CN113350396B - Preparation method of traditional Chinese medicine composition for resisting myocardial ischemia - Google Patents
Preparation method of traditional Chinese medicine composition for resisting myocardial ischemia Download PDFInfo
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- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
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Abstract
The invention relates to a preparation method of a traditional Chinese medicine composition for resisting myocardial ischemia, which comprises the following steps: (1) weighing the following raw materials: weighing the following raw materials in parts by weight: 15 parts of fructus choerospondiatis, 10 parts of radix salviae miltiorrhizae, 10 parts of sandalwood, 10 parts of myrobalan and 10 parts of kapok; (2) water extraction: adding water into the raw materials, and performing hot reflux extraction; filtering, and collecting the water extractive solution; (3) alcohol precipitation: adding ethanol solution into the water extract, precipitating, filtering, collecting filtrate, concentrating to remove ethanol or solvent to obtain water solution of the Chinese medicinal composition for resisting myocardial ischemia. The traditional Chinese medicine composition has the advantages of simple preparation method, wide raw material source and low cost, and has the effects of resisting acute myocardial ischemia of rats caused by ISO and treating coronary heart disease.
Description
Technical Field
The invention relates to the field of traditional Chinese medicines, in particular to a preparation method of a new medicine formula for treating myocardial ischemia.
Background
Myocardial ischemia is a pathological condition in which the supply of blood flow to the heart is reduced, oxygen supply to the heart is reduced, myocardial metabolic disorder is caused, and the heart cannot normally perform physiological functions. Ischemic heart diseases include angina pectoris, myocardial infarction, coronary heart disease, etc., which are attracting wide attention worldwide because of their high prevalence and high mortality. Global disease burden (GBD) research results show that 1000 more than ten thousand new cases of ischemic heart disease worldwide in 2017, 1.2 million patients are found, and more than 800 million people die, which is the first cause of death in the global population. With the improvement of the economic level and the change of life style of residents in China, the prevalence rate and the death rate of ischemic heart diseases in China are continuously increased, nearly 150 thousands of people die of the ischemic heart diseases in 2015 all the country, and the disease is the second death reason of the residents in China which is second to cerebrovascular diseases.
At present, chemical medicines such as nitrates, statins blood fat reducing medicines, antiplatelet preparations and the like are mostly adopted for treating ischemic heart diseases, and no traditional Chinese medicine with exact curative effect is used for clinical treatment at present.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and seeks a preparation method of a traditional Chinese medicine formula with an exact curative effect on myocardial ischemia, so as to widen the medicine resources of ischemic heart diseases.
In order to achieve the aim, the invention provides a preparation method of a traditional Chinese medicine composition for resisting myocardial ischemia, which comprises the following steps:
(1) weighing raw materials
Weighing the following raw materials in parts by weight: 15 parts of fructus choerospondiatis, 10 parts of radix salviae miltiorrhizae, 10 parts of sandalwood, 10 parts of myrobalan and 10 parts of kapok;
(2) water extraction
Adding water into the raw materials, and performing hot reflux extraction; filtering, and collecting the water extractive solution;
(3) alcohol precipitation
Concentrating the water extract, adding ethanol solution, precipitating, filtering, collecting filtrate, concentrating, and removing ethanol or solvent to obtain water solution of the Chinese medicinal composition for resisting myocardial ischemia.
Further, the hot reflux extraction time in the step (2) is 3 times, the adding amount of water in each time is 12 times of the total weight of the raw materials, and the hot reflux extraction time in each time is 1.5 h.
The alcohol precipitation in the step (3) comprises the following specific steps: concentrating the water extract to relative density of 1.1-1.2, adding ethanol until ethanol content is 85%, precipitating, and collecting filtrate; drying to obtain the traditional Chinese medicine composition for resisting myocardial ischemia.
Compared with the prior art, the invention has the following advantages:
1. the medicinal composition is prepared from natural medicinal components, has an improvement effect on biochemical indexes such as glutathione peroxidase activity, superoxide dismutase content, malondialdehyde content and the like in blood and myocardial tissues of acute myocardial ischemia rats and myocardial necrosis area, and has the effects of resisting acute myocardial ischemia of the rats caused by ISO and treating coronary heart disease.
2. The traditional Chinese medicine composition has the advantages of simple preparation method, wide raw material source and low cost.
