Chinese medicinal effective-part composition for treating coronary heart diseases

Technical Field

The invention belongs to the field of medical technology, relates to a medicine for the treatment of coronary heart disease, in particular to the total Radix Salviae Miltiorrhizae, total arasaponin, total alkaloid drogen, amber total sesquiterpene pharmaceutical composition.

Background Art

Coronary heart disease is a serious endanger the health of the people one of the major disease, high mortality rate due to the high incidence, become "human 1st hitman". Middle-aged people against China display the results of the latest research, 1998 to 2008 years, the incidence of coronary heart disease than in the past Chinese men with a view to increasing 26.1%, female increase 19%, my in each of the number of die in various coronary heart disease is estimated that more than 100 million, which is in our population because of the death of the fastest growing. As our Society and ageing changes in the way in which the human life, a China will become the large incidence of coronary heart disease. Therefore, enhancing medicament for the treatment of coronary heart disease study has important social and economic significance.

As the western medicine is gradually awareness of the limitations of the world and the change of the mode and medical disease spectrum , advocate natural medicine has become a worldwide trend, traditional Chinese medicine industry faces unprecedented opportunities. However, modern traditional Chinese medicine industry due to reasons such as the low level, the prevailing Chinese medicine industry backwardness production process, the product quality is not stable, low content of many problems such as science and technology, the Chinese medicine industry due to weak International market competition, traditional Chinese medicine industry is facing a serious challenge. Compound preparation is the characteristics of traditional Chinese medicine is clinically applied, is also the major form Chinese medicinal preparation. With traditional Chinese medicine effective part composition effective substance basic clear, the mechanism of action is relatively clearly, more accurate clinical adapt to the disease, but also a stronger pertinence, safe and effective, suitable for modern manufacturing process technology and the advantages of standard quality, is to possess "three-way" (high efficiency, quick-acting, long-acting), "three small" (dose, toxicity, side effects), "three will" (storage, carrying, easy administration) new and modern characteristics of traditional Chinese medicine.

Coronary heart disease is a Chinese medicine studies faints achingly, chest, vacuum achingly such areas, its pathomechanisms can be summarized as "pain is not through the" and "not sakae the pain". Modern a large number of clinical studies show that the treatment of coronary heart disease is the advantage of the traditional Chinese medicine, compared and western medicine, Chinese medicine for treating coronary heart disease has the following advantage: relatively few toxic side effect, is suitable for long-term application; for a drug can be a plurality of pathological link coronary heart disease; improving patient accompanying symptoms such as dyspnea, hypodynamia, obviously more mental depression; can improve the patient's quality of life, reduces the economic load of a patient, in accordance with the requirements of the health economics. Basic research confirmed that removing blood stasis, Qi, promotes blood circulation, with the method of reducing the lipid, dilating coronary artery, anticoagulant, multiple roles, role includes the affected endothelial function, vulnerable plaque, platelet activation, left ventricular remodeling, vascular reconstruction, such as angiogenesis, the treatment of traditional Chinese medicine starting from the whole, the overall adjustment pathophysiology of coronary heart disease, improving clinical symptoms of chemical synthesis have the advantages of the drug does not can be substituted. The means and methods for the treatment of traditional Chinese medicine from the nature, little side effects, for the world background of the green, Chinese medicine for the treatment of coronary heart disease has become a National and International development of hot spots. In the present in many Chinese medicine for the treatment of coronary heart disease, in order to effectively position as the main active component of the total phenolic acid Radix Salviae Miltiorrhizae, total arasaponin, kudzuvine root anthoxanthin to more and more people are, various traditional Chinese medicines for the treatment of coronary heart disease efficacy of the effective part with different focused, clinical on the great demand of the medicine. Therefore, to provide effective substance basic clear, the mechanism of action is relatively clear, clinical of adapting to disease pertinence are relatively strong, safe and effective, suitable for modern manufacturing technology and standards of quality compound preparation of traditional Chinese medicine effective part has an important clinical significance.

Content of the invention

The purpose of this invention is to provide a traditional Chinese medicine for the treatment of coronary heart disease of the effective part composition, its effective substance basic clear, relatively clear of the mechanism of action, the quality can be controlled, and can remove blood stasis, tongluozhitong, produce the synergistic reaction, the curative effect, provides a better clinical curative effect, safer, more convenient traditional Chinese medicine effective part of the compound composition and its preparation.

The invention can be implemented through the following technical scheme.

The present invention provides the pharmaceutical compositions of the raw materials for the weight ratio of: total Radix Salviae Miltiorrhizae 1.25-1.5 parts, total arasaponin 1-1.5 parts, long pepper total alkaloid 0.02-0.13 parts, amber total sesquiterpene 0.02-0.09 parts.

