CN1846734A - Prince's-feather prepn and its prepn process and application - Google Patents
Prince's-feather prepn and its prepn process and application Download PDFInfo
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Abstract
The present invention provides one kind of Prince's fenther preparation and its preparation and application. The Prince's fenther preparation is prepared with Prince's fenther as main material and proper amount of supplementary material. Compared with available technology, the present invention has obvious curative effect on coronary heart disease, angina, myocardial infaction, cerebral apoplexy and other cardiac and cerebral vascular diseases, fast acting, long acting period and other features. The present invention solves the problem of extracting and separating effective components in Prince's fenther to result in high effective component content in the extract.
Description
Technical field: the present invention relates to a kind of Herba Polygoni Orientalis (the dry spica of polygonaceae plant smartweed Polygonum orientale L.) preparation and preparation method and application thereof, belong to technical field of Chinese medicine.
Background technology: one of cardiovascular and cerebrovascular disease, especially angina pectoris, apoplexy (cerebral embolism) is a sickness rate height in the human diseases history, mortality rate is high disease are called as " first killer ".Along with The development in society and economy, worldwide the sickness rate of cardiovascular and cerebrovascular disease is just in rising trend, becomes commonly encountered diseases, the frequently-occurring disease of harm humans health, is seriously threatening human life and health; The traditional Chinese medical herbal treatment cardiovascular and cerebrovascular disease has curative effect preferably, especially comparatively remarkable advantages is arranged aspect patient's symptom improving, and toxic and side effects is less, so the Chinese traditional treatment cardiovascular and cerebrovascular disease has become the conventional therapy medication of generally adopting clinically, as fleabane injection, the coronary heart disease injection, FUFANG DANSHEN DIWAN, SUXIAO JIUXIN WAN etc., but has effect rapidly, safe and effective, quality controllable Chinese medicine still belongs to phoenix feathers and unicorn horns, and in dosage form, still have many parts not fully up to expectations on safety and the curative effect, especially injection, because fabricating technology falls behind, usually because of tannin in the preparation, the existence of materials such as macromolecular compound, make clinical practice produce extremely strong zest, even cause allergy, cause anaphylactic shock, make clinical practice limited, far can not satisfy clinical demand, develop effective Chinese medicine preparation and paid close attention to by medical educational circles always.Experimental study is the result show, contain a large amount of tannins in the Herba Polygoni Orientalis, flavonoid and phenolic acid that its main effective ingredient is a phenolic hydroxy group, the chemical compound of these band phenolic hydroxyl groups is similar to the chemical constitution of tannin, all contain a large amount of phenolic hydroxyl groups, physicochemical property is approaching, removes tannin with conventional method, keep difficulty of effective ingredient, the present invention adopts polyamide column can effectively separate tannin.
Flos Polygoni Orientalis is arranged as medicinal record (Compendium of Material Medica, editor, publishing house, publication date, the page number 1095) in the Compendium of Materia Medica, cure mainly: removing food stagnancy, the blood that looses, pain relieving.Be used for the treatment of the gastral cavilty vim and vigour and have a pain, Xin Qi Xu pain, mass in abdomen.Oral with Flos Polygoni Orientalis decoction or wine, be accustomed to from ancient times to now and call title by the theory of Chinese medical science and the traditional Chinese medical science, be mainly used in the treatment of gastroenteropathy." medical science main story gastric abscess " said: " the ancient prescription nine types of precordial pain ... its reason of sample does not all lie in the heart in fact at gastral cavilty yet." Wang Kentang " the 4th of Standards of Diagnosis and Treatment miscellaneous diseases " also thinks that successive dynasties side opinion confuses pained, stomachache with one, reason be " gastric abscess is under the heart, thus have take care and pain ".Zhu Danxi " danxi's experiential therapy volume four " spells out, and forefathers' what is called " pained " refers to gastric abscess in fact." Chinese medicine voluminous dictionary " (the new medical college in Jiangsu is compiled. Chinese medicine voluminous dictionary [M]. the 1977:1617 of Shanghai science tech publishing house), (editorial board of State Administration of Traditional Chinese Medicine's " China's book on Chinese herbal medicine " compiles " China's book on Chinese herbal medicine " Shanghai:, " China's book on Chinese herbal medicine " (second) [M], Shanghai: 1999:683) all there is identical record in Shanghai science tech publishing house." Chinese pharmacopoeia version in 2000 is recorded Fructus Polygoni Orientalis (dry mature fruit of polygonaceae plant smartweed Polygonum orientale L.), is used for the treatment of gastroenteropathy." Guizhou Province's Chinese crude drug quality standard " (1988 version, Guizhou Province D/WS-087-88) and " Guizhou Province's Chinese crude drug, national quality of medicinal material standard " (2003 version, DB52/YC261-2003) are recorded the record that Herba Polygoni Orientalis is used for rheumatic arthritis, coronary heart disease, heart peratodynia, but its site of action is dry herb or dry spica and the stem and branch with leaf of Herba Polygoni Orientalis, and Herba Polygoni Orientalis is the dry spica of Herba Polygoni Orientalis among the present invention, press the administrated method of Chinese medicine, medicinal part is obviously different, is two kinds of different agents areas fully.About the modern study of Herba Polygoni Orientalis and Herba Polygoni Orientalis, the report of accidental Herba Polygoni Orientalis chemical constituent and pharmacological action, the clinical practice of Herba Polygoni Orientalis, pharmacological research and chemical constitution study there is no report.Although Flos Polygoni Orientalis is arranged as medicinal record in the Compendium of Material Medica, its usage tradition with crude drug direct oral being used as medicine, exists patient to carry, take inconvenience, and quality is wayward, can not form shortcomings such as circulation of commodities.
" Chinese medicine preparation (02128066.5) of treatment angina pectoris " patent that the inventor has applied for is the compound preparation of Herba Erigerontis and Herba Polygoni Orientalis, the medicinal part of Herba Polygoni Orientalis is dry spica and stem and branch with leaf in the side, both are except that the prescription difference, the agents area of Herba Polygoni Orientalis is also different, and by the curative effect of two prescriptions is carried out pharmacodynamics test relatively, result of the test shows, characteristics such as that the Herba Polygoni Orientalis preparation has is rapid-action, long action time, action intensity are big.In order further to compare the pharmacologically active of the different medicinal parts of Herba Polygoni Orientalis medical material; the inventor has carried out pharmacodynamics test to the pharmacological action of herb, root and the stem of Herba Polygoni Orientalis medical material, stem and branch with leaf, spica; it is the most obvious that result of the test shows that spica improves the effect of myocardial ischemia and coronary artery dilator, and acute myocardial infarction is had significant protective effect.
Summary of the invention: the objective of the invention is to: a kind of Herba Polygoni Orientalis preparation and preparation method and application thereof are provided, the present invention is directed to the deficiencies in the prior art, the Technology that is provided has solved the extraction of effective ingredient and the separation problem of tannin in the Herba Polygoni Orientalis, the extract chemical constituent is clear substantially, active constituent content height, gained preparation have reached safe, effective, quality controllable purpose; Preparation of the present invention can obviously increase cardiac muscle and cerebral ischemia, anoxia, increase coronary flow and cerebral blood flow, reduce myocardial oxygen consumption, improve brain energy metabolism, tangible thrombolytic and function of promoting blood circulation to disperse blood clots are arranged, be used for the treatment of cardiovascular and cerebrovascular diseases such as coronary heart disease, angina pectoris, myocardial infarction, apoplexy.
The present invention constitutes like this: it is that dry spica-Herba Polygoni Orientalis with the Herba Polygoni Orientalis medical material is a raw material, adds suitable adjuvant and is prepared into acceptable dosage form on injection or infusion solutions, freeze-dried powder, injectable powder, drop pill, capsule, tablet, dispersible tablet, soft capsule, granule and other pharmaceutics.
Described preparation is injection or infusion solutions, freeze-dried powder, injectable powder, drop pill.
The preparation method of Herba Polygoni Orientalis preparation is: with Herba Polygoni Orientalis routinely decocting boil technology and extract, filter, filtrate decompression is condensed into extractum, transfer PH to 2～5,, reclaim solvent with n-butyl alcohol or ethyl acetate extraction, residue carries out drying, gets the Herba Polygoni Orientalis extract, extract is prepared into described preparation again.
Specifically, Herba Polygoni Orientalis is decocted with water 2～4 times each 0.5～2 hour, amount of water is 6～20 times of raw material weight, filter, it is 1.05～1.25 extractum that filtrate decompression is concentrated into 30～80 ℃ of relative densities, with the ethanol precipitation processing of 2～4 times of amounts, decompression recycling ethanol, transfer PH to 2～5,, reclaim solvent with n-butyl alcohol or ethyl acetate extraction, residue is with 25～50% dissolve with ethanols, last D
101Macroporous resin column is separated, and with 40～95% ethanol elutions, eluent reclaims ethanol, and residue vacuum drying or spray drying get the Herba Polygoni Orientalis extract, extract are prepared into described preparation again.
