CN100431587C - Composition of medicine for treating cerebral arteriosclerosis, and preparation method - Google Patents
Composition of medicine for treating cerebral arteriosclerosis, and preparation method Download PDFInfo
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- CN100431587C CN100431587C CNB2005101174251A CN200510117425A CN100431587C CN 100431587 C CN100431587 C CN 100431587C CN B2005101174251 A CNB2005101174251 A CN B2005101174251A CN 200510117425 A CN200510117425 A CN 200510117425A CN 100431587 C CN100431587 C CN 100431587C
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Abstract
A Chinese medicine in the form of tablet for treating cerebral arteriosclerosis is prepared from 9 Chinese-medicinal materials including fleece flower root, astragalus root, red sage root, pueraria root, etc. Its preparing process and quality control method are also disclosed.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, relating in particular to a kind of is the pharmaceutical composition and preparation method thereof of the treatment cerebral arteriosclerosis that forms of feedstock production with the Chinese herbal medicine, belongs to the field of Chinese medicines.
Background technology
Cerebrovascular disease is one of maximum disease that threatens human survival, in recent years, variation and blue-collar minimizing along with China's living standard, dietary structure, the quick senescence of population, and the sharp increase of multiple high risk factor, crowd's mesencephalic arteries sclerosis, the prevalence of diseases such as cerebral infarction sequela, cyclic metabolism disorder disease raises year by year, and the trend of younger development is arranged.Cerebral arteriosclerosis is commonly encountered diseases and the frequently-occurring disease in the mid-aged population, it is a kind of modal cerebrovascular disease, and be " underlying diseases " that produces brain atrophy, senile dementia, various acute cerebrovascular disease such as cerebral infarction, subarachnoid hemorrhage etc., betide mostly (trend that has age of onset to shift to an earlier date in recent years) after 50 years old, with advancing age, its sickness rate raises gradually, and cerebral arteriosclerosis has in various degree appearred in old people more than 90%.Studies confirm that cerebrovascular is one of three underlying cause of deaths of more than 40 countries in the whole world.In recent ten years, along with people's understanding in depth to cerebrovascular disease, recognized early treatment for cerebral arteriosclerosis, not only can play and improve clinical symptoms, delay PD, improve quality of life and the health and the intellectual activity of middle-aged and elderly people, and, prevent having great importance of multiple cerebrovascular disease for reducing complication.
Cerebral arteriosclerosis is because non-acute, the blood supply of diffusivity brain essence due to the ductus arteriosus wall degeneration such as cerebral atherosclerosis, arteriolosclerosis and vitreous degeneration reduce, cerebral tissue changes and delayed ischemic neurological deficits, thereby cause a series of nerves and mental symptom, it is the main pathogenesis basis of ischemic cerebrovascular.Clinical manifestation can show as neurasthenic syndrome in early days for carrying out property Aging, and the later stage engenders organic diffusivity cerebral lesion, as vascular dementia, and parkinsonism etc.Epidemiological study is found, cerebral arteriosclerosis develops with the growth at age, the male is more than the women, M-F is 2: 1, and the incidence rate of primary disease and occupation, personality, diet, smoking etc. are proportionate, and the brain worker, have a liking for food animal fat, cholesterol, sugar, salt and happiness and eat the high caloric diet person to suffer from primary disease more.Modern medicine study confirms, the formation of cerebral arteriosclerosis is with fat, cholesterol metabolism is disorderly, it is relevant that endarterium is subjected to the stimulation of cholesterol crystal, thereby cause that arteries is narrow, blood vessel elasticity is organized and is in chronic progressive external ischemia, anaerobic condition for a long time, and the conversion and the petechial hemorrhage of generation brain cell, so that forming cicatrix cyst or diffusivity brain atrophy, the various mental disorders and the neural symptom of cerebral arteriosclerosis appears.Up to now, modern medicine does not still have directly effectively medicine to this disease, mainly take lipid lowerers, improve the medicine of medicine, platelet aggregation inhibitor and some symptomatic treatments of blood circulation, can play the effect of certain disease controlling development, but exist the medication cycle long, side effect is big, state of an illness weakness repeatedly after the drug withdrawal.