The invention pharmaceutical dosage form is a tablet, pill, capsule, soft capsule, granules, oral preparation, auxiliary material is pharmaceutically acceptable the corresponding supplementary product.

Radix Salviae Miltiorrhizae used in the present invention the total phenolic acid content is not lower than 50%, total arasaponin content is not lower than 50%, of the total alkaloid drogen content is not lower than 50%, amber total sesquiterpene content is not lower than 50%.

The invention of a pharmaceutical composition for the treatment of coronary heart disease, the Radix Salviae Miltiorrhizae total phenolic acid is extracted from Radix Salviae Miltiorrhizae, Panax notoginseng total saponin is extracted from, long pepper total alkaloid is extracted from the drogen, amber total sesquiterpene is extracted from the amber; the total Radix Salviae Miltiorrhizae, total arasaponin, total alkaloid drogen, amber total sesquiterpene content is to comply with the above mentioned requirements.

The active ingredient of this composition can be used for preparing the literature method [1-4], can also be purchased from the market, can also be their preparation.

The Radix Salviae Miltiorrhizae total phenolic acid can be prepared by the following method: into coarse powder medicinal Radix Salviae Miltiorrhizae, ultrasonic extraction with ethanol 2 times, 1st subadditive 10 times soak in ethanol 12 hours after ultrasonic extraction; 2nd subadditive 5 times of ultrasonic extraction with ethanol, each 1 hour. Merging extracted liquid, cvvhdf, concentrating the filtrate to 0.2-0.8g crude drugs/ml, by adding SIPI905 macroporous resin, first impurity such as water washing in addition to carbohydrate molish reaction is negative, then using 3-4 times volume 70% ethanol to elute, collect eluant, concentrated under reduced pressure, vacuum drying to constant weight, to get the Radix Salviae Miltiorrhizae total phenolic acid content of not less than 50%, wherein the acid content B shall be not less than 30%.

The above-mentioned ultrasonic extraction, power 250w, frequency 30KHz.

The above-mentioned Radix Salviae Miltiorrhizae total phenolic acid content determination of B dan phenol acid (high performance liquid chromatography) chromatography conditions and system adaptability test: B: with octadecyl silane bonding silica gel as a filler; mobile phase is methanol: acetonitrile: formic acid: water (30 the [...] 10 ; 1 ; 59); flow rate is 1 ml/min; the column temperature 25 the [...] ; detection wavelength 286 nm, peak tanshinpolyphenolate B according to the theoretical plate number in the calculation of 2000 or more.

Preparation of control solution: precision that proper reference substance B takes the Dan phenolic acid , plus 75% methanol to prepare each 1 ml containing 0.44 mg solution, is obtained.

Preparation of sample solution: takes this 2 sheet, porphyrization, heating powder about 0.2g, precision stability, in a conical flask sets has fills , precision by adding 75% methanol 50 ml, weight stability, heating reflow 1h, taking out, weight stability after being cooled, with 75% of the weight of the methanol topping-up reduce, shaking, cvvhdf, get.

Assay method: precision respectively for the sample solution from the reference and the 10  l, measured into the liquid chromatograph.

The above-mentioned Radix Salviae Miltiorrhizae measuring the content of the total acid (ultraviolet-visible-light photometry)

Preparation of control solution: takes the Dan phenolic acid precision that B25mg placed in 100 ml of measuring flask, add the proper amount of methanol is dissolved and diluted to scale, shaking, precision measuring the above-mentioned solution 10 ml, water and dilute to 100 ml configured to 25 the reference substance solution g/mL.

Preparation of sample solution: about takes this 0.1g, precision stability, with 50 ml of measuring flask, dissolved and diluted with the appropriate amount to scale, shaking, precision rectifier 10 ml, separatory funnel in is, by adding ethyl acetate saturated 0.1mol/mL hydrochloric acid 50 ml, shaking, using 0.1mol/mL hydrochloric acid saturated ethyl acetate 3 times, each 20 ml, taking acetic ether, water bath to dryness, the residue is adding methanol to dissolve and quantitative transfer to 25 ml amount in the bottle, to dilute to the scale adds the methyl alcohol , shaking, precision measuring the above-mentioned solution 10 ml with 100 ml of measuring flask, water and dilute to scale, shaking, filtration, filtrate takes continues , get.

Assay method: separately taking reference with the test sample solution, in order to solvent as a blank, according to the ultraviolet-visible spectrophotometry (China pharmacopeia 2005 years Edition of a appendix VA), at 286 nm wavelength measuring absorbance, can be calculated.

The composition of this invention can be directly total arasaponin purchase of commercial goods, products purchased must meet National standards. Preferably total arasaponin is prepared according to the following method: the crude drugs the Panax 70% ethanol extraction, filtration, filtrate concentrated, the macroporous resin column, with 80% ethanol elution, the eluent is decolourizations after concentrating under reduced pressure, refining, drying, to obtain the total arasaponin, wherein the medicine containing arasaponin R1 shall not be less than 5.0%, Ginseng saponin Rg1 not less than 20.0%, Ginseng saponin Rb1 not less than 25.0%.

