CN112716949A - Antineoplastic drug composition, preparation and application - Google Patents
Antineoplastic drug composition, preparation and application Download PDFInfo
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- CN112716949A CN112716949A CN202110144734.7A CN202110144734A CN112716949A CN 112716949 A CN112716949 A CN 112716949A CN 202110144734 A CN202110144734 A CN 202110144734A CN 112716949 A CN112716949 A CN 112716949A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61P3/00—Drugs for disorders of the metabolism
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Abstract
The invention relates to an anti-tumor drug composition, which is a composition of Topotecan, Crizotinib and Metformin, wherein the Topotecan, Crizotinib and Metformin are combined for use, the composition has a good treatment effect on non-small cell lung cancer under the condition of low dose, and in-vitro experiments show that compared with a single drug of Metformin and the combination of Topotecan and Crizotinib, the composition of Topotecan, Crizotinib and Metformin has a stronger inhibition effect on the non-small cell lung cancer, provides a new way of thinking for treating the non-small cell lung cancer generating drug resistance, and simultaneously brings hope for patients suffering from both diabetes and the non-small cell lung cancer, provides scientific basis for the research and development of new drugs, and has a wider application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an anti-tumor medicine composition, a preparation and application.
Background
The mortality rate of lung cancer accounts for the first part of the tumor mortality rate, wherein the lung cancer is morphologically divided into non-small cell lung cancer and small cell lung cancer, wherein the morbidity rate of the non-small cell lung cancer accounts for 85% of the total morbidity rate of the lung cancer, and the 5-year survival rate of the non-small cell lung cancer is only 15%, so that the mortality rate of the lung cancer can be obviously reduced by effectively treating the non-small cell lung cancer, chemotherapy and targeted therapy are two major means for currently treating the non-small cell lung cancer, but the chemotherapy drugs have high toxicity and often cause great side effects, which also become a great obstacle for clinical use of the non-small cell lung cancer, the targeted drugs can target tumor cells, have small influence on normal cells, but the clinical use of the non-small cell lung cancer is limited by the generation of drug resistance, and researches show that diabetes can increase the morbidity rate of the non-small cell lung cancer and is closely related to the poor prognosis, moreover, there are currently a few patients with both diabetes and non-small cell lung cancer, but there is currently no good treatment strategy for this population. Therefore, the mode of combined medication is adopted to increase the anti-tumor curative effect on one hand and increase the indications of the medicament on the other hand.
Topotecan is a semi-synthetic camptothecin derivative, is an inhibitor of topoisomerase, can inhibit the synthesis of DNA so as to inhibit the proliferation of tumors, block the cell cycle and induce apoptosis, is a broad-spectrum antitumor drug, and is currently frequently used for treating solid tumors in clinic. The Crizotinib is a multi-target inhibitor of ALK, MET and ROS, is an ALK-positive non-small cell lung cancer patient target therapeutic drug, but after the patient uses the drug for about 1 year, due to the mutation of other genes, a drug resistance phenomenon is generated, and the patient needs to use a second-generation ALK target drug. Metformin is a first choice drug for treating type II diabetes, and has been found to increase the antitumor activity of various anticancer drugs in recent years, and the antitumor activity of the composition is evaluated based on the combination of Topotecan, Crizotinib and Metformin.
The use of the combination drug has become a new trend of modern anticancer strategies, no research is currently carried out on the combination of Topotecan, Crizotinib and Metformin, and the combination of the three drugs can provide a new treatment method for non-small cell lung cancer patients with drug resistance, and particularly provides a thought for the anti-tumor treatment of patients with both diabetes and non-small cell lung cancer and other drug combinations.
Through searching, no patent publication related to the present patent application has been found.
Disclosure of Invention
The invention aims to overcome the defects of the existing non-small cell lung cancer treatment, and provides a Topotecan, Crizotinib and Metformin anti-tumor composition preparation and application.
The purpose of the invention is realized by the following technical scheme:
a kind of antineoplastic medicine composition, the said composition is the composition of Topotecan, Crizotinib and Metformin.
The administration dosage of the composition can vary according to the administration object, the administration route or the preparation form of the drug, but is premised on ensuring that the composition can achieve effective blood concentration in the body of a mammal.
A formulation comprising the anti-tumor pharmaceutical composition as described above.
The anti-tumor medicine composition is directly mixed to prepare a preparation;
or the Topotecan, Crizotinib and Metformin in the anti-tumor drug composition are respectively mixed with corresponding auxiliary materials to prepare a preparation, and the two are packaged or combined together in a conventional mode.
Or mixing TC and Metformin in the anti-tumor medicine composition with corresponding auxiliary materials respectively, and then mixing to prepare a preparation;
the auxiliary material does not react with the anti-tumor medicine composition or can not influence the curative effect of the anti-tumor medicine composition.
The content of the anti-tumor medicine composition in the preparation is 1-99 wt%.
The auxiliary materials of TC and Metformin comprise a diluting solvent, wherein the diluting solvent is dimethyl sulfoxide and ultrapure water respectively.