In other words, Herba Polygoni Orientalis is decocted with water 2～4 times each 0.5～2 hour, amount of water is 6～20 times of raw material weight, filter, it is 1.05～1. 25 extractum that filtrate decompression is concentrated into 30～80 ℃ of relative densities, with the ethanol precipitation processing of 2～4 times of amounts, decompression recycling ethanol, transfer PH to 2～5,, reclaim solvent with n-butyl alcohol or ethyl acetate extraction, residue is with 25～50% dissolve with ethanols, last D
101Macroporous resin column, with 40～95% ethanol elutions, eluent reclaims ethanol, polyamide column on the residue, with 40～95% ethanol elutions, eluent and stream are worn liquid and are reclaimed ethanol, vacuum drying or spray drying get the Herba Polygoni Orientalis extract, extract are prepared into described preparation again.
In other words, Herba Polygoni Orientalis is decocted with water 2～4 times, each 0.5～2 hour, amount of water is 6～20 times of raw material weight, filters, and it is 1.05～1.25 extractum that filtrate decompression is concentrated into 30～80 ℃ of relative densities, ethanol precipitation with 2～4 times of amounts is handled, decompression recycling ethanol is transferred PH to 2～5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue is with 25～50% dissolve with ethanols, and last polyamide column is with 40～95% ethanol elutions, eluent and stream are worn liquid and are reclaimed ethanol, vacuum drying or spray drying get the Herba Polygoni Orientalis extract, extract are prepared into described preparation again.
The Herba Polygoni Orientalis preparation also can prepare like this: Herba Polygoni Orientalis is adopted the method extraction of normal reflux, dipping with 30～95% ethanol, decompression recycling ethanol, transfer PH to 2～5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue carries out drying, gets the Herba Polygoni Orientalis extract, extract is prepared into described preparation again.Specifically, with Herba Polygoni Orientalis with 30～95% alcohol reflux 2～4 times, each 0.5～2 hour, alcohol adding amount is 6～20 times of raw material weight, filter merging filtrate, decompression recycling ethanol, transfer PH to 2～5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue is with 25～50% dissolve with ethanols, macroporous resin or polyamide column separate, with 40～95% ethanol elutions, eluent reclaims ethanol, and residue adopts vacuum drying or spray drying, get the Herba Polygoni Orientalis extract, again extract is prepared into described preparation.
Injection or infusion solutions in the described preparation prepare like this: the water intaking Flos Carthami extract, add water for injection and 0.9% sodium chloride, and stir evenly, cold preservation filters, and filtrate adds 0.1% active carbon, boiled 30 minutes, put coldly, be filtered to clear and brightly, transfer pH to 6～9 with 10%NaOH, filtering with microporous membrane through 0.25～0.45 μ m, fill was sterilized 30 minutes for 100～115 ℃, promptly.
Lyophilized injectable powder in the described preparation prepares like this: water intaking Flos Carthami extract and mannitol, add water for injection, stir evenly, cold preservation, filter, filtrate adds 0.1% active carbon, boiled 30 minutes, and put coldly, be filtered to clear and bright, transfer pH to 6～9 with 10%NaOH, through the filtering with microporous membrane of 0.25～0.45 μ m, fill, lyophilization, lyophilisation condition is: vacuum 13.332Pa, 0 ℃ of balance solidification point, equilibration time 1.5 hours, the drying time of heating up are 35 ℃ of 8～15 hours, baking temperature under lowest total of the melting point-16 ℃ ,-45 ℃ of conditions, promptly.
Injectable powder in the described preparation prepares like this: water intaking Flos Carthami extract and mannitol, add water for injection, and stir evenly, cold preservation filters, and filtrate adds 0.1% active carbon, boiled 30 minutes, put coldly, be filtered to clear and brightly, transfer pH to 7.5～8.0 with 10%NaOH, filtering with microporous membrane through 0.25～0.45 μ m, the filtrate spray drying, packing, promptly.
Drop pill in the described preparation prepares like this: the Herba Polygoni Orientalis extract is added in the fused 40g Polyethylene Glycol, and mixing drips in vegetable oil under heat-retaining condition and makes drop pill, promptly.
The application of the Herba Polygoni Orientalis preparation that is obtained on preparation treatment cardiovascular and cerebrovascular diseases medicament.
Among the present invention, the Herba Polygoni Orientalis extract is meant all flavonoids of separation acquisition from Herba Polygoni Orientalis and the compositions of phenolic acid compound, and wherein the effective ingredient content of total flavone accounts for 15～80%, and the content of phenolic acid accounts for 1～15%.
Compared with prior art, preparation provided by the present invention is evident in efficacy aspect cardiovascular and cerebrovascular diseases such as treatment coronary heart disease, angina pectoris, myocardial infarction, apoplexy; Have characteristics such as rapid-action, long action time, action intensity are big, overcome the problem that prior art exists; The preparation technology who is provided has solved the extraction of effective ingredient and the separation problem of tannin in the Herba Polygoni Orientalis, and extract active constituent content height, gained preparation have reached safe, effective, stable and controllable for quality purpose.
In order to verify the medicinal effects of preparation of the present invention, the applicant has carried out series of experiment research:
One, pharmacodynamics test
1. to the influence of acute myocardial infarction due to the anesthetized dog coronary ligation:
Be subjected to the reagent thing: Herba Polygoni Orientalis injection (SH), inventor's development; FUFANG HONGCAO DONGGANFENZHEN (WHG), Guizhou Yibai Pharmaceutical Co., Ltd produces, lot number 20040615; FUFANG DANSHEN ZHUSHEYE (FD), Shanghai first Shanghai first pharmaceutical factory of biochemical Pharma Inc., lot number 010511.
Test method: get 35 of hybrid dogs, body weight is 7-10Kg, and the male and female dual-purpose is divided into 7 groups at random, i.e. (1) sham operated rats; (2) model group: all give the isometric(al) normal saline; (3) positive drug FD group: 2.0ml/kg; (4) SH low dose group: 1g crude drug/kg; (5) dosage group among the SH: 2g crude drug/kg; (6) SH high dose group: 4g crude drug/kg; (7) WHG group: 4.8g crude drug/kg.Every group of 5 animals, the administration volume is 2ml/kg.
Get test and use dog, (after the anesthesia of 30mg crude drug/kg), carry on the back and be fixed on the operating-table, cut off the hair of cervical region, chest and left hind inboard with 3% pentobarbital sodium by the subcutaneous cephalic vein of forelimb.It is subcutaneous that needle electrode is inserted the dog extremity, recording ecg (ECG).Separate trachea and insert tracheal intubation.Separate left side femoral artery, femoral vein, separate femoral vein and insert venous cannulation, slowly constant speed input normal saline (about 1ml/min); Separating femoral artery inserts arterial cannulation (being full of the heparin-saline of 500u/ml in the pipe) and connects pressure transducer (TP-400T), and through amplifying (AP-641G) measurement systolic arterial pressure (SAP), auterial diastole pressure (DAP), mean arterial pressure (MAP), calibration sensitivity is 13.33kPa (100mmHg)/cm.The line connection board that connects monitor directly triggers heart rate numeration instrument (AT-601G) recorded heart rate (HR) by arterial pressure.Fourth, fifth intercostal is opened breast in the left side, exposes heart, and connects artificial respirator.Open pericardium, be sewn in thoracic wall, make the pocket cradle.Expose the right auricle, quiet notes heparin 5-10mg crude drug/kg makes heparinization, clamp the right auricle with auricle clamp, make a pocket sealing, suture is through in a bit of rubber tube, line is colluded into rubber tube with little steel wire, cut an osculum in pocket mouth center, (internal diameter 4-5mm, the mouth of pipe are the oblique angle, and nearly mouth of pipe place is that circle is expanded to insert coronary sinus cannula rapidly, the oblique angle face avoids the mouth of pipe and Dou Bi to be close to, the portion of expanding is for making coronary sinus blood unlikely excessive), with pocket suture tension in the small rubber hose, withstand intubate by small rubber hose, to avoid hemorrhage, rapidly intubate is accurately inserted coronary sinus, place, ligation right auricle pocket suture, fixedly intubate.The far-end of this intubate connects a tee T to be on the waiting list blood.With descending 1/3 place, a sham operated rats not ligation of threading in No. 0 silk thread ligation ramus descendens anterior arteriae coronariae sinistrae.12 the mapping point seams in position are put the epicardial electrogram electrode near selecting infarct, and selecting a control point away from infarct, carry out mapping with hand-held insulated metal point-like electrode by the mapping dot sequency, through pick off (JB-642G), amplifier (AB-621G), with eight road physiology monitor record epicardial electrogram (EECG) (calibrations: 1mm=1mv).Ligation 15min is after systolic arterial pressure (SAP), diastolic pressure (DAP), mean arterial pressure (MAP), heart rate (HR) are directly write down in femoral vein constant flow pump constant speed administration (1ml/min), and traces EECG and arterial pressure (BP) curve in eight road physiology monitors.Before the record ligation, after ligation 15min and the administration 10,15,30,45,60,90, EECG, the SAP of 120min, DAP, MAP, HR.Add up ST field offset ∑-ST of each mapping point EECG, and the ST section is raised 〉=the above N-ST of 2mv.Each group is respectively at before the administration and behind the administration 60min, and left ventricle is got blood and surveyed arterial partial pressure of oxygen, and coronary sinus is got blood and surveyed coronary sinus blood oxygen pressure, poor (the Δ Po of both partial pressure of oxygens
2=tremulous pulse Po
2-vein Po
2) the reflecting myocardium oxygen consumption; Each group is respectively at before the ligation, femoral vein is got blood behind ligation 15min, the administration 60min, with kit measurement serum CK, LDH value.After experiment finishes, take out heart immediately, behind normal saline flush away blood, take by weighing heavy whole-heartedly and ventricular weight, and the ventricle crosscut become 5, and place 37 ℃ of 1%TTC solution 15min that dyes, cut off the non-infarct that each myocardium sheet is colored, undyed infarct cardiac muscle is weighed, obtain infarction size heavily respectively divided by heavy or ventricle whole-heartedly and account for heavy whole-heartedly or account for the heavy percentage rate of ventricle.The results are shown in Table 1, table 2.