Drawings
FIG. 1 is a standard curve preparation HPLC chromatogram;
in the figure, A-a reference substance, B-a test solution and C-a negative reference solution;
FIG. 2 is a comparison of pathological sections of rat myocardium under different treatments.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1
The preparation process of the traditional Chinese medicine composition comprises the following screening examples:
first, extraction process
1) Weighing raw materials
Weighing the following raw materials in parts by weight according to the prescription: 15 parts of fructus choerospondiatis, 10 parts of radix salviae miltiorrhizae, 10 parts of sandalwood, 10 parts of myrobalan and 10 parts of kapok;
(2) water extraction
Adding water into the raw materials, and performing hot reflux extraction; filtering, and collecting the water extractive solution;
(3) alcohol precipitation
Concentrating the extractive solution to relative density of 1.1-1.2, adding ethanol to a certain concentration, precipitating, collecting filtrate, concentrating, and removing ethanol to obtain SXK water solution of the Chinese medicinal composition for resisting myocardial ischemia.
Second, optimization of extraction Process
1 instruments and materials
1.1 high performance liquid chromatograph (Dinex Ultiate 3000, dean instruments ltd., usa), electric heating blowing dry box (GZX-9070MBE, shanghai bocheng realty ltd. medical equipment factory), ultrasonic cleaner (SB-5200DT, ningbo xinyi ultrasonic equipment ltd.), rotary evaporator (RE-52AA, shanghai subsun biochemical equipment factory), digital display type electric heating constant temperature water bath (XMTD-204, shanghai bocheng realy ltd. medical equipment factory). Electronic analytical balance (CPA225D, sartorius scientific instruments ltd).
1.2 materials of salvia miltiorrhiza medicinal material (batch No. 1601002, Hebei Quantai pharmaceutical Co., Ltd.), tanshinone IIA reference substance (Chinese food and drug testing institute, batch No. 110766-; acetonitrile (chromatography alcohol, DikmaPure).
2 methods and results
2.1 assay of tanshinone IIA
2.1.1 chromatographic conditions and System suitability test: a Diamonsil C18 column (250 mm. times.4.6 mm, 5 μm) was used; acetonitrile (A) -phosphoric acid water (B) is used as a mobile phase, and gradient elution is carried out according to the setting conditions of the table 1; the column temperature is 20 ℃; the detection wavelength is 270 nm; the number of theoretical plates should not be less than 60000 calculated according to tanshinone IIA peak.
Table 1 mobile phase set-up conditions
2.1.2 preparation of control solution the tanshinone IIA 5.0012mg was weighed out accurately, placed in a 5mL volumetric flask, dissolved and diluted to the mark with methanol and shaken well. Precisely transferring 1mL of the above prepared reference solution, placing in a 50mL volumetric flask, adding methanol to dilute to scale, shaking to obtain tanshinone IIA reference solution with concentration of 20.0048 μ g/mL-1.
2.1.3 preparation of test solution SXK aqueous solution was prepared, and the volume was determined to be 100mL and shaken up to obtain the final product.
2.1.4 preparation of negative control solution, weighing the whole formula of medicinal materials lacking Saviae Miltiorrhizae radix, preparing a sample without Saviae Miltiorrhizae radix by the same process, fixing volume to 100mL, and shaking up to obtain the final product.
2.1.5 specificity test the above-mentioned control solution, test solution and negative control solution are filtered through 0.45 μm microporous filter membrane, and 10 μ L of each sample is introduced. The results are shown in FIG. 1: in the chromatogram of the test sample, the peak is separated from other components at the same retention time as the chromatogram of the tanshinone IIA reference sample; in the chromatogram of the negative control solution, no interference peak is observed at the position corresponding to the chromatographic peak of the tanshinone IIA control, which indicates that the tanshinone IIA has specificity under the chromatographic conditions.
2.1.6 the determination method comprises precisely sucking 10 μ L of each of the reference solution and the sample solution, injecting into high performance liquid chromatograph, and determining.