In recent ten years, adopt the Chinese medicine cerebral arteriosclerosis to do a large amount of theoretical researches, basic research and clinical research work, the scientific research prescription of a collection of determined curative effect is used for clinical, has obtained gratifying clinical effectiveness.A large amount of clinical practices confirms that the early stage cerebral arteriosclerosis of Chinese medicine has clinical efficacy preferably, not only can play to alleviate or alleviate clinical symptoms, delays PD, reduce the effect of complication, and every physiological and pathological index has obtained correction.In addition, also obtained deep progress, disclosed large quantities of special efficacies, for the Chinese medicine cerebral arteriosclerosis provides material base with Chinese medicine of " blood circulation promoting and blood stasis dispelling " effect to cerebral arteriosclerosis for the modern pharmacological research of Chinese crude drug.But but lag behind the paces of clinical research as the research and development of the Chinese patent medicine new drug for the treatment of " cerebral arteriosclerosis ".Major part is in the treatment at apoplexy and apoplexy sequela in the new Chinese medicine of the Chinese patent medicine of existing national standard and exploitation in recent years, and also not causing sufficient attention for the hazardness of " underlying diseases " cerebral arteriosclerosis of multiple cerebrovascular disease, blank has appearred in the new drug research and the exploitation of treatment cerebral arteriosclerosis.
The medicine of treatment cerebrovascular disease is quite a lot in the Chinese patent medicine of listing at present, but great majority all are that the medicine that carries out the early treatment at cerebral arteriosclerosis does not but cause study of pharmacy worker's attention based on the medicine of treatment apoplexy acute attack and apoplexy sequela.Therefore, research and development determined curative effect, treatment cerebral arteriosclerosis new product safe and reliable, taking convenience have crucial meaning.
Summary of the invention
The main technical problem to be solved of the present invention is to overcome the deficiencies in the prior art, and the pharmaceutical composition of the treatment cerebral arteriosclerosis of a kind of determined curative effect, safe and reliable, taking convenience is provided.
The main technical problem to be solved of the present invention realizes by following technological approaches:
A kind of pharmaceutical composition for the treatment of cerebral arteriosclerosis, make by following bulk drugs:
Radix Polygoni Multiflori Preparata 30-40 part, Radix Astragali 30-40 part, Radix Salviae Miltiorrhizae 25-35 part, Radix Puerariae 25-35 part, Folium Ginkgo 25-35 part, Rhizoma Chuanxiong 25-35 part, Rhizoma Alismatis 25-35 part, Rhizoma Gastrodiae 20-30 part, Ramulus Uncariae Cum Uncis 20-30 part.
Preferably, pharmaceutical composition of the present invention is made by following bulk drugs:
35 parts of Radix Polygoni Multiflori Preparatas, 35 parts of the Radixs Astragali, 30 parts of Radix Salviae Miltiorrhizaes, 30 parts of Radix Puerariaes, 30 parts of Folium Ginkgos, 30 parts of Rhizoma Chuanxiongs, 30 parts of Rhizoma Alismatis, 25 parts in Rhizoma Gastrodiae, 25 parts of Ramulus Uncariae Cum Uncis.