Table 1 SH is to influence (X ± S) (n=5) of myocardial infarction ∑-ST (mv) due to the anesthetized dog coronary ligation
| Group | Dosage (the g crude drug/kg) | Before the ligation | After the ligation | After the administration | ||||||
| 15min | 10min | 15min | 30min | 45min | 60min | 90min | 120min | |||
| Pseudo-operation group | 1.55± 1.00 | 2.50± 1.14 | 2.65± 1.28 | 3.45± 0.63 | 3.15± 1.06 | 3.55± 1.21 | 3.55± 1.51 | 3.45± 1.21 | 3.45± 1.91 | |
| Model group | 2.85± 1.14 | 11.35± 2.29 ## | 12.35± 2.50 ## | 13.6± 3.71 ## | 14.8± 2.42 ## | 13.65± 3.46 ## | 14.10± 3.26 ## | 13.75± 4.12 ## | 14.65± 5.32 ## | |
| The FD group | 2.0ml/k g | 1.80± 1.27 | 10.10± 4.16 ## | 9.10± 4.04 | 7.00± 2.34 ** | 8.65± 3.55 * | 8.10± 2.06 * | 8.65± 3.11 * | 10.10± 2.69 | 9.55± 3.42 |
| Low dose group | 1.0 | 1.30± 0.93 | 12.45± 4.60 ## | 12.85± 5.50 | 8.17± 2.90 * | 9.20± 3.61 * | 15.05± 3.64 | 13.20± 4.66 | 14.25± 4.81 | 14.25± 6.37 |
| Middle dosage group | 2.0 | 2.45± 1.05 | 12.60± 3.62 ## | 9.02± 2.01 * | 8.21± 2.12 ** | 9.50± 2.87 * | 7.39± 3.02 * | 8.65± 2.64 * | 14.35± 2.69 | 14.75± 4.52 |
| High dose group | 4.0 | 2.85± 1.26 | 12.10± 3.13 ## | 8.25± 2.86 * | 6.60± 2.45 ** | 6.10± 3.22 ** | 5.75± 1.90 ** | 7.13± 4.02 * | 7.67± 3.66 * | 9.60± 3.03 |
| The WHG group | 4.8 | 2.11± 1.09 | 11.56± 3.7 8## | 10.63± 4.67 | 6.87± 2.02 ** | 8.66± 3.68 * | 8.23± 3.26 * | 9.20± 3.88 | 9.75± 3.13 | 11.21± 2.54 |
Annotate: compare with puppet operation group
##P＜0.01; Compare with model group
*P＜0.05,
*P＜0.01.
The result shows, the SH injection can reduce myocardial infarction ∑ Rising-moon T due to the anesthetized dog coronary ligation, and part-time point and model group comparing difference be (P＜0.05, P＜0.01) significantly, show that this preparation can obviously alleviate degree of myocardial ischemia, and be good dose dependent with the dosage increase.Characteristics such as that middle and high dosage group SH injection and existing preparation FUFANG DANSHEN ZHUSHEYE, FUFANG HONGCAO DONGGANFENZHEN relatively have is rapid-action, long action time, action intensity are big.
Table 2 SH is to influence (X ± S) (n=5) of myocardial infarction infarction size due to the anesthetized dog coronary ligation
| Group | Dosage (the g crude drug/kg) | Heavy (g) whole-heartedly | Ventricle heavy (g) | Infarcted myocardium heavy (g) | Infarct/(%) whole-heartedly | Infarct/ventricle (%) |
| Sham operated rats | - | 60.08 ±6.50 | 48.02 ±5.72 | 0.00 ±0.00 | 0.00 ±0.00 | 0.00 ±0.00 |
| Model group | - | 60.05 ±8.03 | 48.22 ±6.35 | 6.85 ±2.04 | 10.47 ±1.61 ## | 13.33 ±2.16 ## |
| The FD group | 2.0ml/kg | 61.33 ±6.43 | 49.24 ±5.03 | 3.03 ±1.03 | 4.38 ±1.24 ** | 6.13 ±1.56 ** |
| Low dosage | 1.0 | 60.31 ±6.01 | 49.21 ±7.71 | 7.09 ±2.13 | 7.23 ±1.35 * | 9.52 ±2.03 * |
| Middle dosage | 2.0 | 61.31 ±6.36 | 48.84 ±4.53 | 5.05 ±1.07 | 6.61 ±1.02 ** | 7.01 ±1.24 ** |
| High dose | 4.0 | 61.24 ±5.51 | 49.47 ±3.80 | 3.19 ±1.01 | 5.08 ±1.76 ** | 6.36 ±2.14 ** |
| WHG | 4.8 | 61.07 ±6.59 | 48.36 ±5.61 | 4.25 ±1.23 | 5.77 ±1.02 ** | 6.85 ±1.43 ** |
Annotate: compare with sham operated rats
##P＜0.01; Compare with model group
*P＜0.05,
*P＜0.01.
Result of the test shows: the SH injection can reduce myocardial infarct size due to the anesthetized dog coronary ligation, with remarkable (P＜0.05 of model group comparing difference, P＜0.01), show that this preparation improves significantly to the myocardial ischemia tool of anesthetized dog anterior descending coronary caused by ligature, can obviously alleviate degree of myocardial ischemia, and be good dose dependent with the dosage increase.
2.SH the influence of injection chmice acute cerebral anoxia
Get 100 of Kunming mouses, body weight 18～22g is divided into 10 groups at random, and 10 every group, difference vein SH:1.0g crude drug/kg, 2.0g crude drug/kg, 4.0g crude drug/kg, FD:2.0ml/kg, WHG:4.8 crude drug/kg; Irritate stomach and give SH:4.0g crude drug/kg, 8.0g crude drug/kg, FD:4.0ml/kg, WHG9.6 crude drug/kg, matched group give the normal saline of the capacity of grade.Behind the successive administration 3d, by broken end only, time that stops by breathing to dehiscing behind the stopwatch record mice broken end and mouth breathing number of times are as the anoxia enduring index immediately with mice for 30min after the last administration.The results are shown in Table 3.
The influence of table 3 pair chmice acute cerebral anoxia (x ± s, n=10)
| Group | Dosage (the g crude drug/kg) | The number of times of dehiscing | (s) pants continuous time |
| Matched group | - | 7.2±2.15 | 11.6±1.66 |
| SH(i.v) | 1.0 | 9.0±1.90 | 13.9±1.98* |
| 2.0 | 9.1±2.22 | 16.4±1.18** | |
| 4.0 | 9.4±3.11 | 17.1±1.21** | |
| FD(i.v) | 2.0ml/kg | 8.5±1.17 | 13.8±2.25* |
| WHG(i.v) | 4.8 | 8.2±1.38 | 13.6±1.09* |
| SH(p.o) | 4.0 | 8.6±2.30 | 14.1±2.33* |
| 8.0 | 9.1±2.30 | 15.8±1.42** | |
| FD(p.o) | 4.0ml/kg | 8.3±1.06 | 14.1±1.81* |
| WHG(p.o) | 9.6 | 7.6±2.22 | 13.5±1.69* |
Compare with the normal saline group,
*P＜0.05,
*P＜0.01.
The result shows, all can obviously prolong mice broken end dehisce number of times and pant the time (P＜0.05, P＜0.01) behind SH injection drug administration by injection and the gastric infusion.Illustrate that this preparation can pass through blood brain barrier, improve the ability of the anti-acute anoxia of mouse brain, improve brain energy metabolism.Intravenous administration has the advantages that dosage is little, action intensity is big; Middle and high dosage group SH injection intravenous administration and existing preparation FUFANG DANSHEN ZHUSHEYE, FUFANG HONGCAO DONGGANFENZHEN relatively have stronger physiologically active (P＜0.01).