The composition of this invention can be used for total alkaloid-mentioned method for preparing of the following: the SFE-CO₂ extraction, the total alkaloid-mentioned shall be not less than 50%, wherein piperine content of not less than 30%, the cyclodextrin, result to 2-6 times the supercritical CO₂ extract inclusion β-CD, plus 4 times water, inclusion time 2h, β-CD inclusion compound is obtained.

The above-mentioned total alkaloid piperine content determination of the (high performance liquid chromatography)

Chromatographic conditions and system adaptability test: with octadecyl silane bonding silica gel as a filler; methanol: aqueous solution (the 77 [...] 23) as the mobile phase; flow rate is 1 ml/min; the column temperature 25 the [...] ; detection wavelength is 343 nm. The peak calculated by piperine, theoretical plate number in the 2000 or more.

Preparation of control solution: proper amount with precision weighing piperine, made adds the methyl alcohol each 1 ml containing 40 the solution   g, is obtained.

Preparation of sample solution: takes this 2 sheet, porphyrization, heating powder about 0.5g, precision stability, with 50 ml of measuring flask, adds the methyl alcohol 45 ml, ultrasonic processing (power 250W, frequency 20kHz) 30 min, a cup, adds the methyl alcohol to scale, shaking, filtration, filtrate takes continues , get.

Assay method: precision respectively for the sample solution from the reference and the 10  l, measured into the liquid chromatograph.

The above-mentioned determination of the total alkaloids

Preparation of control solution: precision weighing piperine reference substance 5 mg, placing 10 ml of measuring flask, dissolve and dilute to the scale adds the methyl alcohol , shaking, taking 2 ml to 25 ml in capacity bottle, respectively add 5 ml buffer solution (pH=5), 2 ml polybromide thymol blue test solution, shaking, then adding chcl constant volume, full shaking, into the separatory funnel in, put layered, taking chloroform level (lower level fluid), filtering, to obtain the.

Preparation of sample solution: takes this powder about 0.5g, precision stability, with 50 ml of measuring flask, add chcl 35 ml, ultrasonic processing (power 250W, frequency 20kHz) 30 min, after cooling, adding 5 ml   pH=5 the buffer solution, 2 ml polybromide thymol blue test solution, shaking, then adding chcl constant volume, full shaking, shift-person in separatory funnel, placing layered, taking chloroform level (lower level fluid) filtering, to obtain the.

Assay method: separately taking reference with the test sample solution, to chcl as a blank, according to the ultraviolet-visible spectrophotometry (China pharmacopeia 2005 years Edition of a appendix VA), at 343 nm wavelength measuring absorbance, can be calculated.

The composition of the invention in total sesquiterpene succinylsuccinate can be used the following method for preparing: the composition of the invention in total sesquiterpene succinylsuccinate can be used the following method for preparing: adopt SFE-CO₂ extraction, that is, total sesquiterpene content of not less than 50%, the cyclodextrin, result to 2-6 times the supercritical CO₂ extract inclusion β-CD, plus 4 times water, inclusion time 2h, β-CD inclusion compound is obtained.

Another purpose of this invention is to provide the preparation of the pharmaceutical compositions of the present invention method, this method can adopt the field of pharmacy the conventional method, carried out using conventional pharmaceutical excipients. To adopt the general method, for example, total Radix Salviae Miltiorrhizae, total arasaponin, total alkaloid drogen, amber total sesquiterpene after mixing uniformly, and arbitrary one or more than one kind of the commonly used carriers on pharmacy mixed or accessories, and then made into various oral dosage forms. The carrier such as excipient, filler, diluent, lubricant, wetting agent, disintegrating agent, surface active agent, preservative, sweetener, perfume. In particular, the carrier such as starch, dextrin, lactose, microcrystalline cellulose, hydroxypropylmenthyl cellulose, polyethylene glycol, magnesium stearate, micronized silica gel, glucose, mannitol, xylitol, glycin.

According to need, the pharmaceutical compositions of the invention can be made into a formulation suitable for oral administration, can be any dosage form of the following: a tablet, capsule, soft capsule, granule, pill, tablet, oral disintegrating tablet, pill.

Another purpose of this invention is to provide the pharmaceutical composition of this invention in the treatment of coronary heart disease, heart failure, arrhythmia and other aspects of the application.

Compared with the prior art, the beneficial results of this invention are: the pharmaceutical composition contains the total phenolic acid Radix Salviae Miltiorrhizae, total arasaponin, total alkaloid drogen, amber [...] , to, produce the synergistic reaction, the pharmacodynamical test prove that the curative effect is prominent.

