CN116370476B

CN116370476B - Chemotherapy medicine composition and application thereof

Info

Publication number: CN116370476B
Application number: CN202310436293.7A
Authority: CN
Inventors: 高宁; 姜秀星; 袁亮; 杨佳旺
Original assignee: Zunyi Medical University
Current assignee: Zunyi Medical University
Priority date: 2023-04-21
Filing date: 2023-04-21
Publication date: 2024-01-30
Anticipated expiration: 2043-04-21
Also published as: CN116370476A

Abstract

The invention relates to the technical field of chemotherapeutic drugs, and discloses a chemotherapeutic drug composition and application thereof, wherein the active ingredients of the drug composition comprise YM155 and ceritinib, and the mass ratio of the YM155 to the ceritinib is 4:2.025. according to the scheme, by combining YM155 and ceritinib, on one hand, YM155 cooperates with the inhibition effect of ceritinib on tumor cells, so that the treatment effect of chemotherapy is improved; on the other hand, YM155 can also obviously reduce the situation that the critinib inevitably kills normal cells to generate adverse reaction, reduce the drug resistance of tumor cells to the critinib in the long-term treatment process, and promote the treatment effect when the medicine is taken for a long time.

Description

Chemotherapy medicine composition and application thereof

Technical Field

The invention relates to the technical field of chemotherapeutic drugs, in particular to a chemotherapeutic drug composition and application thereof.

Background

Chemotherapy is one of the main methods for treating triple negative breast cancer, and is a treatment mode for preventing proliferation, infiltration and metastasis of triple negative breast cancer cells by using chemical medicines until the triple negative breast cancer cells are finally killed. However, some clinical first-line chemotherapeutics commonly used at present inevitably damage normal cells of human body while killing triple negative breast cancer cells due to weak selectivity, so that adverse reactions of the medicines occur. And the time for treating the triple negative breast cancer is relatively long, and drug resistance or drug resistance is easy to generate in the long-time treatment process.

How to improve the curative effect, reduce adverse drug reactions and prevent drug resistance on the premise of not damaging normal cells of a human body is a difficult point to overcome when a chemotherapeutic drug is used for treating cancers.

Disclosure of Invention

The invention aims to provide a chemotherapeutic medicine composition and application thereof, so as to solve the technical problems of limited treatment effect and serious adverse reaction caused by weak selectivity in the existing chemotherapeutic technology for treating triple negative breast cancer.

In order to achieve the above purpose, the invention adopts the following technical scheme: a chemotherapeutic pharmaceutical composition, the active ingredients of which comprise YM155 and ceritinib.

The principle and the advantages of the scheme are as follows: ceritinib (Cer, cas: 1032900-25-6) is used to treat metastatic non-small cell lung cancer (NSCLC) patients who are positive for Anaplastic Lymphoma Kinase (ALK), have a progressive tumor condition, or are intolerant to Crizotinib. YM155 (Sepantronium Bromide) (Survivin inhibitor) is a potent Survivin inhibitor that acts by inhibiting Survivin promoter activity and is effective in inhibiting human cancer cell lines (mutant p53 or short p 53). However, the killing effect of YM155 on tumor cells appears to be concentration dependent. In order to reduce the dosage of the medicine and avoid the side effects, the inventor combines the two medicines on the premise that the medicines are used singly and have no cytotoxicity to normal cells and tumor cells; the inventor experiment finds that the combination of the two medicines with low dosage can effectively inhibit the proliferation of tumor cells and induce the apoptosis of the tumor cells, and has unexpected technical effects.

Compared with the fact that the inhibition effect is limited when the two are used independently, the YM155 and the ceritinib are used in combination, the synergistic effect can be achieved, the inhibition effect of the ceritinib is improved, and the effect of inhibiting and killing triple negative breast cancer cells is improved. The inventor experiment shows that when the pharmaceutical composition of the scheme is used for inhibiting breast cancer MDA-MB-231 cells, MCF-7 cells and BT549 cells, under the condition of using YM155, the effects of inhibiting and killing the tumor cells are greatly improved, and the effect of YM155 combined with the ceritinib is obviously superior to the effect of single use of the two, and the effects have a synergistic effect.

In addition, the scheme can obviously reduce the situation that the critinib inevitably kills normal cells to generate adverse reaction by combining YM155 with the critinib, can reduce the drug resistance of tumor cells to the critinib in the long-term treatment process, and improves the inhibition effect of long-term treatment.