3. the therapeutical effect of intraluminal middle cerebral artery occlusion in rats bolt collimation method focal brain ischemia-reperfusion injury model is got about 280 of male SD rat, be divided into 11 groups by the random packet principle, comprise five drug administration by injection groups, SH:1.0g crude drug/kg, 2.0g crude drug/kg, 4.0g crude drug/kg, FD:2.0 crude drug/kg, WHG:4.8 crude drug/kg; Irritate stomach group, SH:4.0g crude drug/kg, 8.0g crude drug/kg, FD:4.0 crude drug/kg, WHG:4.8 crude drug/kg for four; Sham operated rats, model group.Every treated animal 20-30, the administration volume is 0.4ml/100g/.Administration in continuous in advance two days, once a day; 0.5h carries out administration for the third time before the modeling; 4h, 12h carry out fourth, fifth administration respectively after the modeling, promptly are administered five times altogether.The then equal approach of model group and sham operated rats rat gives the isometric(al) normal saline.
Modeling method is anaesthetized rat with 10% chloral hydrate 3.5ml/kg lumbar injection (ip), the neck median incision, and separation, ligation left carotid, external carotid artery and bifurcated artery thereof separate the left side internal carotid artery.Be equipped with line, far-end placement bulldog clamp at the internal carotid artery near-end, common carotid artery crotch otch inserts the 4-0 nylon wire, and its degree of depth is about 17～20mm, and the bolt line enters internal carotid artery, goes into cranium to anterior cerebral artery, all blood flows sources of blocking-up middle cerebral artery.Remove bulldog clamp, tighten fully line, cut off unnecessary the end of a thread, wound is with iodophor disinfection, last skin suture, and operation finishes to steam again and raises.Sham operated rats is except that plug wire not, and all the other steps are the same.All the other seven groups of rats are by above-mentioned operation method modeling.
The standard of modeling success: obvious operation side (i.e. left side) Horner disease (left side blepharoptosis, enophthalmos,enophthalmus) and operation side (promptly) hemiplegia Signs (can not the full extension left fore, topple over to the left during walking or turn-take) be arranged after animal surgery is clear-headed.Be defined as last experimental subject according to can the survive rat of 24h of above-mentioned standard, and carry out behavioristics's scoring and fast broken end get brain and measure every index.
The neuroethology result of the test promptly has hemiplegia sample symptom to occur after regaining consciousness through the rat anesthesia of cerebral infarction, mainly show as in the operation offside forelimb in various degree and receive, the shoulder inward turning, muscular tension reduces, push away right shoulder to side shifting, resistance descends, even some animal also occurs ceaselessly to the side phenomenon of turn-taking.The rat of survival in 24 hours is carried out the neuroethology scoring, and each administration group of SH and compound Salviae Miltiorrhizae group rat and model group compare, and the neuroethology obstacle of rat improves (P＜0.01) significantly.The sham operated rats animal behavior is no abnormal.Intravenous administration has the advantages that dosage is little, action intensity is big; Middle and high dosage group SH injection intravenous administration and existing preparation FUFANG DANSHEN ZHUSHEYE, FUFANG HONGCAO DONGGANFENZHEN relatively have stronger physiologically active (P＜0.01).The results are shown in Table 4.
The influence of table 4 pair rat neuroethology (x ± s)
| Group | Dosage (the g crude drug/kg) | Number of animals | The neuroethology scoring |
| Sham operated rats | - | 19 | 0.28±0.29** |
| Model control group | - | 18 | 2.33±0.94 |
| SH(i.v) | 1.0 | 18 | 1.62±0.65* |
| 2.0 | 19 | 1.02±0.48** | |
| 4.0 | 18 | 1.11±0.76** | |
| FD(i.v) | 2.0ml/kg | 19 | 1.51±0.81* |
| WHG(i.v) | 4.8 | 18 | 1.57±0.88* |
| SH(p.o) | 4.0 | 20 | 1.60±0.61* |
| 8.0 | 17 | 1.52±0.59* | |
| FD(p.o) | 4.0ml/kg | 18 | 1.47±0.68* |
| WHG(p.o) | 9.6 | 18 | 1.69±0.62* |
Compare with model group: * P＜0.05; * P＜0.01
The neuroethology standards of grading
MCAO postoperative 24h rat carries out rank scores by the method for Bederson to the behavior of animal, and standard is as follows:
0 grade: do not observe nervous symptoms (0 minute);
1 grade: carry tail when unsettled, the operation offside forelimb of animal shows as wrist elbow flexing, the shoulder inward turning, and the elbow abduction is close to thoracic wall (1 minute);
2 grades: animal is placed on the smooth flat, and pushing hands art side is takeed on to side shifting the time, and resistance reduces (2 minutes);
3 grades: to operation side ring is changeed or turn-take (3 minutes) during the animal walking freely;
4 grades: collapse from physical exhaustion, limbs do not have spontaneous activity (4 minutes).
After brain water content was measured the neuroethology scoring, broken end was got the Mus brain fast.Downcut left brain rear section and be weighed as weight in wet base respectively, put 120 ℃ of baking box bakings (4h), be weighed as dry weight then, calculate brain water content.The results are shown in Table 5.
Brain water content (%)=(weight in wet base-dry weight)/weight in wet base * 100%.
The influence of table 5 pair rat brain water content (x ± s)
| Group | Dosage (the g crude drug/kg) | Number of animals | Brain water content (%) |
| Sham operated rats | - | 10 | 78.06±0.72** |
| Model control group | - | 10 | 71.79±0.84 |
| SH(i.v) | 1.0 | 10 | 70.31±1.03** |
| 2.0 | 10 | 69.81±0.36** | |
| 4.0 | 10 | 70.42±0.71** | |
| FD(i.v) | 2.0ml/kg | 10 | 69.03±0.64** |
| WHG(i.v) | 4.8 | 10 | 70.13±0.36** |
| SH(p.o) | 4.0 | 10 | 70.11±0.54** |
| 8.0 | 10 | 70.69±0.63** | |
| FD(p.o) | 4.0ml/kg | 10 | 70.14±0.76** |
| WHG(p.o) | 9.6 | 10 | 70.93±0.59* |
With model group contrast, * P＜0.05, * * P＜0.01.
Result of the test shows that the model group brain water content is significantly higher than sham operated rats, rat brain water content showed increased after the modeling; Each administration group brain water content of SH then is starkly lower than model control group (P＜0.01), illustrates that this preparation can significantly reduce brain water content.
8 every group of modeling success back survival 24h rats are got in the influence of rat cerebral infarction scope, get left brain fast, remove olfactory bulb, cerebellum and low brain stem, freezing 25 minutes.The crown then four blade of cutting is cut into five with full brain.First cutter spacing is the utmost point and optic chiasma line midpoint before brain, and second cutter spacing is in optic chiasma, and the 3rd cutter is at infundibulum, and four blade is between the infundibular stalk and the leaf tail utmost point.Then rapidly the brain sheet is put in 2% red tetrazolium (TTC), lucifuge, 37 ℃ of temperature were incubated 30 minutes, shook once every 10min therebetween, and the dyeing back is fixed with 4% paraformaldehyde.Coloration result: normal structure takes on a red color, and blocking tissue is white in color.Full brain is weighed, and the pale infarct district sheared off weigh, calculate brain infarction area (%).The results are shown in Table 6.
The influence of table 6 pair rat cerebral infarction area (x ± s)
| Group | Dosage (the g crude drug/kg) | Number of animals | Brain infarction area (%) |
| Sham operated rats | - | 10 | 0.00±0.00 |
| Model control group | - | 8 | 24.36±6.35 |
| SH(i.v) | 1.0 | 8 | 15.66±8.47* |
| 2.0 | 8 | 9.35±3.62** | |
| 4.0 | 8 | 8.32±6.55** | |
| FD(i.v) | 2.0ml/kg | 8 | 11.74±5.66* |
| WHG(i.v) | 4.8 | 8 | 14.63±7.25* |
| SH(p.o) | 4.0 | 8 | 15.73±5.62* |
| 8.0 | 8 | 10.73±6.42** | |
| FD(p.o) | 4.0ml/kg | 8 | 16.13±5.87* |
| WHG(p.o) | 9.6 | 8 | 14.91±6.52* |
With model group contrast, P＜0.05, * * P＜0.01.
Result of the test shows that cerebral tissue infraction degree is obvious behind the cerebral ischemia re-pouring 24h.Each administration group of SH all can make cerebral infarct size percentage ratio obviously descend (P＜0.05, P＜0.01).Intravenous administration has the advantages that dosage is little, action intensity is big; Middle and high dosage group SH injection intravenous administration and existing preparation FUFANG DANSHEN ZHUSHEYE, FUFANG HONGCAO DONGGANFENZHEN relatively have stronger physiologically active (P＜0.01).
4. Herba Polygoni Orientalis medical material different parts extract is to the influence of rat acute myocardial infarction
Be subjected to the reagent thing: get Herba Polygoni Orientalis herb, root and stem, stem and branch with leaf, spica, prepare injection (1g crude drug/ml) in accordance with the law; Sham operated rats (N.S), model group (N.S), FUFANG DANSHEN ZHUSHEYE (FD, Shanghai first Shanghai first pharmaceutical factory of biochemical Pharma Inc., lot number 010511).