Mode of execution

In order to this invention a detailed description of further, give specific embodiment, but only as set out the invention, and is not to limit the scope of, the invention.

Example 1 granular formulation of the pharmaceutical compositions of the present invention, a tablet or a capsule dosage forms

Granule preparation: process for preparing granules using conventional, total takes the salvia miltiorrhiza 1.5 parts, total arasaponin 1.5 parts, long pepper total alkaloid 0.02 parts, amber total sesquiterpene 0.02 parts, auxiliary material in right amount. Mixing, granulation, siebtechnik, drying, the granule formulation of pharmaceutical compositions is prepared.

The preparation of tablet: the prepared by further pressing the particles, drying, in other words make the total Radix Salviae Miltiorrhizae-containing 1.5 parts, total arasaponin 1.5 parts, long pepper total alkaloid 0.02 parts, amber total sesquiterpene 0.02 parts of the tablet formulation of the pharmaceutical composition.

Capsule preparation: the prepared particles into the capsule shell, make capsule, containing Radix Salviae Miltiorrhizae obtain the total phenolic acid 1.2 parts, total arasaponin 1 parts, long pepper total alkaloid 0.02 parts, amber total sesquiterpene 0.02 parts of the tablet formulation of the pharmaceutical composition.

Embodiment 2 the composition of the present invention the drop pill dosage form

Preparing: by employing the conventional process for preparing dropping pills, total takes the salvia miltiorrhiza 1.25 parts, total arasaponin 1.2 parts, long pepper total alkaloid 0.10 parts, amber total sesquiterpene 0.08 parts, auxiliary material in right amount, of the pharmaceutical composition.

Embodiment 3 the composition of the present invention soft capsule dosage forms

Preparing: by employing the conventional process for preparing soft capsule, total takes the salvia miltiorrhiza 1.25 parts, total arasaponin 1 parts, long pepper total alkaloid 0.12 parts, amber total sesquiterpene 0.07 parts, auxiliary material in right amount, mixing, with gelatin makes the pouch shell material, pressed into the soft capsule, the soft capsule of pharmaceutical composition.

Embodiment 4 the composition of the present invention the pellet formulation

Preparation: the process of conventional preparation micropill, total takes the salvia miltiorrhiza 1.25 parts, total arasaponin 1 parts, long pepper total alkaloid 0.05 parts, amber total sesquiterpene 0.05 parts, auxiliary material in right amount, prepared micropill of this pharmaceutical composition.

Embodiment 5 the composition of the present invention orally disintegrating tablet

Preparation: the process of conventional preparation of oral disintegrating tablet, total takes the salvia miltiorrhiza 1.25 parts, total arasaponin 1 parts, long pepper total alkaloid 0.07 parts, amber total sesquiterpene 0.04 parts, auxiliary material in right amount, the oral disintegrating tablet pharmaceutical composition.

Embodiment 6 the dispersible tablet composition of the present invention

Preparing: process for preparing a dispersible tablet, total takes the salvia miltiorrhiza 1.25 parts, total arasaponin 1 parts, long pepper total alkaloid 0.03 parts, amber total sesquiterpene 0.03 parts, auxiliary material in right amount, the prepared dispersible tablet of this pharmaceutical composition.

Example 7 effect of the compositions of the present invention test

(A) the prescription of the compositions of the present invention is compatibility test

In order to look at different total Radix Salviae Miltiorrhizae of the compatibility of, total arasaponin, total alkaloid drogen, amber total sesquiterpene potency, find the best drug effect prescription, the test selected total Radix Salviae Miltiorrhizae, total arasaponin, total alkaloid drogen, amber total sesquiterpene as of the 4 factors, and promising to the 2 level, the second level of four factors L₈ (2⁷) test.

Table 1 factor level design table

Table 2L₈ (2⁷) orthogonal design table

Animal random is divided into 9 groups of: model group , gathers the heart crisp group , drogen + amber total [...] total alkaloids, total arasaponin + amber total [...] , total arasaponin total alkaloid group drogen +, + amber total [...] total Radix Salviae Miltiorrhizae, drogen + total alkaloid group total Radix Salviae Miltiorrhizae, + Sanchi general soap glucoside group total Radix Salviae Miltiorrhizae, total Radix Salviae Miltiorrhizae-mentioned total arasaponin + + + amber total [...] total alkaloids. Drugs to 0.5% CMC is dissolved to the desired concentration, the volume is administration of 3 ml/kg, route of administration for duodenography.

Test carried out according to the literature method. Ligation 2 hours later, the following transverse heart ligature 5 sheet, dyeing N-BT, the multimedia color pathological text analysis system, in order to fix-like distance measuring total myocardial area and infarcted myocardial area, observing the extent of myocardial infarction; result (t test) statistical treatment.