Preferably, the mass ratio of the YM155 to the ceritinib is 4:2.025 to 3.24.

The beneficial effects are that: the YM155 and the ceritinib with the mass ratio can effectively inhibit the formation of tumor cells, and have unexpected technical effects. The inventors have found experimentally that when a tumor is treated with a combination of YM155 and ceritinib, the minimum mass ratio of the actual dosage of YM155 to the actual dosage of ceritinib is 0.4mg to 0.2025mg; under the synergistic effect of the two, the dosage of the two medicines can be effectively reduced, the cost is reduced, and the adverse reaction of patients to ceritinib and the treatment risk of drug resistance can be reduced. The inventor experiment finds that if the mass ratio is higher than the mass ratio (for example, 4:1.5 is selected), the ideal inhibition effect cannot be achieved; if the mass ratio is lower than this, the normal cells of the patient are inevitably affected, which causes adverse reactions and adversely damages the health of the patient.

Preferably, the active ingredient is present in free form in molecular or ionic state.

The beneficial effects are that: in the scheme, before using YM155 and ceritinib, physiological saline or 5% glucose injection is needed to prepare YM155 into YM155 injection or ceritinib into ceritinib solution, so that the YM155 and the ceritinib are dissolved in the solution, and the dispersion is facilitated, and the drug effect is fully exerted.

The scheme also provides application of the chemotherapeutic medicine composition in preparing an anti-tumor medicine, wherein the tumor aimed by the anti-tumor medicine is in-situ or recurrent triple negative breast cancer.

The beneficial effects are that: the anti-tumor medicine is prepared from a chemotherapeutic medicine composition, the chemotherapeutic medicine composition consists of YM155 and ceritinib, and the YM155 and the ceritinib are combined to have remarkable inhibition effect on human triple negative breast cancer cells MDA-MB-231 and BT549 cells, and have weaker sensitization effect on non-triple negative breast cancer cells MCF-7 cells, so that the YM155 and the ceritinib can be used for treating triple negative breast cancer. The combination of YM155 and ceritinib showed good triple negative breast cancer cell inhibition. Triple negative breast cancer refers to breast cancer with negative Estrogen Receptor (ER), progestogen Receptor (PR) and protooncogene Her-2 as cancer tissue immunohistochemical examination results, and has the disadvantages of poor prognosis and high death risk.

Preferably, the active ingredients of the pharmaceutical composition include YM155 and ceritinib.

The beneficial effects are that: according to the scheme, by combining YM155 and ceritinib, on one hand, YM155 cooperates with the inhibition effect of ceritinib on tumor cells, so that the treatment effect of chemotherapy is improved; on the other hand, YM155 can also obviously reduce the situation that the critinib inevitably kills normal cells to generate adverse reaction, reduce the drug resistance of tumor cells to the critinib in the long-term treatment process, and promote the treatment effect when the medicine is taken for a long time.

Preferably, the pharmaceutical composition is administered intravenously.

The beneficial effects are that: the scheme adopts the administration mode, which not only accords with the traditional administration habit, but also is more convenient. Intravenous administration is a conventional mode of administration of YM155 and ceritinib. The injection of the ceritinib in the combination drug of the invention is a discontinuous administration mode which is the same as that of the single-use ceritinib injection. Because the medicine ceritinib has longer metabolism time in human body, the discontinuous medication mode can reduce toxic and side effects. Even though the YM155 is used cooperatively to form the pharmaceutical composition, the dosage of some ceritinib can be reduced, the administration mode is still adopted, and the traditional administration habit is met. When the medicine combination of the invention is applied, the step of injecting YM155 injection is only added, and no other special operation method is adopted, thus being more convenient. The actual amount of YM155 in the pharmaceutical composition of the present invention is far less than that of retinib. Experiments prove that the YM155 synergistic critinib can not only inhibit and kill various malignant tumor cells, but also reduce the dosage, shorten the treatment period and reduce the occurrence of toxic and side effects. Even in reverse, under the action of the prior clinical chemotherapeutic medicine ceritinib medium, the inventor of the application discovers that the YM155 has the effect of effectively inducing autophagy of various tumor cells and has the effect of killing various malignant tumor cells with reliable effect and practical value. .

Preferably, the YM155 is used in an amount of 0.4 mg/kg.bw.

Preferably, the dose of the ceritinib is 0.675-0.81 mg/kg.bw.