2.1.7 preparation of standard curve, diluting the reference solution with methanol by 2, 4, 6, 8, 10 times, precisely sucking 10 μ L, injecting into high performance liquid chromatograph, and measuring according to the chromatographic condition of '2.1.1'. Taking the chromatographic peak area as the ordinate and the content of tanshinone IIA as the abscissa, drawing a standard curve by using Excel software to obtain a regression equation of Y-69.66X +0.2946 (R)2＝0.9998)。
2.1.8 precision test: continuously taking 10 μ L of the control solution under the item of '2.1.2', respectively injecting samples into 6 needles, recording the peak area of each needle, and as a result, the peak area RSD of the tanshinone IIA is 1.86%, which indicates that the precision of the instrument is good.
2.1.9 stability test: the SXK aqueous solution is prepared according to the method under item 2.1.2, the samples are respectively injected for 2, 4, 6, 8 and 10 hours, the content of tanshinone IIA is measured according to the chromatographic condition under item 2.1.1, and the RSD is calculated to be 1.13 percent, which shows that the stability of the tanshinone IIA in the SXK aqueous solution is good after the tanshinone IIA is placed for at least 10 hours.
2.2 orthogonal experimental design: taking the yield and the paste yield of the tanshinone IIA in the extracting solution as the investigation indexes, selecting the alcohol precipitation concentration in the step (3), the extraction times in the step (1), the water adding amount and the extraction time to carry out L according to the level of 4 factors and 39(34) Orthogonal experimental design, factor level table (see table 2).
TABLE 2 level table of the factor extracted from the orthogonal test of the Chinese medicinal composition
2.2.1 extraction method: weighing according to the prescriptionThe total amount of the whole formula of the medicine is 55g, and 9 parts of the medicine are respectively taken. Test L with orthogonal design9(34) Selecting four factor levels, namely A alcohol precipitation concentration, B extraction frequency, C water addition amount and D extraction time, referring to table 2, decocting and filtering in water according to an orthogonal test scheme, adding 75-85% ethanol solution into filtrate, standing to separate out precipitate, filtering, and concentrating the filtrate to 100ml to obtain 9 sample solutions for orthogonal tests.
2.2.2 determination of paste yield 50mL of each sample solution under each condition in the item 2.2.1 is precisely measured, the sample solutions are placed in an evaporating dish dried to constant weight, the evaporation is carried out by evaporation in a water bath, the drying is carried out at 80 ℃ under reduced pressure to constant weight, the quality is precisely weighed, and the paste yield is calculated.
2.2.3 evaluation index and result analysis the orthogonal test results were combined by visual analysis and analysis of variance, and the results are shown in tables 3 and 4.
TABLE 3 water extraction and alcohol precipitation orthogonal test visual analysis chart of the Chinese medicinal composition of the invention
TABLE 4 analysis of composite score variance results
According to the results of visual analysis and variance analysis, the range of comprehensive scores shows that the primary and secondary actions of all factors are B>D>C>A, the extraction times have the greatest influence on the content of tanshinone IIA, the extraction time, the water addition amount and the alcohol precipitation concentration are used, and the optimal water extraction and alcohol precipitation process combination is A3B3C3D2. Namely, the extract is extracted by hot reflux for 3 times by 12 times of water, each time lasts for 1.5 hours, and after the extract is precipitated by 85% ethanol, the filtrate is taken.
2.2.4 confirmatory experiment, weighing 3 parts of medicinal materials according to the prescription proportion, wherein each part is 55g, carrying out 3 times of confirmatory experiment according to the optimal water extraction and alcohol precipitation process, and determining the content of tanshinone IIA and the paste collection rate. The result shows that the comprehensive score of the dry extract yield of the content of the preferred process tanshinone IIA is the highest, and the RSD is 2.21 percent. The results show that the preferred process is stable and feasible.
Example 2
Examples of production
1) Weighing raw materials
Weighing the following raw materials in parts by weight according to the prescription: 15 parts of fructus choerospondiatis, 10 parts of radix salviae miltiorrhizae, 10 parts of sandalwood, 10 parts of myrobalan and 10 parts of kapok;
(2) water extraction
Adding 12 times of water by weight into the raw materials, and extracting for 3 times by hot reflux, wherein each time is 1.5 h; filtering, and mixing extractive solutions;
(3) alcohol precipitation
Mixing the extracting solutions, concentrating the extracting solutions until the relative density is 1.1-1.2, adding ethanol until the ethanol content in the solution is 85%, precipitating, and taking the filtrate to obtain the aqueous extract of the traditional Chinese medicine composition.