Table 3 composition of this invention (protects heart Kang) to different compatibility impact on area of myocardial infarction RAT myocardial infarction (X±SD, n=8)

Note: with the model group, *P <0.05, **P <0.01.

By orthogonal directviewing with the analysis of variance, the result shows that the total phenolic acid Radix Salviae Miltiorrhizae, total arasaponin, total alkaloid drogen, amber total sesquiterpene the area of the myocardial infarction are the effects are prominent (P <0.05), therefore the total Radix Salviae Miltiorrhizae, total arasaponin, total alkaloid drogen, amber total sesquiterpene 4 to extract protects heart Kang a prescription.

Composition (II) different ratio the muscle blocks test models

The compositions of the present invention by the slenderizing the following pharmocodynamics tests prove that: the healthy adult dog 30 only, dual-purpose of female, random is divided into 5 groups, each group of 6 is only: to the total phenolic acid Radix Salviae Miltiorrhizae 1.25 parts, total arasaponin 1 parts, the total alkaloid profiles 0.02 parts, amber total sesquiterpene 0.02 A group as composition, to total Radix Salviae Miltiorrhizae 1.25 parts, total arasaponin 1.2 parts, the total alkaloid profiles 0.04 parts, amber total sesquiterpene 0.06 B group as composition, total Radix Salviae Miltiorrhizae 1.5 parts, total arasaponin 1.5 parts, the total alkaloid profiles 0.06 parts, amber total sesquiterpene 0.08 C group for the composition, the negative control group of physiological saline, medicinal gathers the heart crisp group positive western medicine, a total of 5 group.

Test method: before in ischemia, ischemia 15 min (before administration), of the 15, 30, 60, 90,120,180 min recording extraepicardial the change of the values. Observing the indicators extraepicardial values: rise to ST paragraph 2mv of the above digital (NST) and ST duan Sheng the sum of the target value before and after the change of the observation administration, and calculates the range of the extent of myocardial ischemia. Venous blood effectively, blood oxygen measuring instrument for measuring respectively in coronary sinuses, artery blood oxygen content, and through the coronary artery blood flow (CABF) calculating myocardial oxygen consumption (MOC), serum creatine kinase (CK), lactate dehydrogenase (LDH), plasma endothlin (ET), thromboxane (TXB2) and 6-keto-prostandin F_1α (6-Keto-PGF_1α). After 180 min recording is finished, immediately taken off heart, NS liquid flushing, weighing, heart ligation line, parallel to the coronary groove is cut partially into the ventricle 5 sheet, is placed in the dyeing liquid nitro-four [...]   (N-BT), normal temperature dyeing 15 min. Medical Image analysis system is used for measuring myocardial both sides of each sheet (non-N-BT dyeing area) blocks the area with must blocks the area (dyeing area N-BT), calculate the area of each piece of the cardiac muscle, blocks the area ventricular total area and the total area. Calculated for blocks the area ventricular and the percentage of the heart. The experimental result of the statistical processing, in order to judge the significance test t.

Experimental result:

1, the dog myocardial ischemia (∑-ST) the degree of influence:

Results are shown in table 4. The duodenography administration, the composition of the invention A, B, C group are obviously reduce myocardial ischemia (∑-ST) the degree of the effect. Wherein the composition after group medicine C 30 min drug that can play a role, and continue until after 180 min, the animal before ∑-ST (387.81±37 . 67) to mv (205.38±15 . 17) mv, dropped (46.62±11 . 72) %, composition the C 30 min -180 mi ∑-ST   n of the difference between the former and compare with statistical significance (P <0.01-0.05); composition after medicine B 45 min drug that can play a role, and continue until after 180 min, the animal before ∑-ST (394.24±62 . 59) to mv (241.70±71 . 37) mv, dropped (30.16±16 . 69) %, composition the B 45 min -180 min ∑-ST of the comparison the control group with statistical significance of the difference (P <0.01-0.05); composition after medicine A 60 min drug that can play a role, and continue until after 120 min, the animal before ∑-ST (399.22±60 . 53) to mv (297.56±59 . 98) mv, dropped (25.57±13 . 09) %, composition the A 60 min -120 min ∑-ST of the comparison the control group with statistical significance of the difference (P <0.05).