Test method: get 70 of SD rats, be divided into 7 groups at random, 10 every group, be respectively normal saline matched group, positive controls (FD), herb, root and stem, stem and branch with leaf, spica and (be 1g crude drug/ml).Each treated animal is fixed on the Mus plate with 20% urethane 1.0g/kg intraperitoneal anesthesia before the test, behind the record normal ECG.Connect artificial respirator before opening the thoracic cavity, behind the ligation ramus descendens anterior arteriae coronariae sinistrae, close the thoracic cavity rapidly, recover to breathe, recording ecg has the obvious J point person of raising to be the successful sign of operation (reject and obvious myocardial infarction electrocardiographic wave person do not occur).At once each organizes femoral vein administration 4ml/kg respectively, and the normal saline matched group is given with the volume normal saline.After the record ligation 5,15,30,60, each time point electrocardiogram of 120min, calculate each time J point and be offset total mv number, and carry out statistical disposition, the results are shown in Table 7.After the off-test, take out heart immediately, clean surplus blood, cut off atrium and each trunk, fascia, auricle etc. with normal saline, take by weighing ventricular weight, then cardiac muscle is cut into 5 of equal thickness, places 37 ℃ of 0.5%N-BT dyeing liquors 10min that dyes, take out and cut off the non-infarcted myocardium that is colored, the undyed infarct cardiac muscle of weighing, be calculated as follows myocardial ischemia district percentage rate, carry out statistical disposition, the results are shown in Table 8.
The influence of J point displacement behind the table 7 pair ligation ramus descendens anterior arteriae coronariae sinistrae (X ± SD)
| Group | Dosage (g/kg) | n | Before the ligation | After the ligation (min) | ||||
| 5 | 15 | 30 | 60 | 120 | ||||
| Sham-operation | - | 10 | 0.08±0.02 | 0.10±0.04 | 0.11±0.03 | 0.11±0.02 | 0.09±0.04 | 0.09±0.03 |
| Model | - | 10 | 0.10±0.03 | 0.51±0.15 | 0.46±0.15 | 0.50±0.13 | 0.48±0.14 | 0.45±0.14 |
| FD | 4.0 | 10 | 0.09±0.04 | 0.38±0.12 * | 0.33±0.12 * | 0.39±0.15 | 0.35±0.09 * | 0.42±0.09 |
| Herb | 4.0 | 10 | 0.10±0.03 | 0.53±0.10 | 0.47±0.10 | 0.38±0.10 * | 0.41±0.15 | 0.44±0.11 |
| Root and stem | 4.0 | 10 | 0.10±0.03 | 0.44±0.12 | 0.40±0.12 | 0.42±0.12 | 0.40±0.11 | 0.41±0.16 |
| Stem and branch with leaf | 4.0 | 10 | 0.10±0.04 | 0.50±0.12 | 0.31±0.08 * | 0.38±0.11 * | 0.39±0.13 | 0.40±0.11 |
| Spica | 4.0 | 10 | 0.10±0.02 | 0.36±0.15 * | 0.03±0.11 * | 0.35±0.15 * | 0.32±0.16 * | 0.38±0.08 |
Compare * P＜0.05 with matched group
The influence of table 8 pair acute myocardial infarction scope (X ± SD)
| Group | Dosage (g/kg) | n | Ventricle heavy (g) | Infarct heavy (g) | Infarct/ventricle (%) |
| Sham-operation | - | 10 | 0.796±0.195 | 0.000±0.000 | 0.00±0.00 |
| Model | - | 10 | 0.795±0.163 | 0.163±0.057 | 20.08±3.24 |
| FD | 4.0 | 10 | 0.821±0.110 | 0.120±0.034 | 14.88±5.08 * |
| Herb | 4.0 | 10 | 0.803±0.181 | 0.123±0.059 | 15.16±5.23 * |
| Root and stem | 4.0 | 10 | 0.804±0.154 | 0.138±0.048 | 17.11±4.21 |
| Stem and branch with leaf | 4.0 | 10 | 0.861±0.119 | 0.123±0.042 | 14.61±5.56 * |
| Spica | 4.0 | 10 | 0.806±0.173 | 0.110±0.022 | 13.93±5.08 ** |
Compare * P＜0.05 * * P＜0.01 with matched group
Result of the test shows; dig up the roots and outer each sample of stem all can improve the ischemic myocardial electrocardiogram in various degree; the percentage rate in myocardial ischemia district is reduced; acute myocardial infarction there is significant protective effect; with model group significant difference (P＜0.05, P＜0.01) is arranged more all, wherein spica has the characteristics of long action time, action intensity big (P＜0.01).The spica that Herba Polygoni Orientalis is described is a Herba Polygoni Orientalis effective site.The result of physicochemical property research shows that the content of flavone and liposoluble ingredient is higher in the spica, and prompting flavone and liposoluble ingredient are the effective ingredient of Herba Polygoni Orientalis.
5. test being got in the influence of extrasomatic rabbit heart coronary flow hits hindbrain with rabbit and causes dusk, open breast rapidly and take out heart, press Langendorff method aortic cannulation, after heart is fixed on the perfusion device, with 38 ± 0.5 ℃ of constant temperature and uninterruptedly feed Ringer-Lock ' the s liquid perfusion of pure oxygen.Perfusion pressure is constant to be 50CmH
2O.After treating that perfusion is stable, take to intersect dose regimen, inject for reagent liquid, the flow value that the observed and recorded administration is forward and backward 1 minute by the perfusion side pipe respectively.The intersection delivery time is 10min.The results are shown in Table 9.
The influence of table 9 pair extrasomatic rabbit heart coronary flow (X ± SD)
| Medicine | Dose (ml) | n | Coronary flow (ml/min) | |||
| Before the administration | After the administration | Value added | Increment rate (%) | |||
| Herb | 0.5 | 15 | 12.3±3.5 | 14.9±3.0 * | 2.6±1.3 | 21.2±10.2 |
| Root and stem | 0.5 | 14 | 12.9±2.5 | 14.1±3.1 | 1.24±0.8 | 9.32±8.8 |
| Stem and branch with leaf | 0.5 | 13 | 12.6±2.4 | 15.3±3.0 * | 2.7±0.9 | 22.4±6.3 |
| Spica | 0.5 | 15 | 12.5±3.0 | 16.3±3.7 ** | 3.8±2.7 | 31.1±12.8 |
| FD | 0.5 | 13 | 13.1±2.9 | 15.6±2.3 * | 2.5±0.7 | 19.8±5.2 |
Compare before the medicine with behind the medicine: * p＜0.05 * * p＜0.01
The result as seen from table, each sample all can make the extrasomatic rabbit heart coronary flow increase except that sample root and stem, compare before its value added medication with after the medication, the result all has significance or utmost point significant difference (p＜0.05, p＜0.01) to illustrate that this product has tangible coronary artery dilator effect, wherein the fruit ear effect is the strongest, makes coronary flow increase by 31% respectively.
6. abnormal toxicity test: get mice by " Chinese pharmacopoeia version in 2000 two appendix XI C " undue toxicity's inspection technique " checks.The result of the test of three batches of SH injection shows that experimental animal is not seen death and other toxic reactions at the appointed time.
Two, Study on Forming
The screening of adjuvant:
Among the present invention, used pharmaceutic adjuvant comprises one or more in mannitol, lactose, sorbitol, calcium lactate, gelatin hydrolysate, glucose, sodium chloride, fructose, dextran, propylene glycol, glycerol, Polyethylene Glycol, sodium stearate, glycerin gelatine, dextrin, starch, the vegetable oil.
1. the selection of the different filler kinds of injection
The applicant finds in development, suitable filler, liquor strength, filler loading are powder injection formulation molding and stable key factor, in order to guarantee the quality of preparation, the applicant, investigates the kind of filler to the appearance character of product, color and luster, porousness, villous shape material formation etc. is observed relatively with mannitol, glucose, lactose, dextran, calcium lactate; The water intaking Flos Carthami extract adds the suitable quantity of water dissolving, adds the filler mixed dissolution respectively, 0.22 μ m membrane filtration postlyophilization, every XiLin bottle-packaging solution 2ml.Lyophilisation condition: vacuum 13.332Pa, 0 ℃ of balance solidification point, equilibration time 1.5 hours, the drying time of heating up are 8～15 hours under lowest total of the melting point-16 ℃ ,-45 ℃ of conditions, 35 ℃ of baking temperatures.Result such as following table:
The screening of filler kind
| The filler kind | Filler: medicinal liquid (mg: ml) | The finished product appearance character |
| Mannitol | 10∶2 10∶1 20∶1 | Good moldability good moldability good moldability |
| Glucose | 10∶2 10∶1 20∶1 | Atrophy, the duricrust atrophy is arranged, the duricrust atrophy is arranged, duricrust is arranged |
| Lactose | 10∶2 10∶1 20∶1 | Atrophy, the duricrust atrophy is arranged, the duricrust atrophy is arranged, duricrust is arranged |
| Calcium lactate | 10∶2 10∶1 20∶1 | Atrophy, duricrust, the atrophy of rehydration difference arranged, duricrust is arranged, the atrophy of rehydration difference, have duricrust, rehydration poor |
| Dextran | 10∶2 10∶1 20∶1 | Atrophy, the atrophy of fine hair shape, the atrophy of fine hair shape, fine hair shape |
| Blank medicinal liquid | 1ml 2ml 3ml | Color and luster is inhomogeneous, not molding of atrophy |
Result of the test shows, when the amount of adding mannitol is 0.5～2g in the 100ml medicinal liquid, can keep sample lyophilizing preceding volume and shape, no duricrust, and color and luster is good, not atrophy, sample is loose porous shape structure, and rehydration is good.Take all factors into consideration from finished product color and luster, dissolubility, formability, economic dispatch aspect, filler is finally selected mannitol for use.
