CN110801445B - Composition containing benzo-hydropyranol derivative and emodin type anthraquinone compound, and dosage form and application thereof - Google Patents

Composition containing benzo-hydropyranol derivative and emodin type anthraquinone compound, and dosage form and application thereof Download PDF

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CN110801445B
CN110801445B CN201911254041.2A CN201911254041A CN110801445B CN 110801445 B CN110801445 B CN 110801445B CN 201911254041 A CN201911254041 A CN 201911254041A CN 110801445 B CN110801445 B CN 110801445B
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gallate
epigallocatechin
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赵一弘
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Zhongshan Wanyuan New Drugs Research And Development Co ltd
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Abstract

The invention provides a composition containing a benzo-hydropyranol derivative and an emodin type anthraquinone compound, and a preparation form and application thereof. The composition can generate a synergistic inhibition effect on the proliferation of liver cancer HepG2 cells (the combination index CI is less than 1).

Description

Composition containing benzo-hydrogenated pyranol derivative and emodin anthraquinone compound, and dosage form and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a composition containing a benzo-hydropyranol derivative and an emodin anthraquinone compound, and a dosage form and application thereof.
Background
Flavanols are a class of compounds with various physiological and pharmacological activities and containing a chromanol structure, and are present in water honeylocust fruits, cocoa, tea, red wine, fruits and vegetables. An article by Lewandowska U et al (Lewandowska U, szewczyk K, owczarek K, et al. Flavenols from Japanese clinic (Chaenomes japonica) from experiment in front of human and fresh cancer cell in vivo and fresh cancer cells in Bax/Bcl-2mRNA ratio J.Nutrition and cancer, 2013, 65 (2): 273-285.) reports that Flavanols extracted from Malus japonicus inhibit the invasiveness of human breast cancer and prostate cell carcinoma and improve the ratio of Bax and Bcl-2 mRNA. Chinese patent CN 201210547318.2 also discloses a new flavanol compound in the wild sweet bean, its preparation method and application, the flavanol compound is separated from the wild sweet bean, and has obvious anticancer and marine fouling organism resisting activity, and at the same time, has obvious inhibiting effect on tumor, human cervical carcinoma, human chronic myelogenous leukemia or human acute myelogenous leukemia cell. However, not all Flavanols have good antitumor activity, for example, studies by Williamson G et al (Williamson G, dionisi F, renouf M. Flavanols from green tea and phenolic acids from coffee. Critical cosmetic evaluation of the pharmacological data in human after consumption of simple doses of vitamins. Mol Nutr food.2011 55. Study by Nakai M et al (Nakai M. Fukui Y. Asamis S. Et al. Inherent efficacy of organic tea polysaccharides in vitamin catechin [ J ] J. Journal of Agricultural catechin, vitamin E. Epigallocatechin, (-3-4593. Epigallocatechin, (-) -3-4593-11. Epigallocatechin, (-) -3-4593-11) and various epigallocatechin gallate 3-459 3-53. Epigallocatechin, (-) -3-epigallocatechin, (-3-4593) 3-epigallocatechin, (-) -3-11. Epigallocatechin, (-) -epigallocatechin 3-gallate and epigallocatechin 3-4. Epigallocatechin, (-) -2,53, respectively, however, some of the flavanols in the above mentioned article have been found to have unsatisfactory antitumor activity against various tumor cell lines.
Anthraquinone compounds are chemical components with quinoid structures, and are widely distributed in plants such as polygonum multiflorum, cassia seeds, aloe and the like, and a plurality of antitumor drugs containing the anthraquinone structures, including daunorubicin, doxorubicin and mitoxantrone, are carried in newly-compiled pharmaceutics (17 th edition). Chinese patent CN 201810319871.8 also discloses anthraquinone compounds, which are natural products obtained by fermenting and purifying actinomycetes with rice, have obvious antitumor activity, especially have obvious proliferation inhibition effect on PC3 cells of human prostate cancer cell strains and SW620 cells of human colon cancer cell strains, and can be used for developing antitumor drugs. However, not all anthraquinones have a good antitumor activity, and for example, wu Xiaohui, in his Ph's Proc. Thesis on the chemical composition, quality control and in vivo metabolism of cassia seed [ D ]. Huazhong university of science and technology, 2010. Discloses various anthraquinones as active ingredients isolated and extracted from cassia seed, including the following compounds:
Figure SMS_2
、
Figure SMS_5
、
Figure SMS_8
、
Figure SMS_3
、
Figure SMS_6
、
Figure SMS_9
、
Figure SMS_10
、
Figure SMS_1
、
Figure SMS_4
and
Figure SMS_7
and the like. However, it is found through experiments that some anthraquinone compounds in the above mentioned article have unsatisfactory antitumor activity for various tumor cell lines.
Aiming at the problem that part of flavanol compounds or anthraquinone compounds have poor antitumor activity on various tumor cell strains, a composition is found by combining the respective advantages of the two compounds, so that the two compounds cooperate to promote the antitumor activity.
Disclosure of Invention
The object of the present invention is to provide a composition containing a chromanol derivative and an anthraquinone compound, which can produce a synergistic antitumor effect.
In order to achieve the above object, according to one aspect of the present invention, there is provided a composition comprising a chromanol derivative and an anthraquinone compound, characterized in that the molar ratio of the chromanol derivative to the anthraquinone compound in the composition is 1 to 100 to 1; preferably, the mol ratio of the benzo-hydropyranol derivative to the anthraquinone compound is 16-100.
Further, the benzo-hydropyranol derivative comprises one or more of an epicatechin compound, an epigallocatechin compound and a catechin compound, and the anthraquinone compound comprises one or more of an emodin-type compound and an alizarin-type compound.
Further, the epicatechin-based compound includes (-) -epicatechin-3-O-gallate; the epicatechin compounds comprise one or more of (-) -epicatechin, (-) -epicatechin 3-O-gallate and (-) -epicatechin3-O- (3' -O-methyl) gallate; the epigallocatechin compound comprises one or more of (-) -epigallocatechin, (-) -epigallocatechin 3-O-gallate, (-) -epigallocatechin3, 5-di-O-gallate or (-) -epigallocatechin 3-O-p-coumarate; the catechin compounds include one or more of (+) catechin and (-) -catechin 3-O-gallate.
Further, the emodin-type compound comprises the following compounds:
Figure SMS_12
、
Figure SMS_17
and
Figure SMS_19
one or more of; the alizarin type compound comprises the following compounds:
Figure SMS_13
、
Figure SMS_15
、
Figure SMS_18
、
Figure SMS_20
、
Figure SMS_11
、
Figure SMS_14
and
Figure SMS_16
one or more of (a).
Furthermore, the medicinal composition can be used for preparing medicaments for resisting tumors or controlling body weight, blood sugar, blood pressure, blood fat and the like.
Further, the raw materials of the anti-tumor medicine prepared by using the medicinal composition comprise: pharmaceutical compositions, diluents and lubricants. Wherein the weight ratio of the medicinal composition, the diluent and the lubricant is as follows: 1:0.8-1.5:0.4-0.8.
Further, the diluent comprises one or more of pregelatinized starch, dextrin, sucrose, microcrystalline cellulose, sorbitol, mannitol, lactose, calcium sulfate, calcium hydrogen phosphate and calcium phosphate; the lubricant comprises one or more of sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, paraffin oil, paraffin wax, glyceryl monostearate, glyceryl monopalmitate, sodium acetate, sodium chloride, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, polyoxyethylene monostearate and polyoxyethylene lauryl ether.
Further, the dosage form of the anti-tumor medicine is granules, capsules or tablets; the preparation method of the granules comprises the following steps: mixing the medicinal composition, diluent and lubricant. The preparation method of the capsule comprises the following steps: the medicine is applied
Mixing the composition, diluent and lubricant, and encapsulating. The preparation method of the tablet comprises the following steps: mixing the medicinal composition, diluent and lubricant, and tabletting.
The technical effects obtained by the invention are as follows:
the medicinal composition can improve the anti-activity effect of the benzo-hydropyranol derivatives and the anthraquinone compounds on various cancer cells such as liver cancer HepG2 cells and the like, and can also be used for preparing medicaments for controlling weight, blood sugar, blood pressure and blood fat.