Example 3
Application examples
1 Material
1.1 animal healthy SD rats with half of male and female, weight 200-250 g. Provided by GLP center of TCM university in Heilongjiang, license number SCXK- (Jing) 2009-0001.
1.2 Instrument KY2000 semi-automatic biochemical analyzer (Shimadzu corporation, Japan); 756PC Spectrum UV Spectrophotometer (Shanghai spectrometer Co., Ltd.); BL-420F biological function experimental system.
1.3 reagent GSH-Px test kit (batch No. 20180626), SOD kit (batch No. 20181105), and MDA kit (batch No. 20171214), all purchased from Nanjing institute of bioengineering.
1.4 the drug isoproterenol hydrochloride (Shanghai Hefeng pharmaceuticals, Inc.); dioxin xuekang capsules (guoduo group ltd); example 2 an aqueous solution of the resulting traditional Chinese medicine composition SXK was prepared.
2 method
2.1 Isoprenol (Iso) InductionEstablishment of induced acute myocardial ischemia model: rats were randomly divided into a blank group, a model group, SXK high, medium and low 3 dose groups and a positive control drug (dioxemcon capsule), and SXK of an aqueous solution was administered in terms of body surface area according to normal administration doses, which were respectively a high, medium and low dose group: 4mL (L (after drying the Chinese medicinal composition prepared in the above example 1, the concentration is 0.4g/mL, 0.2g/mL, 0.1g/mL high, medium and low three concentrations are used as high, medium and low dose groups, and the gavage administration is carried out at 1mL/100 g) of the positive control group is 4mL (equivalent to 30 mg. kg. of Di' ao Xinxuekang)-1). The blank and model groups were given the corresponding volume of distilled water and all rats were gavaged continuously for 15 days, 1 time/day. According to literature reports (influence of dihydroquercetin on the protective effect and the oxidative stress level of myocardial ischemia model rats, quality of things, lucidity, loyalty and the like, Shizhen Chinese medicine, 2019,30 (10): 2370-2372) and pre-test, from day 12, the rest groups except the blank group are 5 mg-kg-1The dose of (2) was i.p. injection of isoproterenol 1 times/day for 3 consecutive days.
2.2 detection index and method
2.2.1 electrocardiographic detection: after the last gavage, rats were anesthetized with 10% chloral hydrate by intraperitoneal injection (3 ml. kg)-1) After anaesthesia, the patient lies on the back and is fixed on an operating table, one side of a needle electrode is inserted into the subcutaneous skin of the four limbs of a rat, the other side of the needle electrode is connected with a BL-420F biological function experiment system, a standard II-lead electrocardiogram is recorded, the electrocardiogram change before and after modeling is observed, the voltage value of the J point of the electrocardiogram and the T wave change before and after modeling are compared, the T wave height measurement takes a P-R section as a base line, 5 continuous waveforms are measured, the average value of the waveforms is taken, and statistical analysis is carried out.
2.2.2 measurement of GSH-Px, SOD and MDA in serum: blood is taken from abdominal aorta of a rat through a cannula, a part of blood plasma is taken to separate blood serum, and the content of GSH-Px, SOD and MDA in the blood serum is measured according to the operation of a kit instruction.
2.2.3 preparation of myocardial tissue pathological section: the apical tissues were removed, fixed in 10% formaldehyde, HE stained, and the histomorphometry of each group of specimens was observed under a light microscope.
2.3 statistical treatment: using SPSS 13.0 software, data are expressed in x + -s, and the comparison between two groups using t-test, P <0.05 is statistically significant.
3 results
3.1 Effect on acute myocardial ischemia rat Electrocardiogram: after injecting Iso, as shown in table 5, T wave of the model group was increased and J point was shifted down compared with the control group, indicating myocardial ischemia; the SXK high dose significantly improved the J-point and T-wave amplitude of change (p <0.05) compared to the model group.
Table 5 effects of isoproterenol on T-wave height and J-point height (x ± s, n ═ 10)
Comparison with blank group▲P<0.05，▲▲P<0.01; comparison with model group■P<0.05，■■P<0.01。
3.2 Effect on serum GSH-Px, SOD, MDA: after injecting Iso, the GSH-Px and SOD activity in the rat serum is obviously reduced, and the MDA content is obviously increased. Compared with the model group, activities of GSH-Px and SOD in the serum of the rat of SXK three dose groups are increased to a certain degree, and MDA content is reduced, wherein, SXK high dose can obviously increase the activity of GSH-Px in the serum of the rat (p is less than 0.05), and can obviously reduce the MDA content in the serum of the rat (p is less than 0.05). See table 6.