The beneficial effects are that: the inventor obtains single dose of YM155 and ceritinib by converting the result through animal experiments. In Experimental example 2, the single dose of YM155 was 5 mg/kg.bw, and the single dose of ceritinib was 10 mg/kg.bw. The conversion basis is given by the U.S. Food and Drug Administration (FDA) in the "estimate of safe dosing of healthy adult subjects in drug clinical trials" (Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers), the conversion ratio of the injected dose to the human and mouse (i.e., nude mice in experimental verification) required to achieve the same biological effect (1:12.3).

Preferably, the YM155 and ceritinib are administered at a frequency ratio of 10:3.

the beneficial effects are that: the scheme adopts the administration frequency, the use of the low-toxicity YM155 can reduce the administration times and dosage of the ceritinib, the adverse reaction and drug resistance caused by the administration are reduced while the inhibition effect is improved, and the inhibition effect of the ceritinib in the long-term treatment process is improved.

Drawings

FIG. 1 shows the inhibition curves of the combination of ceritinib single and ceritinib with YM155 (the subject is breast cancer cells, and the concentration of YM155 is constant) of experimental example 1.

FIG. 2 shows the cancer cell inhibition curves of YM155 alone and YM155 in combination with ceritinib of Experimental example 1 (the subjects were breast cancer cells, and the concentration of ceritinib was constant).

FIG. 3 is a graph showing tumor volumes of experimental mice after 21 days of treatment in experimental example 2.

FIG. 4 is a graph showing the change in body weight of the experimental mice of experimental example 2.

Fig. 5 is a graph showing the change in survival rate of experimental mice of experimental example 2.

Detailed Description

Example 1

A chemotherapeutic medicine composition of the scheme consists of active ingredients YM155 and ceritinib, wherein the structural formula of YM155 is shown in a formula (I), and the structural formula of ceritinib is shown in a formula (II).

When it is known that the pharmaceutical composition provided by the present invention can improve the curative effect and reduce adverse reactions, and the pharmaceutical composition of the present invention is adopted to avoid drug resistance or drug tolerance, it is fully possible for those skilled in the art to determine the ratio between the two components of YM155 and ceritinib by routine experiments of the system for specific malignant tumors. For a plurality of malignant tumor cells selected during experimental verification of the invention, the pharmaceutical composition is preferably prepared by adopting the proportion, and the mass ratio of the total drug quantity of YM155 to the total drug quantity of the ceritinib is 4 mg:2.025-2.43 mg in one treatment course (10 days). The dose ratio was converted based on the animal experimental dose (experimental example 2). The conversion basis is given by the U.S. Food and Drug Administration (FDA) in the "estimate of safe dosing of healthy adult subjects in drug clinical trials" (Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers), the conversion ratio of the injected dose to the human and mouse (i.e., nude mice in experimental verification) required to achieve the same biological effect (1:12.3).

The active ingredient in this embodiment is present in free form or in the form of a pharmaceutically acceptable salt. Specifically, before using YM155 and ceritinib in this solution, YM155 needs to be prepared into YM155 injection or ceritinib needs to be prepared into ceritinib solution by using normal saline or 5% glucose injection, so that the YM155 and the ceritinib are dissolved in the solution, which is helpful for dispersion and full play of drug effect.

The scheme also provides application of the chemotherapeutic medicine composition in preparing an anti-tumor medicine, wherein active ingredients of the medicine composition comprise YM155 and ceritinib, and tumors targeted by the anti-tumor medicine are in-situ or recurrent triple negative breast cancer. The drug combination is administrated intravenously; the dosage of YM155 was 0.4 mg/kg.bw, and the dosage of ceritinib was 0.81 mg/kg.bw; the dosing frequency ratio of YM155 and ceritinib was 10:3.

Specifically, when the pharmaceutical composition of the scheme is used for preparing an anti-tumor drug and treating in-situ or recurrent triple negative breast cancer, YM155 and ceritinib are uniformly and repeatedly administered (the ratio of total drug amount is kept to be 4mg: 2.025-2.43 mg, and the embodiment specifically takes 4mg:2.43mg as an example, the specific application method of the pharmaceutical composition of the scheme is as follows:

(1) YM155 was administered intravenously once daily at a dose of YM 155:patient weight=0.4 mg/kg (YM 155 was formulated as YM155 injection using physiological saline or 5% dextrose injection, in this example, physiological saline);

(2) on the same day as the YM155 injection according to step (1), the first time of the ceritinib injection was intravenously injected according to the dose of ceritinib: patient weight=0.81 mg/kg (the ceritinib injection is prepared by using physiological saline or 5% glucose injection, the glucose injection used in the present example);

(3) by the fifth day, the same dose of ceritinib injection is injected once again by vein according to the dose described in the step (2); cycling according to steps (1) - (3);

(4) from the tenth day, it is determined whether or not to cycle according to the methods of steps (1) to (3), and the number of cycles and the intermediate withdrawal time, according to the bearing capacity and the therapeutic effect of the patient's body.