The pharmaceutical composition of the invention can produce synergistic inhibition under specific inhibition effect (CI < 1).
Detailed description of the preferred embodiments
The benzo-hydropyranol derivatives of the present invention, such as (-) -epigallocatechin 3-O-gallate), (-) -epigallocatechin), (-) -epicatechin (-), (-) -epicatechin 3-O-gallate (-), (-) -epicatechin3-O- (3' -O-methyl) gallate, (-) -epigallocatechin 3-O-gallate ((-) -epigallocatechin 3-Ogallate), (-) -epigallocatechin3, 5-di-O-gallate ((-) -epigallocatechin3, 5-di-O-gallate), (-) -epigallocatechin 3-O-p-coumarate ((-) -epigallocatechin 3-O-pcoumaroate), (+) -catechin ((+) -catechin) and (-) -catechin3-O-gallate ((-) -catechin 3-O-gallate), which are denoted F1-F10, respectively; with simultaneous addition of anthraquinones, e.g.
Figure SMS_22
、
Figure SMS_25
、
Figure SMS_28
、
Figure SMS_23
、
Figure SMS_24
、
Figure SMS_27
、
Figure SMS_29
、
Figure SMS_21
、
Figure SMS_26
And
Figure SMS_30
respectively designated as A1-A10.
Example groups 1 to 100
Examples groups 1-100 pharmaceutical compositions are a chromanol derivative and an anthraquinone compound, wherein the chromanol derivative and the anthraquinone compound are, in order, F1 and A1-A10, F2 and A1-A10, F3 and A1-A10, F4 and A1-A10, F5 and A1-A10, F6 and A1-A10, F7 and A1-A10, F8 and A1-A10, F9 and A1-A10, F10 and A1-A10; the molar ratio of the benzo-hydro-pyranol derivatives to the anthraquinones in each example group was 0.01, 0.03, 0.06, 0.16, 0.40, 1.00, 2.50, 6.30, 16.00, 40.00 and 100.00, respectively, and the pharmaceutical compositions of the present invention were obtained by mixing the above benzo-hydro-pyranol derivatives with the anthraquinones. The raw materials of the antitumor drugs in the example groups 1 to 100 include: pharmaceutical compositions, diluents and lubricants. The weight ratio of the medicinal composition, the diluent and the lubricant in each embodiment group is respectively as follows: 1:0.8:0.4,1:1.5:0.8,1:0.8:0.8,1:1.5:0.4, 1:0.9:0.5,1:1.2:0.7,1:1:0.6,1:1:0.5,1:1:0.7,1:0.9:0.6. The diluents in each embodiment group are pregelatinized starch, dextrin, sucrose, microcrystalline cellulose, sorbitol, mannitol, lactose, calcium sulfate and calcium hydrophosphate in turn; the lubricant in each example group is sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, paraffin oil, paraffin, glyceryl monostearate, glyceryl monopalmitate, sodium acetate and sodium chloride in sequence. Mixing the medicinal composition, diluent and lubricant, and tabletting to obtain the antitumor medicine.
Comparative examples 1 to 20
The difference from the first group of examples in example 1 is only that only one of F1-F10 or A1-A10, diluent and lubricant are respectively used as raw materials of the antineoplastic medicine in each proportion, wherein the diluent is calcium phosphate, and the lubricant is DL-leucine.
Comparative example group 21
The ratio is totally 100 pairs, differing from the examples 1 to 100 only in that the molar ratios of F1 to A1-A10, F2 to A1-A10, F3 to A1-A10, F4 to A1-A10, F5 to A1-A10, F6 to A1-A10, F7 to A1-A10, F8 to A1-A10, F9 to A1-A10 and F10 to A1-A10 are all 120.
Comparative example group 22
The ratio of 100 groups is included, and differs from the examples of groups 1 to 100 only in that the molar ratio of F1 to A1-A10, F2 to A1-A10, F3 to A1-A10, F4 to A1-A10, F5 to A1-A10, F6 to A1-A10, F7 to A1-A10, F8 to A1-A10, F9 to A1-A10 and F10 to A1-A10 is 1.
MTT method is adopted to determine the effect of the antitumor drugs prepared by the compounds in the example groups 1-100, the comparative examples 1-20 and the comparative example groups 21-22 on the proliferation of various tumor cells. Taking liver cancer HepG2 cell as an example, the liver cancer HepG2 cell is recovered to RPMI1640 culture solution containing 10% fetal bovine serum, and is cultured for 24h in an incubator with the concentration of 5% CO2 at 37 ℃; setting blank group (without cell, culture solution and without drug), control group (with cell, culture solution and without drug) and example drug-adding group (with cell, culture solution and drug in example groups 1-100) as shown in Table 1 and comparative drug-adding group (with cell, culture solution and drug in comparative examples 1-20 and comparative examples 21-22) as shown in Table 1 and Table 2, digesting the cells from the culture dish by pancreatin and re-inoculating the cells into 96-well plate to make the number of cells