2, the dog myocardial ischemia range of the impact of (N-ST)

Results are shown in table 5. Control group to the 0.5% CMC rear, myocardial ischemia range no obvious change (N-ST). Composition A, B, C group have a different degree of reducing myocardial ischemia scope of the role of (N-ST), wherein the composition after group medicine C 30 min drug that can play a role, and continue until after 180 min. Before the animal N-ST (29.93±0 . 82) sign measuring point to a (23.83±3 . 31) a mark point, a decrease of (18.80±10 . 55) %, composition C group -30 min 180 min before of the medicine N-ST and compare with statistical significance of the difference (P <0.01-0.05); composition after medicine B 45 min drug that can play a role, and continue until after 180 min, before the animal N-ST 29.55±0 . 75mv sign measuring point to a (24.87±3 . 27) a mark point, a decrease of (15.39±12 . 17) %, composition B group -45 min 180 min before and with medicine compared with statistical significance of differences in the control group (P <0.01-0.05); composition after medicine A 60 min drug play a role, and continue until after 90 min, before the animal N-ST (29.37±0 . 86) to a mv sign measuring point (28.11±1 . 01) a mark point, a decrease of (4.92±2 . 78) %, composition B group -45 min 180 min before and with medicine compared with statistical significance of differences in the control group (P <0.05).

The above results show that, composition A, B, C the experimental acute canine myocardial ischemia with remarkable improving effect, the extent of myocardial ischemia can be significantly reduced (∑-ST), narrow (N-ST) myocardial ischemia range.

3, the dog range of acute myocardial infarction (measuring process for dyeing N-BT) impact of:

Results are shown in table 6. A protects heart Kang composition, B, can reduce the area of animal myocardial infarction area C, compare there is significant difference (P <0.05 or P <0.01), wherein the composition C group myocardial infarction area area of the ventricle of the heart and respectively (2.91±1 . 30) %, (6.54±2 . 41) %, compare with statistical significance of the difference (P <0.01); composition myocardial infarction area B group area of the ventricle of the heart and respectively 4.22±2 . 45%, (9.17±3 . 85) %, reducing the control group compared with statistical significance of the difference (P <0.01); composition myocardial infarction area A group area of the ventricle of the heart and respectively (5.89±1 . 71) %, (13.47±5 . 27) %, reducing the control group compared with statistical significance of the difference (P <0.05).

In a word, composition A, B, C, the total Radix Salviae Miltiorrhizae is 1.25-1.5 parts, total arasaponin 1-1.5 parts, long pepper total alkaloid 0.02-0.13 parts, amber total sesquiterpene 0.02-0.09 parts proportion between, has good resistance to myocardial ischemia.

(C) the composition of the invention on RAT thrombus formation and the impact of the blood viscosity

The compositions of the invention inhibit thrombosis, reduce the blood viscosity by the following pharmocodynamics tests prove that: the healthy male SD RAT 60 only, random divided into 6 groups, each group of 10 only: protects heart Kang high, middle, low-dose group, protects heart Kang high, middle, low-dose group, normal control group, model control group, western medicine positive medicament aspirine control group. Intragastrically to the medicine, continuous administration 7 day, administration section 6d, unless the blank control group, each group of RAT subcutaneous injection hydrochloric acid adrenergic 0.08 ml/100g mouse heavy, 2 times/day, interval 4h, continuous 2d. Each group injection adrenergic between the RAT is immersed in ice-water bath 4 min, temperature of the 5 [...]. Section 2d and using the same method the operation is repeated 1 time. After the last administration 1h, the chloral hydrate (300 mg/kg) anesthesia, silicon polyethylene cannula puncture neck total artery, taking 2 ml blood is used for determining the thrombus, blood taking 3 ml (heparin anticoagulant) used for determining the blood viscosity.

Test results are as follows:

1. The formed thrombus of blood stasis the impact of the RAT

From table 7 it can be seen, and the blank set of comparison, the length of the thrombus models, wet weight, dry weight has significantly increased, prompting blood stasis model reproducing a successful. Compared with the model group, each dosing group protects heart Kang Pian , thrombus length of aspirin group, humid weight and dry weight compare there is significant difference.

Table 7. The composition of the invention (protects heart Kang) formed thrombus to the impact of the RAT( )

Note: with the model group^* P <0.05,^** P <0.01 (the same below)

2. The impact of the blood viscosity

The table 8 can be seen, with the model control group comparison, Huxin Kandy extract 360g crude drug/kg dose group of RAT whole blood viscosity in the ocular 5S^-1, 30S^-11 lower are obviously significantly reduced (P <0.01), the ocular 100S^-, 200S^-1 is obviously reduced under (P <0.05); Huxin Kandy extract 180g crude drug/kg dose group of RAT whole blood viscosity in the ocular 5S^-1 and 30S^-1 apparent lowered under (P <0.05), the ocular 100S^-1, 200S^-1 the trend is reduced, Huxin Kandy extract 90g crude drug/kg dose group of RAT whole blood viscosity a downward trend. Aspirine group of RAT whole blood viscosity in the ocular 5S^-1 are significantly reduced (P <0.01), the ocular 30S^-11 apparent lowered under (P <0.05), the ocular 100S^-1, 200S^-1 the trend is reduced. All the group of the RAT plasma viscosity compare no obvious difference.