It is clear to those skilled in the art that the concentration of the injection should be determined according to factors such as the bearing capacity of the patient's body, the number of "cycles" in step (4) may be generally 1 to 4 times, and the "intermediate withdrawal time" may be generally 1 to 2 weeks; for patients with particularly poor body condition, it is even possible to use steps (1) and (2) as a medication cycle or a treatment course (i.e. to pause the medication from day six).

Experimental example 1: cell experiment

1. Cell selection and active culture

The experiment selects human breast cancer cells MDA-MB-231, MCF-7 and BT549. Wherein, human breast cancer cells MDA-MB-231, MCF-7 and BT549 are cultured in DMEM+10% FBS complete culture medium, and the above cells are all at 37 ℃ and CO with 5% concentration ₂ Culturing in a saturated humidity cell incubator.

2. Experimental methods and results

After each tumor cell line had stabilized, cells were plated in 96-well plates with 5000 cells per well, each containing 90 μl of complete medium, and then treated with drugs. MTT assay was performed on the treated cells to determine the effect of the drug on cell activity: after 48 hours of dosing, 20. Mu.L of a solution of 5mg/mL thiazole blue (MTT) in Phosphate Buffer (PBS) was added to each well and incubation was continued for 4 hours. The upper medium was aspirated, 150 μl of Dimethylsulfoxide (DMSO) was added to each well for solubilization, and after 10 minutes of solubilization on a shaker, absorbance values were measured at a495 with a microplate reader, and cell viability was calculated according to the following formula:

percent cell viability = (treatment group absorbance-blank well absorbance)/(control group absorbance-blank well absorbance) ×100%.

The specific experimental grouping mode is as follows:

human breast cancer cells MDA-MB-231, MCF-7, BT549 were grouped and treated as follows:

(1) Control group: treatment was performed with 10. Mu.L of the complete medium solution.

(2) Ceritinib group: the complete culture medium is used to prepare the ceritinib solution with the concentration of 0, 1, 2, 4, 6, 8 and 10 mu M (mu mol/L), and 10 mu L of treatment is added to each well to make the final concentration of the ceritinib solution be 0, 0.1, 0.2, 0.4, 0.6, 0.8 and 1.0 mu M. The experimental results are shown in fig. 1.

(3) YM155 group: YM155 solutions at concentrations of 0, 0.5, 1, 2, 4, 6, 8, 10, 20. Mu.M (. Mu.mol/L) were prepared with complete medium, and 10. Mu.L of treatment was added to each well to give final concentrations of 0, 0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 2.0. Mu.M. The experimental results are shown in fig. 2.

(4) Combination group: ceritinib and YM155 combined pharmaceutical group

The combination of ceritinib and YM155 used two experimental protocols:

scheme one: the complete culture medium was used to prepare 0, 1, 2, 4, 6, 8, 10. Mu.M of ceritinib solution and 20. Mu.M of YM155 mixed liquor, and 10. Mu.L of mixed liquor was added to each well to make the final concentration of ceritinib effect be 0, 0.1, 0.2, 0.4, 0.6, 0.8, 1. Mu.M and the final concentration of YM155 effect be 2. Mu.M, and the experimental results are shown in FIG. 1.

As can be seen from fig. 1, ceritinib itself has a certain concentration-dependent cancer cell inhibitory effect at a high dose, whereas the same concentration of ceritinib has an enhanced cancer cell inhibitory effect under the action of YM 155.

Scheme II: the YM155 solution with the concentration of 0, 0.5, 1, 2, 4, 6, 8, 10 and 20 mu M and the ceritinib mixed liquor with the concentration of 5 mu M are prepared by using a complete culture medium, 10 mu L of mixed liquor is added to each hole for treatment, so that the final working concentration of the YM155 is 0, 0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0 and 2.0 mu M, and the final working concentration of the ceritinib is 0.5 mu M, and the experimental results are shown in figure 2.

