take 100 mg of irinotecan and 40 g of polyethylene glycol 2000, and add them together into 60 ml of phosphate buffer solution, and after fully dissolving, a liquid preparation containing irinotecan is obtained.

Embodiment 30-32: weight percentage of entrapped drug

Example 30

Take 1 mg of topotecan and 40 g of polyethylene glycol 2000, add them together into 60 ml of phosphate buffer, and after fully dissolving, a liquid preparation containing 0.001 wt% topotecan is obtained.

Example 31

Take 100 mg of topotecan and 40 g of polyethylene glycol 2000, add them together into 60 ml of phosphate buffer, and after fully dissolving, a liquid preparation containing 0.1 wt % topotecan is obtained.

Example 32

Take 10g of topotecan and 40g of polyethylene glycol 2000, add them together into 50ml of phosphate buffer solution, and after fully dissolving, a liquid preparation containing 10wt% topotecan is obtained.

Examples 33-34: Different preparation methods

Example 33

Take the active dose of topotecan and 40g of polyethylene glycol 2000, and add them together into 60ml of phosphate buffer solution. After fully dissolving, a liquid preparation containing topotecan is obtained. Store it at -20°C or below for later use, and reconstitute it before use. Dissolved, injected into the body.

Example 34

First prepare a 40wt% polyethylene glycol 2000 solution, store it at -20°C or below for later use, redissolve it before use, add the active dose of topotecan, fully dissolve it, and use it directly.

Examples 35-38: Different vehicles

Example 35

Take 100 mg of topotecan and 40 g of polyethylene glycol 2000, add them together into 60 ml of normal saline, and after fully dissolving, obtain a topotecan preparation in which the solvent is normal saline.

Example 36

Take 100 mg of topotecan and 40 g of polyethylene glycol 2000, add them together into 60 ml of phosphate buffered saline, and after fully dissolving, obtain a topotecan preparation in which the solvent is phosphate buffered saline.

Example 37

Take 100 mg of topotecan and 40 g of polyethylene glycol 2000, add them together into 60 ml of tissue culture medium, and after fully dissolving, obtain a topotecan preparation in which the solvent is tissue culture medium.

Example 38

Take 100mg of topotecan and 40g of polyethylene glycol 2000, and add them together into 60ml of water/ethanol (95:5, v/v) mixed solution. After fully dissolving, a topotecan preparation whose solvent is a water/ethanol mixed solution is obtained.

Examples 39-41: Active loop closure rate of entrapped drugs

Example 39

Co-dissolve 6 mg of topotecan and 40 g of polyethylene glycol (molecular weight 200, 400, 1000, 2000) in 100 ml of phosphate buffer, stir at room temperature until completely dissolved, adjust the pH to pH 7.4, and determine the drug equilibrium closed-loop by HPLC The results are shown in Figure 4.

Example 40

Co-dissolve 6 mg of topotecan and 40 g of monomethyl polyethylene glycol (molecular weight 2000, 5000) in 100 ml of phosphate buffer, stir at room temperature until completely dissolved, adjust the pH to pH 7.4, and measure the drug equilibrium loop closure rate by HPLC , the results are shown in Figure 4.

Example 41

5 mg of hydroxycamptothecin and 40 g of monomethyl polyethylene glycol 5000 were co-dissolved in 100 ml of phosphate buffer, stirred at room temperature until completely dissolved, adjusted to pH 7.4, and the drug equilibrium ring-closing rate was determined by HPLC, the results are shown in Fig. 3.

Example 42

5 mg of topotecan and 40 g of monomethyl polyethylene glycol 5000 were co-dissolved in 100 ml of phosphate buffer, stirred at room temperature until completely dissolved, and the pH was adjusted to pH 6.4. The drug equilibrium ring-closing rate was determined by HPLC to be 82.1%.

Example 43

5 mg of topotecan and 40 g of monomethyl polyethylene glycol 5000 were co-dissolved in 100 ml of phosphate buffer, stirred at room temperature until completely dissolved, and the pH was adjusted to pH 8.0. The drug equilibrium ring-closing rate was determined by HPLC to be 22.9%.

Example 42: Pharmacodynamic evaluation of the S180 sarcoma model of a preparation that simply adds polyethylene glycol to increase the active loop closure rate of camptothecin compounds

Take the well-grown 7-11 day old S180 tumor, make 1-2×10 ⁷ /ml cell suspension from the tumor tissue, inoculate 0.2ml/mouse subcutaneously in the left axilla of the mouse, and record it as day 0. 24 hours after the inoculation, the cages were randomly divided, and the samples of each group were injected intratumorally on the first day, the third day, and the fifth day, each time at 0.1 ml per mouse. On the 6th day, the animals were sacrificed, the body weight and tumor weight were weighed, the average tumor weight of each group was calculated, and the tumor inhibition rate was calculated according to the following formula and t test was performed.

Efficacy evaluation criteria: tumor inhibition rate < 40% is invalid; tumor inhibition rate ≥ 40, and p < 0.05 after statistical processing is effective. The results obtained are shown in Table 1 and Figure 5. It can be seen that at the same dose, the PEG additive group is better than the drug alone group.

Table 1 Pharmacodynamic evaluation of S180 sarcoma model in vivo

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Claims (6)

1. a liquid preparation, is characterized in that, take Polyethylene Glycol as additive, and camptothecin drug analog derivative is active component, and water is the disperse medium of main body is solvent, and three is cooperatively formed; Wherein, polyethyleneglycol content is the 5%-90wt% of liquid preparation; Medicine carrying capacity is the 0.001-10wt% of liquid preparation; Solvent pH scope is between 6.5-8, and camptothecin drug analog derivative effective closed-loop form is 15%-80%; Wherein:

Described camptothecin drug analog derivative is selected from hydrophobic camptothecine, 10-hydroxycamptothecine, 9-nitrocamptothecin, 9-aminocamptothecin, SN38, Exatecan, Karenitecin, lucky miaow for health, gefitinib, or hydrophilic topotecan, irinotecan one or a combination set of;

Water/the alcohol mixed solution of described solvent to be pure water, normal saline, buffer solution, body fluid, tissue culture medium or volume ratio be 95:5.

2. liquid preparation according to claim 1, is characterized in that:

(1) molecular weight of Polyethylene Glycol is between 200-20000, and is one or more mixture wherein; And

(2) Polyethylene Glycol end is connected to function end group, this end group is any one in hydrophilic hydroxyl, amino, carboxyl, imidazole radicals, aldehyde radical, cyano group, nitro, or hydrophobic alkyl, sterin, alkoxyl, amide ester group, halogen atom, trichloromethyl, ester group, sulfydryl, any one in pi-allyl.

3. a preparation method for liquid preparation as claimed in claim 1, is characterized in that being selected from one of following:

(1) medicine of Polyethylene Glycol and active dose is dissolved in solvent jointly, after fully dissolving, in≤-20 DEG C at store for future use, use front redissolution, injection in body;

(2) first Polyethylene Glycol is dissolved in solvent, in≤-20 DEG C at store for future use, use front redissolution, add the dry powder drug of active dose, after fully dissolving, directly use.

4. the application of liquid preparation as claimed in claim 1 in preparation tumor preparation.

5. application according to claim 4, it is characterized in that described tumor, its classification is sarcoma, the cerebral tumor of carcinosarcoma or former or secondary, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, renal carcinoma, carcinoma of prostate, bladder cancer, colon and rectum carcinoma, carcinoma of testis or incidence cancer.

6. application according to claim 4, is characterized in that described preparation is by oral administration, intravenous injection, subcutaneous injection, intramuscular injection or intratumor injection administration.