Table 8. The composition of the invention (protects heart Kang) the effects of the RAT's blood viscosity (n=10,   )

Note: with the model group^* P <0.05,^** P <0.01 (the same below)

The experimental results show, RAT continuous intragastrically administered 7 days, Huxin Kandy extract obviously shorten the length of the thrombus (P <0.05), significantly reducing the thromboxin humid weight and dry weight (P <0.05); obviously reduce ocular 5S^-1, 30S^-1 and 100S^-1 of whole blood viscosity under (P <0.05). Huxin Kandy extract has obvious that inhibiting the formation of thrombus, the role of the blood viscosity is reduced.

The (four) protects heart Kang the impact of rabbit platelet aggregation

The compositions of the invention inhibit the role of platelet aggregation, is composed of the following pharmocodynamics tests prove that: the large ears rabbit male Japan 60 only, in the harsh before taking blood through the artery measuring platelet aggregation, according to the platelet aggregation level and weight, random divided into 6 groups of, grouping and to the medicine kilowattmeter 1. 1 times/day, continuous intragastrically 7d, after the last administration 1h, in harsh taking blood through the artery, measuring platelet aggregation. Test results are presented below:

Table 9. The protects heart Kang Pian the impact of rabbit platelet aggregation( N=10, %)

Note: with the blank group^* P <0.05,^** P <0.01.

Table 9 shows, when the inducer to induce aggregation, all groups before administering platelet aggregation rate no obvious difference; after administration of high dosage group protects heart Kang Pian platelet aggregation rate compare has declined (P <0.01), a small dose of the platelet aggregation rate of the group a have no obvious difference from the control group, compared with the blank group positive group, a downward trend in platelet aggregation (P <0.05). The result shows that, Huxin Kandy extract has prominent role to inhibit platelet aggregation.

Embodiment 14 of the compositions of the present invention discuss the mechanism of action

(A) anti-cadiomyocyte hypoxia/reoxygenation injury study of the mechanism

In order to study the composition of the invention for myocardial cell protection function, the test to myocardial cell replication hypoxia/reoxygenation injury model, the SOD activity of the cardiac muscle cells, MDA content and apoptosic cadiomyocyte associated factor Bcl-2, Bax expressed as inspection targets, the cultured cardiac cells random is divided into 6 groups of (in particular see table below), radical injury to myocardial protects heart Kang Kangcell oxygen the study of the role of apoptosis, the results are as follows:

1, the compositions of the invention against hypoxia/reoxygenation injury of myocardial cells the effects of SOD activity in table 10.

Table 10. Hypoxia/reoxygenation injury to myocardial cells the effects of SOD activity( N=8)

Note: with the blank group : *P <0.01; comparison with hypoxia/re- reaerationon group : **P <0.01; and comparison gathers Bei Shuangzu :^delta P <0.01,^△△ P> 0.05.

Hypoxia/re- reaerationon group SOD activity in blank control group (P <0.01); the SOD activity in the treatment of the anoxic/and then rising notably reaerationon group (P <0.01). gathers Bei Shuangzu and the composition of the present invention group, are clear differences in the low dose group (P <0.01), and with the middle, high dose group of difference does not very significantly (P> 0.05).

2, the compositions of the invention against hypoxia/reoxygenation injury of myocardial cell content of MDA in table 11.

Table 11. Hypoxia/reoxygenation injury to myocardial cells content of MDA( N=8)

Note: with the blank group : *P <0.01; comparison with hypoxia/re- reaerationon group : **P <0.01; and comparison gathers Bei Shuangzu :^delta P <0.05,^△△ P> 0.05.

Hypoxia/re- reaerationon group MDA content is blank control group obviously rise (P <0.01); the content of all the treatment with MDA is compared to hypoxia/re- reaerationon group are obviously drop (P <0.01). gathers Bei Shuangzu and the composition of the present invention group, are clear differences in the low dose group (P <0.05), and with the middle, high dose group of difference does not very significantly (P> 0.05).

3, the compositions of the invention against hypoxia/reoxygenation injury of myocardial apoptosis gene Bcl-2, Bax the influence of protein expression in table 12.

Table 12. Hypoxia/reoxygenation injury to myocardial apoptosis gene Bcl-2, Bax the influence of protein expression( N=8)

Note: with the blank group : *P <0.01; comparison with hypoxia/re- reaerationon group : **P <0.01; and comparison gathers Bei Shuangzu :^delta P <0.01,^△△ P> 0.05.

The result shows that, hypoxia/re- reaerationon group compared with the blank control group, bcl-2 decrease in expression of (P <0.01), expression of bax (P <0.01). gathers Bei Shuangzu and the composition of the invention is high, middle, low-dose group compared with hypoxia/re- reaerationon group bcl-2 can obviously raise the expression (P <0.01), reduced expression of bax (P <0.01). gathers Bei Shuangzu and the composition of the present invention group, are clear differences in the low dose group (P <0.01), and with the middle, high dose group of difference does not very significantly (P> 0.05).

