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A pharmaceutical composition containing small molecule targeting drug gefitinib and its application in the preparation of antitumor drugs

A technology of gefitinib and a composition, which is applied in the field of pharmaceutical compositions with anticancer activity, can solve the problems of inability to improve the five-year overall survival period of non-small cell lung cancer patients, being in the experimental stage, and the patients having no treatment plan.

Inactive Publication Date: 2018-08-17
FUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Gefitinib is a poorly soluble drug, and its solubility in aqueous solution is pH-dependent, that is, the lower the pH, the greater the solubility in aqueous solution, and it is almost insoluble in water with a pH value of about 7; Patients with mutations have a certain therapeutic effect, but most NSCLC patients develop drug resistance after 1 year of application of gefitinib, and the disease progresses significantly. Subsequent studies have found that the main reason for drug resistance is due to the new mutations in some patients that are resistant to gefitinib. Resistance to non-small cell lung cancer, so even treatment with gefitinib (tyrosine kinase inhibitor) still does not improve five-year overall survival in patients with non-small cell lung cancer
Currently, there is no effective treatment plan for patients with this secondary drug resistance, and each method is in the experimental stage

Method used

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  • A pharmaceutical composition containing small molecule targeting drug gefitinib and its application in the preparation of antitumor drugs
  • A pharmaceutical composition containing small molecule targeting drug gefitinib and its application in the preparation of antitumor drugs
  • A pharmaceutical composition containing small molecule targeting drug gefitinib and its application in the preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Inhibitory effects of ursolic acid and gefitinib alone and in combination for 24, 48, and 72 h on the proliferation of A549 cell lines: the standard MTT colorimetric method was used to determine the effect of different combination ratios of ursolic acid and gefitinib on A549 cell lines growth inhibitory activity.

[0021] Digest the cells in the logarithmic phase with trypsin, count the cells, and make 8×10 4 / ml cell concentration, the prepared cell suspension, 100 μl per well was inoculated into a 96-well plate, placed in 37 ° C, 5% CO 2 In the incubator; discard the old medium, and add 100 μl of medium containing different drug concentration gradients to each well. Placed at 37°C, 5% CO 2 Culture in the incubator for 24, 48 and 72 h, discard the drug-containing medium, add 100 μl of serum-free phenol red-free medium containing MTT (0.5 mg / ml) to each well, and continue to incubate for 4 h; carefully pipette the Add 150 µL of DMSO to each well of the supernatant, s...

Embodiment 2

[0025] King’s modified formula was used to calculate the synergistic effect of the combined administration of ursolic acid and gefitinib on A549 cells at different ratios for 24, 48, and 72 h, and the optimal drug ratio was screened out. The results are shown in the table. 1-3 shown. Calculate the inhibitory rate EA of A549 cells under the condition of UA=10 μM, calculate the inhibitory rates of A549 cells with different gefitinib concentrations EB1, EB2, EB3, etc., and then calculate the combined administration of the two in different The inhibitory rates against A549 cells under the ratio are EC1, EC2, EC3, etc., and the q value of the combined drug index is calculated by the following formula, q=EC / (EB+EA-EB*EA), when the q value>1.15, it is a synergistic effect , 0.85<q<1.15 is an additive effect, and q<0.85 is an antagonistic effect. The final drug efficacy of the combination of the two drugs was further judged by the calculation of the combination drug index.

[0026] ...

Embodiment 3

[0030] Ursolic acid and gefitinib alone and in combination for 24, 48, and 72 h inhibit the proliferation of H1975 cells, the steps are the same as in Example 1, and the results are as follows Figure 4-6 shown.

[0031] Such as Figure 4As shown, after 24 h of drug action, the effect of UA on inhibiting the proliferation of H1975 cells under the condition of 10 μM was not obvious; Gefitinib could significantly inhibit the proliferation of H1975 cells under the condition of ≥25 μM; when Gefitinib ≥ 5 μM can significantly inhibit the proliferation of H1975 cells when the two are administered together, and the inhibition of cell proliferation is more obvious with the increase of the concentration, and the combined administration can synergistically inhibit tumor cells. proliferate; as Figure 5 As shown, after 48 hours of drug action, UA can significantly inhibit the proliferation of cells under the condition of 10 μM; Gefitinib can effectively inhibit the proliferation of H19...

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Abstract

The invention provides a pharmaceutical composition containing small-molecule targeted drug gefitinib and application of the pharmaceutical composition to the preparation of antitumor drugs. The pharmaceutical composition is characterized by comprising active components including ursolic acid and gefitinib. When the mass ratio of ursolic acid to gefitinib is 10-20:1-25, the ursolic acid and gefitinib can be combined and coordinated to resist the proliferation of tumor cells. The pharmaceutical composition has the advantages that due to the fact that the epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor gefitinib and the efficient and low-toxicity antitumor natural ursolic acid are combined, targeted inhibition of the tumor cells can be achieved, the proliferation of the tumor cells can be inhibited in a coordinated manner, the toxic and side effects of drugs can be reduced, tumor treatment effect can be increased, and the pharmaceutical composition is applicable to the preparation of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of antitumor drugs, in particular, the invention relates to a pharmaceutical composition with anticancer activity. Background technique [0002] Ursolic acid is 3β-hydroxy-ursolic-12-ene-28-acid (3β-hydroxy-urs-12-en-28-oic acid, referred to as UA), also known as ursolic acid, which belongs to a-amyresinol (a-amyrin) type pentacyclic triterpenes, its relative molecular weight is 456.68, molecular formula is C 30 h 48 o 3 , as shown in formula I, it is a natural active compound that is widely distributed in nature, mainly in the form of free or glycosides, and it is widely distributed in various natural plants such as loquat leaves, bearberries, hawthorns, and Hedyotis diffusa, It is also one of the main active ingredients of many traditional Chinese medicines, and has a wide range of pharmacological effects, such as anti-cancer, liver protection, anti-inflammation, anti-virus, anti-oxidation, etc. Among them, the a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/56A61K31/5377A61P35/00
CPCA61K31/5377A61K31/56A61K2300/00
Inventor 邵敬伟郑桂容江凯
Owner FUZHOU UNIV
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