Cerebral arteriosclerosis is arteriocerebral retrograde affection, and its morbidity is relevant with the decay of organ functions such as the heart, liver,spleen,kidney, and sick position is at brain, and pathogenesis mainly shows as deficiency of kidney essence, and brain is lost and filled, the retardance of the expectorant stasis of blood, and the brain network is obstructed." void " is the basis of morbidity, as Zhang Zhongjing institute cloud " dizziness must be due to deficiency "; " stasis of blood " is the pathologic basis of primary disease, and Qing Dynasty's Wang Qingren is said in errors in Medicine Corrected: " vigour was both empty, can not reach in blood vessel, and the blood vessel depletion of QI must stop and the stasis of blood." if the internal organs weakness of QI, qi as the commander of blood, the capable then blood of gas is capable; the deficiency of vital energy is blood stasis then, clinical observation, cerebral arteriosclerosis patient all has Blood stasis in various degree; whole blood viscosity, plasma viscosity generally raise, and serum cholesterol, triglyceride are also most higher, and blood is dense adhesive aggregation and coagulates state." expectorant " is the pathological essence of primary disease, and a little less than cerebral arteriosclerosis patient's aged debility gas, water Tianjin is not changed, and does not precise and tinyly give birth to, and stops in the turbid damp, whenever easily causes expectorant and stops in turbid.Expectorant is turbid to be tangible cloudy matter, with blood flow nowhere less than, the property of its viscous both can stagnate in blood vessel wall, occludes lumen, can make again blood thick sluggish, and then produce blood stasis.This shows that the pathogenesis of cerebral arteriosclerosis can be summarized as void, the stasis of blood, expectorant.Weakened body resistance is this, and the domination of pathogen is mark; Weakened body resistance is that essence and blood loses, and the domination of pathogen is the blood stasis stagnation of phlegm; Because the blood stasis stagnation of phlegm, the brain network is obstructed, thrombosis, and brain is lost and is supported, so appearance dizziness, headache, forgetful, symptom such as be insomnia.Therefore, weakened body resistance, blood stasis, stagnation of phlegm are the basic pathogenesis of cerebral arteriosclerosis morbidity, the blood stasis stagnation of phlegm, and the brain network is obstructed to be the key of its pathology.
Cerebral arteriosclerosis is to be main pathology pathological changes with cerebral arteriosclerosis on the basis of GAS, with dizzy, headache, dysmnesia and sleep disorder is the syndrome of main clinical manifestation, primary disease belong to the traditional Chinese medical science dizzy, have a headache, be insomnia, forgetfully wait sick category.On the Chinese medical discrimination typing of primary disease, can be divided into a plurality of pattern of syndrome such as Liver and kidney damage of essence, deficiency of qi and blood, excessive rising of liver-YANG, insufficiency of the spleen stagnation of phlegm, phlegm stagnation in collateral, but a large amount of in recent years research report and clinical practices show that it is the highest to demonstrate,prove sickness rate with phlegm stagnation in collateral, prognosis hazardness maximum.The present invention is just according to this characteristics of incidence, with traditional Chinese medicine and pharmacy theory is guidance, reference for modern medical science is to the understanding of primary disease physiological and pathological, sum up the successes achieved in research and the pharmacological achievement in research of modern Chinese medicine of Chinese medicine cerebral arteriosclerosis in recent ten years, prescription in conjunction with the clinical practice composition, adopt " benefiting QI for activating blood circulation; foster essence is filled out marrow; turbid reducing phlegm disappears " legislation treatment cerebral arteriosclerosis, modern pharmacology studies show that medicine of the present invention has anti-cerebral ischemia, blood fat reducing, suppressing the aorta artery plaque forms, reduce whole blood viscosity, effect such as anticoagulant and analgesia.Through clinical verification, medicine of the present invention not only can improve clinical symptoms, and every physiological and pathological index obtained significant correction, has reached the effect for the treatment of both the principal and secondary aspects of a disease.