2. drop pill choice of base
Drop pill requires preparation to bring into play curative effect rapidly, and medicine contains volatile ingredient in addition, so select fusing point low, the Polyethylene Glycol with good dispersion is made substrate, and the hardness of drop pill, better mobile the results are shown in following table.
Drop pill substrate screening experiment result
| Matrix species | Hardness | Roundness | Hangover |
| Polyethylene Glycol | +++ | +++ | Do not hold in the palm tail |
| Gelatin | ++ | + | A little holds in the palm tail |
| Sodium stearate | + | + | A little holds in the palm tail |
Annotate: +++show fine; ++ show better; + show general
3. the drop pill coolant is selected
Earlier with medicine: the ratio of Polyethylene Glycol=1: 1.5, from methyl-silicone oil (viscosity 1000,200,100), vegetable oil, soybean oil, Oleum Arachidis hypogaeae semen, rapeseed oil, select suitable condensing agent.Decrease speed, molding situation with drop pill are index, with the investigation result of each index by good to poorly using " +++" successively, " ++ ", "+", "-" expression the results are shown in following table.
The selection experimental result of coolant
| Condensing agent | Decrease speed | The molding situation |
| Methyl-silicone oil 1000 | - | - |
| Methyl-silicone oil 200 | + | + |
| Methyl-silicone oil 100 | ++ | + |
| Vegetable oil | +++ | +++ |
| Soybean oil | +++ | - |
| Rapeseed oil | +++ | + |
Annotate: +++show fine; ++ show better; + show general
As seen from the above table, coolant selection vegetable oil is good.
Selecting mannitol for use when therefore the present invention prepares freeze-dried powder is filler, and selecting Polyethylene Glycol for use during the preparation drop pill is that substrate, vegetable oil are coolant.
The specific embodiment:
Embodiment 1: 2 kilograms on water intaking Flos Carthami, decoct with water 3 times, each 1 hour, amount of water was 10 times of raw material weight, filter, merging filtrate is evaporated to relative density 1.15 (temperature is 60 ℃) extractum, handles with the ethanol precipitation of 3 times of amounts, decompression recycling ethanol, transfer PH to 4 with 2%HCl,, reclaim solvent with n-butyl alcohol or ethyl acetate extraction, residue is with an amount of 45% dissolve with ethanol, last polyamide column is used 45% ethanol elution, eluent and flee liquid and reclaim ethanol, the residue vacuum drying, get the Herba Polygoni Orientalis extract, the effective ingredient content of total flavone accounts for 70% in the extract, and the content of phenolic acid accounts for 5%.Herba Polygoni Orientalis extract and an amount of sodium chloride are dissolved in water to 1000ml, filter, and sterilization, packing gets injection.This product uses according to conventional method.
Embodiment 2: 2 kilograms on water intaking Flos Carthami decocts with water each 2 hours 2 times, amount of water is 6 times of raw material weight, filters merging filtrate, be evaporated to relative density 1.05 (temperature is 30 ℃) extractum, ethanol precipitation with 2 times of amounts is handled, and decompression recycling ethanol is transferred PH to 3 with 2%HCl, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue is with an amount of 25% dissolve with ethanol, last D
101Macroporous resin column is used 40% ethanol elution, and eluent reclaims ethanol, and the residue spray drying gets the Herba Polygoni Orientalis extract, and the effective ingredient content of total flavone accounts for 70% in the extract, and the content of phenolic acid accounts for 1%.With Herba Polygoni Orientalis extract and mannitol, add an amount of water for injection, stirring makes dissolving, with saturated sodium bicarbonate solution adjust pH to 7.2～7.8, filter, filtrate is added water for injection to 400ml, mixing, sterilized 30 minutes, cold preservation 24 hours filters with 0.22 μ m microporous filter membrane, add the injection water and be dissolved to 400ml, filter, filtrate is aseptic subpackaged, every bottle of 2ml, lyophilization (16 ℃ of lowest total of the melting point, vacuum 13.332Pa under-45 ℃ of conditions, 0 ℃ of balance solidification point, equilibration time 1.5 hours, drying time of heating up is 8～15 hours, 35 ℃ of baking temperatures), gland promptly gets 200 freeze-dried powders.This product uses according to conventional method.
Embodiment 3: 2 kilograms on water intaking Flos Carthami decocts with water each 0.5 hour 4 times, amount of water is 20 times of raw material weight, filters merging filtrate, be evaporated to relative density 1.25 (temperature is 80 ℃) extractum, ethanol precipitation with 4 times of amounts is handled, and decompression recycling ethanol is transferred PH to 5 with 2%HCl, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, an amount of 50% dissolve with ethanol, last D
101Macroporous resin column is separated, and uses 95% ethanol elution, and eluent reclaims ethanol, and the residue vacuum drying gets the Herba Polygoni Orientalis extract, and the effective ingredient content of total flavone accounts for 70% in the extract, and the content of phenolic acid accounts for 15%.The Herba Polygoni Orientalis extract is added in the fused 40g Polyethylene Glycol, and mixing drips in vegetable oil under heat-retaining condition and makes drop pill, the heavy 50mg of every ball.
Embodiment 4: 2 kilograms on water intaking Flos Carthami, the alcohol reflux with 60% 3 times, each 1 hour, alcohol adding amount is 8 times of raw material weight, filters merging filtrate, decompression recycling ethanol is transferred PH to 3, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue 40% dissolve with ethanol, polyamide column separates, use 80% ethanol elution, eluent reclaims ethanol, and residue adopts spray drying, get the Herba Polygoni Orientalis extract, the effective ingredient content of total flavone accounts for 80% in the extract, and the content of phenolic acid accounts for 6%.Herba Polygoni Orientalis extract and an amount of sodium chloride are dissolved in water to 1000ml, filter, and sterilization, packing gets injection.
Embodiment 5: 2 kilograms on water intaking Flos Carthami, the alcohol reflux with 30% 2 times, each 2 hours, alcohol adding amount is 6 times of raw material weight, filters merging filtrate, decompression recycling ethanol is transferred PH to 2, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue 25% dissolve with ethanol, macroporous resin column is separated, use 40% ethanol elution, eluent reclaims ethanol, and residue adopts vacuum drying, get the Herba Polygoni Orientalis extract, the effective ingredient content of total flavone accounts for 80% in the extract, and the content of phenolic acid accounts for 1%.With Herba Polygoni Orientalis extract and mannitol, add an amount of water for injection, stirring makes dissolving, with saturated sodium bicarbonate solution adjust pH to 7.2～7.8, filter, filtrate is added water for injection to 400ml, mixing, sterilized 30 minutes, cold preservation 24 hours filters with 0.22 μ m microporous filter membrane, add the injection water and be dissolved to 400ml, filter, filtrate is aseptic subpackaged, every bottle of 2ml, lyophilization (lowest total of the melting point-16 ℃, vacuum 13.332Pa under-45 ℃ of conditions, 0 ℃ of balance solidification point, equilibration time 1.5 hours, drying time of heating up is 8～15 hours, 35 ℃ of baking temperatures), gland promptly gets 200 freeze-dried powders.Also can be with the medicine liquid spray drying before the lyophilization, the dry method sterilization is sub-packed in the cillin bottle under the aseptic condition, gets injectable powder.
Embodiment 6: 2 kilograms on water intaking Flos Carthami, the alcohol reflux with 95% 4 times, each 0.5 hour, alcohol adding amount is 20 times of raw material weight, filters merging filtrate, decompression recycling ethanol is transferred PH to 5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue 50% dissolve with ethanol, polyamide column separates, use 95% ethanol elution, eluent reclaims ethanol, and residue adopts spray drying, get the Herba Polygoni Orientalis extract, the effective ingredient content of total flavone accounts for 80% in the extract, and the content of phenolic acid accounts for 15%.The Herba Polygoni Orientalis extract is added in the fused 40g Polyethylene Glycol, and mixing drips in vegetable oil under heat-retaining condition and makes drop pill, the heavy 50mg of every ball.
Embodiment 7: 2 kilograms on water intaking Flos Carthami decocts with water each 1 hour 3 times, amount of water is 10 times of raw material weight, filters merging filtrate, be evaporated to relative density 1.15 (temperature is 60 ℃) extractum, ethanol precipitation with 3 times of amounts is handled, and decompression recycling ethanol is transferred PH to 3, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue 40% dissolve with ethanol, last D
101Macroporous resin column is used 80% ethanol elution, and eluent reclaims ethanol, polyamide column on the residue, use 80% ethanol elution, eluent and stream are worn liquid and are reclaimed ethanol, vacuum drying, get the Herba Polygoni Orientalis extract, the effective ingredient content of total flavone accounts for 15% in the extract, and the content of phenolic acid accounts for 7%.Herba Polygoni Orientalis extract and an amount of sodium chloride are dissolved in water to 1000ml, filter, and sterilization, packing gets injection.