The novel anti-tumor drug composition is applied to the aspect of serving as a cancer treatment drug.
The application of the novel anti-tumor pharmaceutical composition in the aspect of serving as a non-small cell lung adenocarcinoma treatment medicine, in particular to patients suffering from non-small cell lung cancer and diabetes mellitus
The invention has the advantages and positive effects that:
1. the combined medicament combines Topotecan, Crizotinib and Metformin for use, has obvious synergistic effect in the treatment of non-small cell lung cancer under low effective dose, particularly has synergistic effect in the treatment of non-small cell lung cancer, improves the effect of inhibiting tumor, provides a new idea for reducing the treatment of patients when the drug resistance of the non-small cell lung cancer occurs, and provides a scientific basis for the research and development of new medicaments.
2. The invention combines Topotecan, Crizotinib and Metformin into a novel pharmaceutical composition, which is a high-activity anti-tumor pharmaceutical composition, and in vitro experiments show that compared with single drugs of Topotecan, Crizotinib and Metformin, the composition has obvious curative effect on EGFR (epidermal growth factor receptor) mutant non-small cell lung adenocarcinoma, and the development of the composition provides theoretical and experimental basis for clinical treatment of lung cancer and other types of cancers.
3. The combined drug combines Topotecan, Crizotinib and Metformin, and on one hand, the combined drug can inhibit the growth and proliferation of lung cancer cells in multiple targets and multiple mechanisms; on the other hand, the Topotecan, Crizotinib and Metformin combination also reduced the toxic and side effects on cells.
4. The novel anti-tumor composition, namely the combination of Topotecan, Crizotinib and Metformin, is used as a potential drug for treating lung cancer, brings new hopes for lung cancer patients, particularly patients suffering from diabetes and lung cancer, and has more people in China and wider application prospect.
Drawings
FIG. 1 is a graph of the inhibition of H1975 cells by the single agents Metformin, Topotecan, Crizotinib combinations and Topotecan, Crizotinib and Metformin combinations of the present invention; wherein, TC-Topotecan and Crizotinib are combined; TC + Metformmin-Topotecan, Crizotinib, and Metformmin;
FIG. 2 is a graph of CI values for H1975 cells for compositions of the invention; wherein, M + T + C-Topotecan, Crizotinib and Metformin;
FIG. 3 is a graph of the inhibition of HCC827 cells by the combination of single agents Metformin, Topotecan, Crizotinib and Metformin of the invention; wherein, TC-Topotecan and Crizotinib are combined; TC + Metformmin-Topotecan, Crizotinib, and Metformmin;
FIG. 4 is a graph of CI values for HCC827 cells for a composition of the invention; wherein, T + C + M-Topotecan, Crizotinib and Metformin;
Detailed Description
The following detailed description of the embodiments of the present invention is provided for the purpose of illustration and not limitation, and should not be construed as limiting the scope of the invention.
The raw materials used in the invention are conventional commercial products unless otherwise specified; the methods used in the present invention are conventional in the art unless otherwise specified.
A kind of antineoplastic medicine composition, the said composition is the composition of Topotecan, Crizotinib and Metformin.
The administration dosage of the composition can vary according to the administration object, the administration route or the preparation form of the medicament, but is premised on ensuring that the composition can achieve effective blood concentration in the body of a mammal.
A formulation comprising the anti-tumor pharmaceutical composition as described above.
Preferably, the anti-tumor medicine composition is directly mixed to prepare a preparation;
or the Topotecan, Crizotinib and Metformin in the anti-tumor drug composition are respectively mixed with corresponding auxiliary materials to prepare a preparation, and the two are packaged or combined together in a conventional mode;
or the Topotecan, the Crizotinib and the Metformin in the anti-tumor medicine composition are respectively mixed with corresponding auxiliary materials and then are mixed to prepare a preparation;
the adjuvant does not react with the novel antitumor drug composition or cannot affect the curative effect of the novel antitumor drug composition.
Preferably, the content of the novel anti-tumor drug composition in the preparation is 1-99 wt%.
Furthermore, the TC composition and the auxiliary material of Metformin include a diluent solvent, which is dimethyl sulfoxide and ultrapure water, respectively.
The anti-tumor medicine composition is applied to the aspect of being used as a cancer treatment medicine.
The novel anti-tumor pharmaceutical composition is applied to the aspect of serving as a non-small cell lung adenocarcinoma treatment medicine, in particular to the application of the novel anti-tumor pharmaceutical composition to patients suffering from non-small cell lung cancer and diabetes mellitus.
The structural formulas of Topotecan, Crizotinib and Metformin in the invention are shown as follows
In the antitumor pharmaceutical composition of the present invention, preferably, the diluent solvent of TC is dimethyl sulfoxide, and the diluent solvent of Metformin is ultrapure water.
Specifically, the biomaterials, drugs and experimental methods used in the present invention were as follows:
the non-small cell lung cancer cell line used includes two kinds of human lung adenocarcinoma cells NCI-H1975(H1975) and NCI-HCC827 (HCC 827).