(B) on myocardial ischemia RAT inflammatory factor the impact of the

In order to study the composition of the invention on myocardial ischemia RAT inflammatory factor impact, the coronary artery ligation copy myocardial ischemic injury model, random packet, to respectively, after the land 12, 24h kill animals, using ELISA, respectively, immunohistochemistical and method for detecting PCR TNF-α, IL-1, VCAM -1, iNOS, NFkB and IkB with the content of the expression. Results are presented below:

1, the composition of the invention on myocardial ischemia RAT TNF-α, VCAM-1 the impact of the expression

Table 13 composition of this invention (protects heart Kang) on myocardial ischemia RAT TNF-α the impact of the expression (n=5,   A/mm²)

Note: with the model group, **P <0.01; with diltiazem   Group, ΔΔP <0.01.

Table 14 composition of this invention (protects heart Kang) on myocardial ischemia RAT VCAM the impact of the expression (n=5,   A/mm²)

Note: with the model group, **P <0.05; and cardizem group, ΔP <0.05.

From table 13, 14 can be known, and TNF-α VCAM-1 in the normal heart has a certain amount of expression, myocardial ischemia damage significantly enhance the expression of the two, cardizem and protects heart Kang are to lower its expression, compared with the model group, a significant gender differences P <0.05 or P <0.01; Huxin kang Pianzu and cardizem TNF-α comparison differences have significance, P <0.05, but in VCAM-1 sex no significant difference P> 0.05.

2, the composition of the invention on myocardial ischemia RAT IL-1β horizontal, iNos content of

IL-1 in the normal RAT serum expression of a certain level, after myocardial ischemia IL-1 rapid increase in the content, IL-1 protects heart Kang and cardizem the given content is decreased, compared with the model group differences have significance (P <0.05), the differences between two groups were significant (P <0.05). See table 15.

Table 15 composition of this invention (protects heart Kang) to cardiac lacks the blood blood IL-1β content of (n=5,   A/mm²)

Note: with the model group, **P <0.01; and cardizem group, ΔP <0.05.

From table 15 can be known, normal RAT blood content is iNos (5.31±1 . 13) μ / ml, increase rapidly after myocardial ischemia, 24h after 12h is obviously reduced, xiaozhuo and the composition of the invention can lower the level of iNos, two groups have significance difference with the model group, and the differences between the two groups is also significance, P <0.05. See table 16.

Table 16 composition of this invention (protects heart Kang) on myocardial ischemia RAT iNos content of blood (n=5,   A/mm²)

Note: with the model group, *P <0.05; and cardizem group, ΔP <0.05.

From table 16 can know, IL-1, iNOS in the normal RAT serum with a certain level of expression, myocardial ischemia rapid increase in the content of the latter two are, to give Huxin Kandy extracts and cardizem downward IL-1, iNos, two groups have significance difference with the model group, and the differences between the two groups is also significance, P <0.05.

3, the composition of the invention on NFkBP₆₅, IKB the impact of the expression

Normal circumstances NFkBP₆₅ has a relatively low level of expression, myocardial ischemia damage after NFkBP₆₅ increase, cardizem, the compositions of the invention are to lower NFkBP₆₅ expression, but cardizem than the composition of the invention, P <0.05. See table 17.

Table 17 composition of this invention (protects heart Kang) NFkBP65 to myocardial ischemic tissue, the impact of the expression (n=5,   A/mm²)

Note: with the model group, *P <0.05   **P <0.01; and cardizem comparison, ΔP <0.05.

Myocardial ischemic injury can inhibit expression IKB, the composition of the present invention to upregulate its expression, and with the model control group differences have significance, P <0.05. See table 18.

Table 18 composition of this invention (protects heart Kang) the impact of the expression IKB (n=5, A/mm²)

Notes: compared with the model group, *P <0.05   **P <0.01; and cardizem relatively ΔP <0.05.

Normal circumstances NFkBP65, IKB has a relatively low level of expression, myocardial ischemia damage after NFkBP65 IKB increased expression is suppressed, cardizem and Huxin Kandy extract are to lower NFkBP65 expression, upregulate IKB, with the model group, there is significant difference, P <0.05, and cardizem not if Huxin Kandy extract, P <0.05.

The test result shows, the composition of the present invention can significantly improve myocardial ischemia RAT inflammatory factor, downregulation vascular adhesion factor -1 and NO kinase, regulating nuclear transcription factor the expression of KB and IkB, affect the inflammatory signal path is one of the mechanism of action may be the same.

Therefore, the composition of this invention is for passage of the target function of achieving the function of resisting myocardial ischemia.

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