Embodiment 8: 2 kilograms on water intaking Flos Carthami decocts with water each 2 hours 2 times, amount of water is 6 times of raw material weight, filters merging filtrate, be evaporated to relative density 1.05 (temperature is 30 ℃) extractum, ethanol precipitation with 2 times of amounts is handled, and decompression recycling ethanol is transferred PH to 2, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue 25% dissolve with ethanol, last D
101Macroporous resin column is used 40% ethanol elution, and eluent reclaims ethanol, polyamide column on the residue, use 40% ethanol elution, eluent and stream are worn liquid and are reclaimed ethanol, spray drying, get the Herba Polygoni Orientalis extract, the effective ingredient content of total flavone accounts for 15% in the extract, and the content of phenolic acid accounts for 1%.With Herba Polygoni Orientalis extract and mannitol, add an amount of water for injection, stirring makes dissolving, with saturated sodium bicarbonate solution adjust pH to 7.2～7.8, filter, filtrate is added water for injection to 400ml, mixing, sterilized 30 minutes, cold preservation 24 hours filters with 0.22 μ m microporous filter membrane, add the injection water and be dissolved to 400ml, filter, filtrate is aseptic subpackaged, every bottle of 2ml, lyophilization (lowest total of the melting point-16 ℃, vacuum 13.332Pa under-45 ℃ of conditions, 0 ℃ of balance solidification point, equilibration time 1.5 hours, drying time of heating up is 8～15 hours, 35 ℃ of baking temperatures), gland promptly gets 200 freeze-dried powders.Also can be with the medicine liquid spray drying before the lyophilization, the dry method sterilization is sub-packed in the cillin bottle under the aseptic condition, gets injectable powder.
Embodiment 9: 2 kilograms on water intaking Flos Carthami decocts with water each 0.5 hour 4 times, amount of water is 20 times of raw material weight, filters merging filtrate, be evaporated to relative density 1.25 (temperature is 80 ℃) extractum, ethanol precipitation with 4 times of amounts is handled, and decompression recycling ethanol is transferred PH to 5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue 50% dissolve with ethanol, last D
101Macroporous resin column is used 95% ethanol elution, and eluent reclaims ethanol, polyamide column on the residue, use 95% ethanol elution, eluent and stream are worn liquid and are reclaimed ethanol, vacuum drying, get the Herba Polygoni Orientalis extract, the effective ingredient content of total flavone accounts for 15% in the extract, and the content of phenolic acid accounts for 15%.The Herba Polygoni Orientalis extract is added in the fused 40g Polyethylene Glycol, and mixing drips in vegetable oil under heat-retaining condition and makes drop pill, the heavy 50mg of every ball.
Embodiment 10: 2 kilograms on water intaking Flos Carthami, ethanol with 12 times of amounts 50%, carry out percolation according to the percolation under fluid extract and the extractum item (13 pages of 2000 editions appendix of Chinese Pharmacopoeia), the percolate decompression recycling ethanol, transfer PH to 4, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, dissolve with ethanol, polyamide column separates, use 80% ethanol elution, eluent reclaims ethanol, and residue adopts spray drying, gets the Herba Polygoni Orientalis extract, the effective ingredient content of total flavone accounts for 50% in the extract, and the content of phenolic acid accounts for 10%.Extract and an amount of sodium chloride are dissolved in water to 1000ml, filter, and sterilization, packing gets injection; Or with extract and mannitol, add an amount of water for injection, stirring makes dissolving, with saturated sodium bicarbonate solution adjust pH to 7.2～7.8, filter, filtrate is added water for injection to 400ml, mixing, sterilized 30 minutes, cold preservation 24 hours filters with 0.22 μ m microporous filter membrane, add the injection water and be dissolved to 400ml, filter, filtrate is aseptic subpackaged, every bottle of 2ml, lyophilization (lowest total of the melting point-16 ℃, vacuum 13.332Pa under-45 ℃ of conditions, 0 ℃ of balance solidification point, equilibration time 1.5 hours, drying time of heating up is 12～15 hours, 35 ℃ of baking temperatures), gland promptly gets 200 freeze-dried powders.Also can be with the medicine liquid spray drying before the lyophilization, the dry method sterilization is sub-packed in the cillin bottle under the aseptic condition, gets injectable powder.Also extract can be added in the fused 40g Polyethylene Glycol, mixing drips in vegetable oil under heat-retaining condition and makes drop pill, the heavy 50mg of every ball.
Embodiment 11: 2 kilograms on water intaking Flos Carthami, decoct with water 3 times, and each 1 hour, amount of water was 10 times of raw material weight, filtered, and merging filtrate is evaporated to thick paste, and vacuum drying gets the Herba Polygoni Orientalis extract.The effective ingredient content of total flavone accounts for 25% in the extract, and the content of phenolic acid accounts for 1%.Extract adds an amount of dextrin or starch system granule, is sub-packed in to get capsule in the capsule shells, is sub-packed in and gets granule in the aluminum foil bag, and the granule tabletting gets tablet.
Embodiment 12: 2 kilograms on water intaking Flos Carthami, decoct with water 2 times, each 2 hours, amount of water was 6 times of raw material weight, filter, merging filtrate is evaporated to the extractum of relative density 1.15 (temperature is 60 ℃), handles with the ethanol precipitation of 2 times of amounts, decompression recycling ethanol, be concentrated into thick paste, spray drying gets the Herba Polygoni Orientalis extract.The effective ingredient content of total flavone accounts for 50% in the extract, and the content of phenolic acid accounts for 3%.Extract adds the suitable quantity of water dissolving, filters, and makes oral liquid; Extract adds an amount of dextrin or starch system granule, is sub-packed in to get capsule in the capsule shells, is sub-packed in and gets granule in the aluminum foil bag, and the granule tabletting gets tablet.
Embodiment 13: 2 kilograms on water intaking Flos Carthami, and the alcohol reflux with 60% 3 times, each 1 hour, alcohol adding amount was 8 times of raw material weight, filtered, and merging filtrate is evaporated to thick paste, and vacuum drying gets the Herba Polygoni Orientalis extract.The effective ingredient content of total flavone accounts for 50% in the extract, and the content of phenolic acid accounts for 4%.Extract adds the suitable quantity of water dissolving, filters, and makes oral liquid; Extract adds an amount of dextrin or starch system granule, is sub-packed in to get capsule in the capsule shells, is sub-packed in and gets granule in the aluminum foil bag, and the granule tabletting gets tablet.
Embodiment 14: 2 kilograms on water intaking Flos Carthami, decoct with water 4 times, each 0.5 hour, amount of water was 20 times of raw material weight, filtered, merging filtrate, be evaporated to relative density 1.05 (temperature is 30 ℃) extractum, handle decompression recycling ethanol with the ethanol precipitation of 3 times of amounts, to the extractum of relative density 1.10 (temperature is 60 ℃), gained extractum is through D
101Macroporous resin column is separated, and uses 60% ethanol elution, collects eluent, reclaims ethanol, and the residue spray drying gets the Herba Polygoni Orientalis extract, and the effective ingredient content of total flavone accounts for 55% in the extract, and the content of phenolic acid accounts for 4%.Extract adds the suitable quantity of water dissolving, filters, and makes oral liquid; Also extract can be added an amount of dextrin or starch system granule, be sub-packed in and get capsule in the capsule shells, be sub-packed in and get granule in the aluminum foil bag, the granule tabletting gets tablet.
Embodiment 15: 2 kilograms on water intaking Flos Carthami, decoct with water 3 times, each 1 hour, amount of water was 10 times of raw material weight, filtered, merging filtrate, be evaporated to relative density 1.25 (temperature is 80 ℃) extractum, handle decompression recycling ethanol with the ethanol precipitation of 4 times of amounts, to the extractum of relative density 1.10 (temperature is 60 ℃), gained extractum is through D
101Macroporous resin separates, and uses 60% ethanol elution, collects eluent, reclaims ethanol, and the residue vacuum drying gets the Herba Polygoni Orientalis extract, and the effective ingredient content of total flavone accounts for 40% in the extract, and the content of phenolic acid accounts for 4%.Extract adds in the fused 40g Polyethylene Glycol, and mixing drips in vegetable oil under heat-retaining condition and makes drop pill, the heavy 50mg of every ball.
Embodiment 16: 2 kilograms on water intaking Flos Carthami, decoct with water 2 times, each 2 hours, amount of water was 6 times of raw material weight, filtered, merging filtrate, be evaporated to relative density 1.15 (temperature is 60 ℃) extractum, handle decompression recycling ethanol with the ethanol precipitation of 2 times of amounts, to the extractum of relative density 1.10 (temperature is 60 ℃), gained extractum is through D
101Macroporous resin column is separated, and uses 60% ethanol elution, collects eluent, reclaims ethanol, and the residue spray drying gets the Herba Polygoni Orientalis extract, and the effective ingredient content of total flavone accounts for 40% in the extract, and the content of phenolic acid accounts for 1%.Extract adds an amount of vegetable oil, mixing, and the pressing pill promptly gets soft capsule.