As can be seen from fig. 2, YM155 itself does not have a significant cancer cell inhibitory effect, and as the amount of YM155 increases, YM155 does not exhibit a cancer cell inhibitory effect. However, after the addition of 0.5 μm of ceritinib, the composition has a remarkable effect of inhibiting cancer cells, which is not only produced by ceritinib alone, but is achieved by the synergistic effect of ceritinib and YM 155.

In combination with FIGS. 1 and 2, YM155 alone had no significant effect on cell viability. The tumor cell viability of the YM155 co-ceritinib group was lower to a different extent than that of the ceritinib group alone, the combined effects of the two are not added, but the effects of 1+1 is larger than 2, and the two are synergistic, so that the anti-cancer agent has unexpected technical effects on inhibiting cancer cells.

By combining the experimental results of fig. 1 and 2, the combined use of the YM155 and the ceritinib has remarkable inhibition effect on human triple negative breast cancer cells MDA-MB-231 and BT549 cells, and has weaker sensitization effect on non-triple negative breast cancer cells MCF-7 cells, so that the YM155 and the ceritinib can be used for treating triple negative breast cancer. The combination of YM155 and ceritinib showed good triple negative breast cancer cell inhibition.

In fig. 1 to 2, the ordinate indicates the cell viability, that is, the cell viability of the treatment group relative to the control group. The abscissa represents various human tumor cell lines (note: only represented by the distinguishing symbol of the corresponding tumor cells). The values corresponding to the columns are the average values of the groups, and the "I" symbols in the figures indicate the vertical deviations.

It is clear to those skilled in the art that in the cell experiments, the drug effect only corresponds to the drug concentration, not to the total amount of the drug, and at the same time, the drug concentration at the cell level cannot be converted from the concentration in the animal experiments, so that the cell level experiments can only verify that the drug combination of YM155 co-chromene has no significant difference compared with chromene alone. Of course, the effectiveness and reliability of the pharmaceutical combinations of the present invention are also well documented by this verification. When the effect of the medicine combination is further verified through a nude mouse experiment, only one tumor cell is researched.

Experimental example 2: nude mice transplantation tumor model experiment (taking transplantation of human breast cancer MDA-MB-231 cells as an example)

During this experiment, various drugs were injected intraperitoneally into nude mice for comparison (i.e., not intravenously). Thus, the dose was converted based on the injection dose conversion ratio (1:12.3) of human to mouse (i.e., nude mouse in experimental verification) required to achieve the same biological effect, as given by the U.S. Food and Drug Administration (FDA) in the "estimate of safe dose for healthy adult subject in drug clinical trial" (Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers).

1. Selection of nude mice

24 nude mice with 6-8 weeks age and no specific pathogenic microorganism (SPF) level are taken, the weight range is 20+/-2 g, and the nude mice are fed in a day-night alternate room temperature (20-23 ℃) environment and are free to drink and eat.

2. Experimental grouping and dosing (4 groups total)

All nude mice were randomly divided into four groups of 6, each inoculated with 1X 10 on the outside of the right thigh ⁷ The individual used 0.2mL of suspension prepared from human breast cancer MDA-MB-231 cells (the culture of human breast cancer MDA-MB-231 cells was the same as in the "cell experiment" described above), and administration was started after neoplasia as follows.

(1) Control group: the physiological saline with the same volume as the treatment group is injected into the abdominal cavity for 1 time/day;

(2) YM155 group: injecting YM155 into the abdominal cavity for 1 time/day according to the dosage of 5mg/kg of the body weight of the nude mice;

(3) Ceritinib group: injecting chromene intraperitoneally at a dose of 10mg/kg of nude mice body weight 2 times/5 days (i.e. 1 time at 3-day intervals);

(4) Drug combination group of YM155 and ceritinib: injecting YM155 into the abdominal cavity for 1 time/day according to the dosage of 5mg/kg of the body weight of the nude mice; on the same day as the first YM155 injection, ceritinib was injected intraperitoneally at a dose of 10mg/kg of nude mice body weight 1 time at 3-day intervals (the dosing frequency ratio of YM155 and ceritinib was 10:3).

The doses of YM155 and ceritinib in each of the above groups are only those of the drug itself. The concentration to be achieved when formulated into an injection should be clear to those skilled in the art and will not be described in detail.