The cerebral arteriosclerosis pathogenesis is with deficiency of kidney essence, and brain is become homeless to support and is this, with the turbid blood stasis of expectorant, the brain network is obstructed is mark, is the disease for deficiency in origin and excess in superficiality.Control suitable giving consideration to both the incidental and fundamental, Fang Deqi wants.We are from " benefiting QI for activating blood circulation, foster essence are filled out marrow, turbid reducing phlegm disappears " legislation.Be monarch drug with Radix Polygoni Multiflori Preparata, the Radix Astragali, two flavors in the side.The Radix Polygoni Multiflori Preparata sweet in the mouth is warm in nature, goes into Liver and kidney, kind invigorating the liver and kidney, and benefiting essence-blood, and tepor and not dry are mended and oiliness, are that treatment deficiency of the liver and kindey, essence and blood lose empty key medicine, the sweet temperature of the Radix Astragali, the function invigorating the spleen and replenishing QI, qi-supplementing, blood-engendering, the row of enriching blood stagnates.The Radix Astragali is the QI invigorating panacea, " book on Chinese herbal medicine meets former " meaning " Radix Astragali energy tonifying five ZANG-organs is all empty ", " blood being the material foundation of QI; qi being the governor of blood ", QI invigorating energy hemopoietic, and the operation of blood depends on the promotion of gas, the capable then blood of gas is capable, and the stagnation of QI is blood stasis then, Radix Astragali activating qi and collateral, walk and do not keep, with the handsome blood of gas, blood can be brought about the desired sensation and be moved, and is monarch with the Radix Polygoni Multiflori Preparata and the Radix Astragali therefore, both can mend its deficiency of kidney essence, all deficiency of five ZANG-organs damage originally, can draw the blood operation again; Fang Zhongchen is with Radix Salviae Miltiorrhizae, Folium Ginkgo, Rhizoma Chuanxiong, Radix Puerariae.More than four flavors be all the medicine of blood circulation promoting and blood stasis dispelling, Folium Ginkgo promoting blood circulation and stopping pain; Radix Salviae Miltiorrhizae blood circulation promoting and blood stasis dispelling and just not hindering, the blood four directions of therefore leading to; Record in the Rhizoma Chuanxiong blood-activating and qi-promoting, " herbal classic ": this product " main apoplexy is gone into brain ", Rhizoma Chuanxiong energy blood circulation promoting and blood stasis dispelling has the circulation of qi promoting effect concurrently, and property is kind wanders away, and can strengthen the effect of promoting the circulation of blood dissipating blood stasis, and the QI and blood tonify without causing stagnation of leading to; Radix Puerariae sweet in the mouth suffering is cool in nature, but can clear sun rise loose, removing blood stasis again, share with Rhizoma Chuanxiong etc. and to lead to the brain network, sending up the lucid YANG, awake clear key makes the oriented of property of medicine row.More than four the flavor mutual compatibility, the blood circulation promoting and blood stasis dispelling circulation of qi promoting, blood circulation promoting improves the cerebrum ischemia anoxia; Assistant is with Rhizoma Alismatis, Rhizoma Gastrodiae, Ramulus Uncariae Cum Uncis, and Rhizoma Alismatis gas is flat, sweet in the mouth and light, Compendium of Material Medica call its " taste have damp and hot; then nose heave and blurred vision tinnitus for eliminating dampness by diuresis heat, row phlegm retention; Rhizoma Alismatis oozes that it is wet, and then heat is also removed, and rustic must the order; clearing heat in QI system rises; weather is bright refreshing, thus Rhizoma Alismatis has foster the five internal organs, physical strength profiting, controls dizziness, the merit of clever knowledge ", in we, work the turbid expectorant effect that disappears.The Rhizoma Gastrodiae sugariness is flat, and the Ramulus Uncariae Cum Uncis sweet in the mouth is slightly cold, and the two all has the breath liver-wind, the function of suppressing the hyperactive liver sun, and the key medicine of, headache dizzy for controlling, and effect is remarkable, plays the effect of alleviation clinical symptoms in we.
Make a general survey of full side, all medicine compatibilities, through-supplementation, blood stasis dispelling and just not hindering is set upright and is not stayed the stasis of blood, gather altogether benefiting QI for activating blood circulation, support that essence is filled out marrow, turbid effect of reducing phlegm disappears.Blood stasis is gone, and expectorant is turbid to disappear, and QI and blood is filled, and the brain network is smooth, and brain must be supported, and then all diseases more.