The drugs used are Topotecan standard, Crizotinib standard and Metformin standard. Respectively dissolving Topotecan and Crizotinib in dimethyl sulfoxide to prepare mother liquor with Topotecan concentration of 100mmol/L and Crizotinib concentration of 100mmol/L, dissolving Metformin in ultrapure water to prepare Metformin with Metformin concentration of 100mmol/L, and storing at-20 ℃. When used, diluted to the appropriate concentrations listed in the table.
MTT detects the cytotoxic effect of the combined medicine, and the lung cancer cells are cultured in a cell culture medium of RPMI1640 containing 1% penicillin-streptomycin solution and 10% fetal bovine serum. Digesting the cells with pancreatin, and counting the cells with a hemocytometerCounting, adjusting cell density to 5 × 104cell/mL, seeded in 96-well plates with blank and control wells. Culturing for 24h, sucking out the original culture medium, adding corresponding drug concentration, culturing for 48-72 h, adding MTT solution into each hole, continuously incubating for 4h, adding 100 mu L dimethyl sulfoxide into each hole, standing for 10min, measuring absorbance (OD) value of each hole by using an enzyme-labeling instrument (490nm, 630nm), and calculating the cell inhibition rate according to the following formula.
The cell inhibition ratio (%) × (1- (experimental OD-blank OD)/(control OD-blank OD)) × 100%.
IC50: also known as the half-effective inhibitory concentration, i.e., the concentration of drug at which cell viability is half. Solving a linear regression equation according to the MTT result and calculating IC50The value is obtained.
Evaluating the effects of the Topotecan, Crizotiib and Metformin composition, TC and single medicament Metformin by adopting the Combination Index (CI) of the medicament, and applying computer software Compu Syn calculation, wherein CI is less than 1, which indicates that the composition has synergistic effect; CI ═ 1, meaning that the composition has an additive effect; CI > 1 indicates that the composition is antagonistic.
Example 1
The proliferation inhibition of H1975 and HCC827 cells by the single drugs Topotecan, Crizotinib and Metformin was investigated
IC of three single drugs on three cells50The values are shown in Table 1.
TABLE 1 IC of Lung cancer cells with single drugs Topotecan, Crizotinib and Metformin50Value of
Example 2
The results of experiments on the inhibition of H1975 cell proliferation by single agent Metformin, TC, and Topotecan, Crizotinib, and Metformin compositions at various concentrations are shown in FIG. 1, and the CI values of the compositions are shown in FIG. 2. As can be seen from FIGS. 1 and 2, the CI of the composition is < 1, indicating that the Topotecan, Crizotinib and Metformin compositions are very effective compared to Metformin alone and TC.
Example 3
The results of experiments on the inhibitory effect of different concentrations of single agent Metformin, TC and Topotecan, Crizotinib and Metformin compositions on HCC827 cell proliferation are shown in figure 1, and CI values of the compositions are shown in figure 2. As can be seen from FIGS. 1 and 2, the CI of the composition is < 1, indicating that the Topotecan, Crizotinib and Metformin compositions are very effective compared to Metformin alone and TC.
Although the embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that: various substitutions, changes and modifications are possible without departing from the spirit and scope of the invention and the appended claims, and therefore the scope of the invention is not limited to the embodiments disclosed.
Claims (8)
1. An antitumor drug composition, which is characterized in that: the composition is a composition of Topotecan, Crizotinib and Metformin.
2. The administration dosage of the composition can vary according to the administration object, the administration route or the preparation form of the drug, but is premised on ensuring that the composition can achieve effective blood concentration in the body of a mammal.
3. A formulation comprising the antitumor pharmaceutical composition as described in claims 1 and 2.
4. The formulation comprising an antineoplastic pharmaceutical composition according to claim 3, wherein:
respectively mixing Topotecan, Crizotinib and Metforin in the anti-tumor drug composition with corresponding auxiliary materials to prepare a preparation, and packaging or combining the Topotecan, Crizotinib and Metforin the anti-tumor drug composition in a conventional manner;
or the Topotecan, the Crizotinib and the Metformin in the anti-tumor medicine composition are respectively mixed with corresponding auxiliary materials and then are mixed to prepare a preparation;
the auxiliary material does not react with the anti-tumor medicine composition or can not influence the curative effect of the anti-tumor medicine composition.
5. The formulation comprising an antitumor pharmaceutical composition according to claim 3 or 4, characterized in that: the content of the anti-tumor medicine composition in the preparation is 1-99 wt%.
6. The antitumor pharmaceutical composition as claimed in claim 4, wherein: the auxiliary materials of Topotecan, Crizotinib and Metformin comprise diluent solvents which are dimethyl sulfoxide and ultrapure water respectively.
7. The antitumor pharmaceutical composition as claimed in claim 1 or 2, for use as a medicament for treating cancer.
8. The antitumor pharmaceutical composition as claimed in claim 1 or 2, for use as a therapeutic agent for non-small cell lung adenocarcinoma, especially for use in patients with non-small cell lung cancer and diabetes.
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