3. Measurement and recording

(1) Body weight of each group of nude mice was measured and recorded once every 7 days later;

(2) Measuring the length and width of the tumor by using a vernier caliper after every 21 days, and recording the volume of the tumor body part of each group of nude mice once; tumor volume was calculated according to the following formula:

tumor volume (mm) ³⁾ =tumor length (mm) ×square of tumor width (mm) ² )

The experimental results are shown in fig. 3-5, and the ordinate in fig. 3 represents the tumor volume of each group of nude mice; the abscissa represents the grouping; the values at each point are the actual values of the tumor volumes of each group (the "I" symbol in the figure indicates the up-down deviation). The ordinate in fig. 4 represents the average body weight of each group of nude mice; the abscissa represents a measurement time point; various line nodes represent various treatment groups; the values for each point are the average body weights of the groups. The survival rate of each group of nude mice is shown on the ordinate in fig. 5; the abscissa represents a time node; various line nodes represent various treatment groups.

As can be seen from fig. 3, the tumor volume of the YM155 co-ceritinib group was significantly lower after 21 days of treatment than that of the group of ceritinib alone and YM155 alone. The same applies to fig. 3 where p < 0.01, and it is also assumed that the tumor volume of the group using YM155 co-chronicinib is less likely to be wrong than that of the drug alone and the control group, and the verification result is accurate and reliable.

As can be seen from fig. 4, the mice weight of YM155 co-critinib group was not significantly different from the other drug and control groups alone, compared to the critinib alone, the YM155 alone, and the control group. n.s represents p > 0.05, i.e. the probability of error occurrence due to the difference between the weight of the YM155 co-chromene group and the drug group or the control group alone is greater than 0.05, and since p=0.05 is the statistically acceptable maximum error probability, the error probability of greater than 0.05 is not recognized here, i.e. no significant difference is found.

The verification result recorded in fig. 5 proves that the drug combination of YM155 and the ceritinib chemotherapy is better than the ceritinib alone in inhibiting and killing human breast cancer MDA-MB-231 cells, so that the survival period of the mouse model is prolonged, the dosage can be naturally reduced, the treatment period is shortened, and the toxic and side effects are reduced. The same table in fig. 5 indicates that p < 0.01, and it is also recognized that the treatment effect using YM155 co-chromene group is less likely to be wrong than that of the drug group alone and the control group, and the verification result is also accurate and reliable.

As no obvious toxic or side effect is seen in the description of FIG. 4, the verification result proves that the YM155 is cooperated with the pharmaceutical combination of the ceritinib chemotherapy, and at least no obvious toxic or side effect exists as the ceritinib alone.

It is clear to those skilled in the art that after the verification of the above cell experiment, it can be fully demonstrated that the drug combination of YM155 synergistic critinib chemotherapy has better therapeutic effect on human breast cancer cells, especially triple negative breast cancer (differential and very small) through a nude mouse transplantation tumor model experiment on human breast cancer MDA-MB-231 cells.

The foregoing is merely exemplary of the present invention, and specific technical solutions and/or features that are well known in the art have not been described in detail herein. It should be noted that, for those skilled in the art, several variations and modifications can be made without departing from the technical solution of the present invention, and these should also be regarded as the protection scope of the present invention, which does not affect the effect of the implementation of the present invention and the practical applicability of the patent. The protection scope of the present application shall be subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.

Claims

1. A chemotherapeutic pharmaceutical composition, characterized in that: the active ingredients of the pharmaceutical composition are YM155 and ceritinib; the mass ratio of the YM155 to the ceritinib is 4:2.025 to 3.24.

2. The use of a chemotherapeutic pharmaceutical composition according to claim 1 for the preparation of an antitumor agent, characterized in that: the active ingredient is present in free form or in the form of a pharmaceutically acceptable salt.

3. The use of a chemotherapeutic pharmaceutical composition according to claim 2 for the preparation of an antitumor agent, characterized in that: the tumor aimed by the anti-tumor drug is in-situ or recurrent triple negative breast cancer.

4. Use of a chemotherapeutic pharmaceutical composition according to claim 3 for the preparation of an antitumor agent, characterized in that: the active ingredients of the pharmaceutical composition are YM155 and ceritinib.

5. The use of a chemotherapeutic pharmaceutical composition according to claim 4 for the preparation of an antitumor agent, characterized in that: the drug combination is administrated intravenously.

6. The use of a chemotherapeutic pharmaceutical composition according to claim 5 for the preparation of an antitumor agent, characterized in that: the administration frequency ratio of YM155 to ceritinib is 10:3.