Modern pharmacological research proves: Radix Polygoni Multiflori Preparata has the effect of blood fat reducing and arteriosclerosis.The Radix Astragali has heart tonifying, blood vessel dilating, improves effects such as blood circulation and nutriture.The extract of Folium Ginkgo can improve cerebral ischemia, alleviates ischemic brain injury, blood vessel dilating, and the cerebral blood flow increasing amount suppresses thrombosis, blood fat reducing.Radix Salviae Miltiorrhizae has the blood vessel dilating blood viscosity lowering, quickens to improve the effect of brain microcirculation.Rhizoma Chuanxiong can improve the microcirculation of meninges and periphery, the cerebral blood flow increasing amount, and can increase cardio-arterial compliance in the intracranial, reduce cerebrovascular special resistance; Antilipemic effect.Radix Puerariae extract can improve cerebral circulation and microcirculation, improves hemorheological property and antithrombotic and forms the effect of blood fat reducing.Rhizoma Alismatis has and reduces serum cholesterol, triglyceride preferably, reduces low density lipoprotein, LDL, the effect of high density lipoprotein increasing, but arteriosclerosis simultaneously, and antiplatelet aggregation and antithrombotic form; Rhizoma Gastrodiae and Ramulus Uncariae Cum Uncis all have the cerebral blood flow increasing amount, anticoagulant and antithrombotic effect.
In sum, more than the compatibility of all medicines use, existing is guidance with tradition and modern theory of Chinese medical science, and the support of its modern pharmacological research and clinical research achievement practice is arranged again.
Pharmaceutical composition of the present invention adds various conventional adjuvant required when preparing different dosage form, for example disintegrating agent, lubricant, adhesive etc., method of Chinese medicinal with routine can be prepared into any suitable oral formulations, can be oral liquid, pill, capsule, tablet, powder or granule etc. for example, be preferably tablet.
Preferably, a kind of method for preparing the pharmaceutical composition for the treatment of cerebral arteriosclerosis may further comprise the steps:
(1) take by weighing each raw material by following weight portion:
Radix Polygoni Multiflori Preparata 30-40 part, Radix Astragali 30-40 part, Radix Salviae Miltiorrhizae 25-35 part, Radix Puerariae 25-35 part, Folium Ginkgo 25-35 part, Rhizoma Chuanxiong 25-35 part, Rhizoma Alismatis 25-35 part, Rhizoma Gastrodiae 20-30 part, Ramulus Uncariae Cum Uncis 20-30 part;
(2) Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae, Radix Puerariae, Folium Ginkgo, Rhizoma Alismatis are used alcohol reflux respectively, and merge extractive liquid, filters, and reclaim under reduced pressure gets extractum A; Residual medicine dreg is standby;
(3) Rhizoma Chuanxiong extracts volatile oil, collects the volatile oil beta-cyclodextrin inclusion compound, and it is standby to get dry clathrate; Residual medicine dreg is standby;
(4) step (2) and (3) residual medicine dreg and the Radix Astragali, Rhizoma Gastrodiae, Ramulus Uncariae Cum Uncis are decocted with water; Filter, filtrate decompression adds ethanol precipitation after concentrating again, leaves standstill, and filters, and decompression filtrate recycling ethanol gets extractum B;
(5) extractum A, extractum B and dry clathrate are merged, add adjuvant, spray drying is made finished product through preparations shaping technology.