TABLE 6 Effect on serum GSH-Px, MDA, SOD activity in rats with myocardial ischemia (x + -s, n ═ 10)
Comparison with blank group▲P<0.05，▲▲P<0.01; comparison with model group■P<0.05，■■P<0.01。
3.3 the myocardial cells of the rats in the blank group of the myocardial tissue pathological section are arranged orderly without obvious degeneration and necrosis and inflammatory cell infiltration in intercellular substance. Compared with a blank control group, the myocardial tissue of the model group has obvious ischemic injury, mainly presents myocardial fiber disorder, interstitial edema degeneration, myocardial cell vacuole degeneration, cytoplasm uneven staining, nucleus fixation shrinkage and other obvious pathological morphological structure changes, and indicates that the acute ischemic injury of the myocardium can be caused by the intraperitoneal injection of isoproterenol; compared with the model group, the myocardial necrosis area of each administration group is obviously reduced; the necrotic area of myocardial tissue decreased significantly with increasing doses, indicating SXK decreased the degenerative necrosis of myocardial cells, and the results are shown in FIG. 2.
The etiology of ischemic heart disease (coronary heart disease) is closely related to the generation of cardiac oxygen free radicals, myocardial hypoxia and ischemia induce oxidative stress reaction, a large number of neutrophils are gathered in an ischemic area to accelerate the generation of oxygen free radicals, and a large number of oxygen free radicals are accumulated to cause membrane lipid peroxidation to cause structural abnormality and functional damage of cell membranes, so that myocardial tissue damage is aggravated. Glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) are endogenous enzyme scavengers that counteract the oxidative destruction of free radicals, and Malondialdehyde (MDA) is a stable lipid peroxidated aldehyde acid product widely used to reflect oxidative stress levels. The high-dose composition SXK prepared by the invention has strong oxidation resistance, can improve the activity of GSH-Px and SOD in myocardial tissue, inhibit lipid peroxidation process, reduce the activity of lipid peroxide MDA, relieve the damage of oxygen free radical to myocardium, protect ischemic myocardium and treat ischemic heart disease.
In the research process, the rat can effectively inhibit myocardial tissue ischemia caused by Iso after being orally taken SXK, the height of T-wave and J-point is obviously changed, the activity of GSH-Px and SOD in serum is increased, the MDA content is obviously reduced, and the result shows that SXK can protect myocardial cells and improve the stability of cell membranes. It can be seen from the pathological section that after SXK is taken, the rat has great amount of inflammatory cell infiltration in the myocardial degeneration and necrosis area, disorganized and broken myocardial fiber arrangement, obviously improved myofilament melting and reduced pathological change range. Experiments prove that the traditional Chinese medicine composition SXK prepared by the invention can effectively inhibit myocardial tissue ischemia caused by isoproterenol (Iso) and protect myocardial cells from being damaged, thereby playing a role in treating coronary heart disease.
Claims (3)
1. The preparation method of the traditional Chinese medicine composition for resisting myocardial ischemia is characterized by comprising the following steps:
(1) weighing raw materials
Weighing the following raw materials in parts by weight: 15 parts of fructus choerospondiatis, 10 parts of radix salviae miltiorrhizae, 10 parts of sandalwood, 10 parts of myrobalan and 10 parts of kapok;
(2) water extraction
Adding water into the raw materials, and performing hot reflux extraction; filtering, and collecting the water extractive solution;
(3) alcohol precipitation
Concentrating the water extract, adding ethanol solution, precipitating, filtering, collecting filtrate, concentrating, and removing ethanol or solvent to obtain the final product.
2. The preparation method according to claim 1, wherein the alcohol precipitation in the step (3) comprises the following specific steps: concentrating the water extract to relative density of 1.1-1.2, adding ethanol until ethanol content is 85%, precipitating, and collecting filtrate; drying to obtain the traditional Chinese medicine composition for resisting myocardial ischemia.
3. The preparation method according to claim 2, wherein the number of hot reflux extractions in step (2) is 3, each time water is added in an amount 12 times the total weight of the raw materials, and each time the hot reflux extraction time is 1.5 h.
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