Claims (13)
1. Herba Polygoni Orientalis preparation, it is characterized in that: it is that dry spica-Herba Polygoni Orientalis with the Herba Polygoni Orientalis medical material is a raw material, adds suitable adjuvant and is prepared into acceptable dosage form on injection or infusion solutions, freeze-dried powder, injectable powder, drop pill, capsule, tablet, dispersible tablet, soft capsule, granule and other pharmaceutics.
2. according to the described Herba Polygoni Orientalis preparation of claim 1, it is characterized in that: described preparation is injection or infusion solutions, freeze-dried powder, injectable powder, drop pill.
3. the preparation method of Herba Polygoni Orientalis preparation as claimed in claim 1 or 2, it is characterized in that: with Herba Polygoni Orientalis routinely decocting boil technology and extract, filter, filtrate decompression is condensed into extractum, transfers PH to 2～5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue carries out drying, gets the Herba Polygoni Orientalis extract, extract is prepared into described preparation again.
4. according to the preparation method of the described Herba Polygoni Orientalis preparation of claim 3, it is characterized in that: Herba Polygoni Orientalis is decocted with water 2～4 times, each 0.5～2 hour, amount of water is 6～20 times of raw material weight, filters, and it is 1.05～1.25 extractum that filtrate decompression is concentrated into 30～80 ℃ of relative densities, ethanol precipitation with 2～4 times of amounts is handled, decompression recycling ethanol is transferred PH to 2～5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue separates with 25～50% dissolve with ethanols, last D101 macroporous resin column, with 40～95% ethanol elutions, eluent reclaims ethanol, residue vacuum drying or spray drying get the Herba Polygoni Orientalis extract, extract are prepared into described preparation again.
5. according to the preparation method of the described Herba Polygoni Orientalis preparation of claim 3, it is characterized in that: Herba Polygoni Orientalis is decocted with water 2～4 times, each 0.5～2 hour, amount of water is 6～20 times of raw material weight, filter, it is 1.05～1.25 extractum that filtrate decompression is concentrated into 30～80 ℃ of relative densities, with the ethanol precipitation processing of 2～4 times of amounts, decompression recycling ethanol, transfer PH to 2～5,, reclaim solvent with n-butyl alcohol or ethyl acetate extraction, residue is with 25～50% dissolve with ethanols, last D101 macroporous resin column, with 40～95% ethanol elutions, eluent reclaims ethanol, polyamide column on the residue, with 40～95% ethanol elutions, eluent and stream are worn liquid and are reclaimed ethanol, vacuum drying or spray drying, get the Herba Polygoni Orientalis extract, again extract is prepared into described preparation.
6. according to the preparation method of the described Herba Polygoni Orientalis preparation of claim 3, it is characterized in that: Herba Polygoni Orientalis is decocted with water 2～4 times, each 0.5～2 hour, amount of water is 6～20 times of raw material weight, filters, and it is 1.05～1.25 extractum that filtrate decompression is concentrated into 30～80 ℃ of relative densities, ethanol precipitation with 2～4 times of amounts is handled, decompression recycling ethanol is transferred PH to 2～5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue is with 25～50% dissolve with ethanols, and last polyamide column is with 40～95% ethanol elutions, eluent and stream are worn liquid and are reclaimed ethanol, vacuum drying or spray drying get the Herba Polygoni Orientalis extract, extract are prepared into described preparation again.
7. the preparation method of Herba Polygoni Orientalis preparation as claimed in claim 1 or 2, it is characterized in that: Herba Polygoni Orientalis is adopted the method extraction of normal reflux, dipping with 30～95% ethanol, decompression recycling ethanol, transfer PH to 2～5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue carries out drying, get the Herba Polygoni Orientalis extract, again extract is prepared into described preparation.
8. according to the preparation method of the described Herba Polygoni Orientalis preparation of claim 7, it is characterized in that: with Herba Polygoni Orientalis with 30～95% alcohol reflux 2～4 times, each 0.5～2 hour, alcohol adding amount is 6～20 times of raw material weight, filter merging filtrate, decompression recycling ethanol, transfer PH to 2～5, with n-butyl alcohol or ethyl acetate extraction, reclaim solvent, residue is with 25～50% dissolve with ethanols, macroporous resin or polyamide column separate, with 40～95% ethanol elutions, eluent reclaims ethanol, and residue adopts vacuum drying or spray drying, get the Herba Polygoni Orientalis extract, again extract is prepared into described preparation.
9. according to the preparation method of claim 3,4,5,6,7 or 8 described Herba Polygoni Orientalis preparations, it is characterized in that: injection or infusion solutions in the described preparation prepare like this: the water intaking Flos Carthami extract adds water for injection and 0.9% sodium chloride, stir evenly, cold preservation filters, filtrate adds 0.1% active carbon, boils 30 minutes, puts cold, be filtered to clear and bright, transfer pH to 6～9 with 10%NaOH, through the filtering with microporous membrane of 0.25～0.45 μ m, fill, sterilized 30 minutes for 100～115 ℃, promptly.
10. according to claim 3,4,5,6, the preparation method of 7 or 8 described Herba Polygoni Orientalis preparations, it is characterized in that: the lyophilized injectable powder in the described preparation prepares like this: water intaking Flos Carthami extract and mannitol, add water for injection, stir evenly, cold preservation, filter, filtrate adds 0.1% active carbon, boils 30 minutes, put cold, be filtered to clear and brightly, transfer pH to 6～9 with 10%NaOH, through the filtering with microporous membrane of 0.25～0.45 μ m, fill, lyophilization, lyophilisation condition is: 16 ℃ of lowest total of the melting point, vacuum 13.332Pa under-45 ℃ of conditions, 0 ℃ of balance solidification point, equilibration time 1.5 hours, drying time of heating up is 8～15 hours, 35 ℃ of baking temperatures, promptly.
11. the preparation method according to claim 3,4,5,6,7 or 8 described Herba Polygoni Orientalis preparations is characterized in that: the injectable powder in the described preparation prepares like this: water intaking Flos Carthami extract and mannitol add water for injection, stir evenly, cold preservation filters, filtrate adds 0.1% active carbon, boils 30 minutes, puts cold, be filtered to clear and bright, transfer pH to 7.5～8.0 with 10%NaOH, through the filtering with microporous membrane of 0.25～0.45 μ m, the filtrate spray drying, packing, promptly.
12. preparation method according to claim 3,4,5,6,7 or 8 described Herba Polygoni Orientalis preparations, it is characterized in that: the drop pill in the described preparation prepares like this: the Herba Polygoni Orientalis extract is added in the fused 40g Polyethylene Glycol, mixing, under heat-retaining condition, in vegetable oil, drip and make drop pill, promptly.
13. the application as the Herba Polygoni Orientalis preparation of any acquisition in the claim 1～12 is characterized in that: the application of the preparation of acquisition in preparation treatment cardiovascular and cerebrovascular diseases medicament.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732443B (en) * | 2008-11-26 | 2012-01-11 | 贵州益佰制药股份有限公司 | Application of Herba Polygoni Orientalis-containing composition in preparation of medicaments of treating kidney diseases |
| CN101632724B (en) * | 2008-07-25 | 2012-03-28 | 贵州益佰制药股份有限公司 | Application of polygonum orientale and erigeron breviscapus composition in preparing medicaments for treating cerebrovascular disease and correlative diseases |
| CN101732442B (en) * | 2008-11-26 | 2012-05-30 | 贵州益佰制药股份有限公司 | Application of prince feather-containing composition in preparation of medicaments of treating blood vessels of brain and diseases related to blood vessels of brain |
| CN103623067A (en) * | 2013-11-10 | 2014-03-12 | 周晓华 | Method of treating liver cirrhosis by using polygonum orientale |
| CN104383003A (en) * | 2014-10-29 | 2015-03-04 | 孟萍萍 | Pharmaceutical composition for treating stroke and preparation method thereof |
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2006
- 2006-02-17 CN CNB2006102001358A patent/CN100490843C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101632724B (en) * | 2008-07-25 | 2012-03-28 | 贵州益佰制药股份有限公司 | Application of polygonum orientale and erigeron breviscapus composition in preparing medicaments for treating cerebrovascular disease and correlative diseases |
| CN101732443B (en) * | 2008-11-26 | 2012-01-11 | 贵州益佰制药股份有限公司 | Application of Herba Polygoni Orientalis-containing composition in preparation of medicaments of treating kidney diseases |
| CN101732442B (en) * | 2008-11-26 | 2012-05-30 | 贵州益佰制药股份有限公司 | Application of prince feather-containing composition in preparation of medicaments of treating blood vessels of brain and diseases related to blood vessels of brain |
| CN103623067A (en) * | 2013-11-10 | 2014-03-12 | 周晓华 | Method of treating liver cirrhosis by using polygonum orientale |
| CN104383003A (en) * | 2014-10-29 | 2015-03-04 | 孟萍萍 | Pharmaceutical composition for treating stroke and preparation method thereof |
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