per well of the control group and drug-adding group be 1X 10 3 -1×10 4 37 ℃ and 5% CO 2 Culturing for 24h, adding drug-containing RPMI1640 culture solution 200 μ L shown in Table 1 and Table 2, adding drug-free RPMI1640 culture solution 200 μ L into control group and blank group, each group having 6 parallel wells, culturing for 12h, adding 5mg/mLMTT20 μ L into each well, culturing for 4h, removing supernatant, adding 100 μ LDMSO dissolved sample into each well, and measuring the concentration of each well at 490nm with microplate readerAnd (4) light absorption value. The mean of the absorbance values of 6 wells was taken, and the Inhibition Rate (IR) = (1-mean absorbance for drug addition group/mean absorbance for group) × 100% was calculated according to the formula.
Plotting the Inhibition (IR) against the log of the drug concentration (. Mu.M), linear regression with Excel, and calculating the concentrations of the chromanol derivatives and anthraquinones, IC, respectively, at the time of occurrence of the specific inhibitory effect (fa) according to the regression equation fa (A) And IC fa (B) The value is obtained. For the combination, inhibition Ratio (IR) was plotted against log (c) of the concentration (. Mu.M) of the chromanol derivative in the combination (log (c)), and linear regression was performed using Excel to calculate the concentration of the chromanol derivative in the combination system at the time of fa inhibition, i.e., IC, based on the regression equation fa(mixA) Then, the concentration of the anthraquinone compound in the combination system, i.e. IC, is calculated according to the molar ratio of the benzo-hydropyranol derivative to the anthraquinone compound in the combination system fa(mixB) 。
According to the following formula, the combination of the benzo-hydropyranol derivative and the anthraquinone compound for inhibiting the HepG2 cell of the liver cancer is calculated
The interaction index CI.
Figure SMS_31
When CI <1, synergy is indicated, and smaller CI indicates greater synergy.
The inhibition rate of the chromanol derivatives and the anthraquinones to other tumor cells was determined by the same overall method, and the CI value was calculated based on the results, and the results are shown in table 1.
TABLE 1 test results of liver cancer HepG2 cells
Figure SMS_32
Figure SMS_33
Figure SMS_34
Figure SMS_35
Figure SMS_36
Figure SMS_37
Figure SMS_38
Figure SMS_39
Figure SMS_40
Figure SMS_41
Figure SMS_42
Figure SMS_43
Figure SMS_44
Figure SMS_45
Figure SMS_46
Figure SMS_47
Figure SMS_48
Figure SMS_49
Figure SMS_50
Figure SMS_51
Figure SMS_52
The average CI values at different molar ratios in example groups 1 to 100 and comparative example groups 21 to 22 were calculated to obtain Table 2.
TABLE 2 mean CI values for compositions of different molar ratios
Figure SMS_53
As can be seen from the test results of the HEPG2 cells of the example groups 1-100 and the comparative examples 1-20 in Table 1, the highest inhibition rate of the drug on the liver cancer HepG2 cells in each example group is 70-90%, and the highest inhibition rate of the drug on the liver cancer HepG2 cells in each comparative example group is less than 50%, which indicates that the drug in the example group has a good inhibition effect on the liver cancer HepG2 cells. Meanwhile, as can be seen from the average CI values of the example groups 1 to 100 and the comparative example groups 21 to 22 in table 2, the CI values in the example groups were less than 1 in the range of 1 to 100.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.

Claims (1)

1. Use of a composition comprising only a chromanol derivative and an anthraquinone compound as active ingredients for the manufacture of a medicament for the treatment of liver cancer, wherein the chromanol derivative is selected from the group consisting of: one of (-) -epigallocatechin 3-O-gallate, (-) -epicatechin 3-O-gallate and (-) -epicatechin3-O- (3' -O-methyl) gallate, (-) -epigallocatechin 3-O-gallate, (-) -epigallocatechin3, 5-di-O-gallate, (-) -epigallocatechin 3-O-p-coumarate, (+) catechin and (-) -catechin 3-O-gallate; the anthraquinone compound is a compound shown as follows:
Figure QLYQS_1
、
Figure QLYQS_2
and
Figure QLYQS_3
wherein the molar ratio of the benzohydropyranol derivative to the anthraquinone compound is (0.01 to 100): 1, the dosage form of the medicine is tablets and capsulesIt can be made into dosage form or granule.
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