In the above-mentioned preparation method, in the step (2) preferably with Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae, Radix Puerariae, Folium Ginkgo, Rhizoma Alismatis with 75% alcohol reflux 2 times, reflux for the first time and add the ethanol of 8 times of weight of medical material, reflux, extract, 2 hours, reflux for the second time and add the ethanol of 6 times of weight, reflux, extract, 1.5 hours, merge extractive liquid,, filter, it is that 80 ℃ of relative densities when measuring are 1.10 pure extractum A that filtrate decompression is concentrated into temperature; When step (3) is extracted Rhizoma Chuanxiong volatile oil, preferably Rhizoma Chuanxiong is added water retting 30 minutes, amount of water is 8 times of weight of Rhizoma Chuanxiong, and extraction time is 4 hours; When volatile oil was used beta-cyclodextrin inclusion compound, it was that 40 minutes, enclose temperature are 40 ℃ that the beta-schardinger dextrin-addition is preferably 6 times of weight of volatile oil, preferred enclose time; With step (2) and (3) residual medicine dreg and the Radix Astragali, Rhizoma Gastrodiae, when Ramulus Uncariae Cum Uncis decocts with water, preferably decoct with water 2 times, decoct the water that adds 10 times of weight of medical material for the first time in the step (4), decocted 2 hours, decoction for the second time adds the water of 8 times of weight, decocts 1.5 hours; Collecting decoction filters, and it is that 80 ℃ of relative densities when measuring are 1.15 aqueous extract that filtrate decompression is concentrated into temperature, reuse 65% ethanol carries out precipitate with ethanol, left standstill 48 hours, and filtered, the filtrate pressurization is reclaimed ethanol and is concentrated into temperature is that 80 ℃ of relative densities when measuring are 1.10 extractum B.
Another technical problem to be solved by this invention provides a kind of quality control standard by the prepared tablet of pharmaceutical composition of the present invention.
Another technical problem to be solved by this invention realizes by following technological approaches:
The quality control standard of the prepared tablet of pharmaceutical composition of the present invention, this tablet is made by following bulk drugs:
Radix Polygoni Multiflori Preparata 30-40 part, Radix Astragali 30-40 part, Radix Salviae Miltiorrhizae 25-35 part, Radix Puerariae 25-35 part, Folium Ginkgo 25-35 part, Rhizoma Chuanxiong 25-35 part, Rhizoma Alismatis 25-35 part, Rhizoma Gastrodiae 20-30 part, Ramulus Uncariae Cum Uncis 20-30 part;
Comprise following content:
(1) character: this product is a Film coated tablets, removes to show yellowish-brown behind the film-coat; Mildly bitter flavor is puckery;
(2) adopting thin layer chromatography that the Radix Astragali, Radix Puerariae, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae are carried out thin layer differentiates;
(3) adopt high effective liquid chromatography for measuring 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside content, every contains Radix Polygoni Multiflori Preparata with 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside meter, must not be less than 0.40mg.
In the quality standard of the present invention the Radix Astragali, Radix Puerariae, Rhizoma Chuanxiong, red rooted salvia have been carried out the thin layer discriminating, good through investigation method separating degree, collection of illustrative plates is clear, and speckle is obvious, favorable reproducibility.
Radix Polygoni Multiflori Preparata is a monarch drug in the medicine of the present invention, therefore to contained effective ingredient 2,3,5,4 in the Radix Polygoni Multiflori Preparata medical material '-tetrahydroxystilbene-2-O-β-D-glucoside carries out assay.Assay method is selected high performance liquid chromatography for use, its method is with reference to " Radix Polygoni Multiflori a medical material of Chinese pharmacopoeia version in 2000 content assaying method, through investigation to extraction, separation, condition determination, determined the preparation method of need testing solution and reference substance solution, and high effective liquid chromatography for measuring 2,3,5,4 '-method of tetrahydroxystilbene-2-O-β-D-glucoside content, and carried out investigation, method stability test, precision test, repeatability experiment, recovery test of linear relationship etc.The result shows, this content assaying method precision, favorable reproducibility, and method is stable, through 10 batch samples 20 being detected the investigation of data, determine that content limit is every and contains Radix Polygoni Multiflori Preparata with 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside meter, must not be less than 0.40mg.
In Radix Polygoni Multiflori Preparata quality of medicinal material standard, increased the assay item, measure in the Radix Polygoni Multiflori Preparata medical material 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside content, and it is extracted rate of transform investigate.
Usage and consumption: the dosage of medicine of the present invention depends on concrete dosage form, factors such as patient's age, body weight, health status.As guidance: tablet: obey 3, every day 3 times at every turn.Every specification 0.5g, every contains crude drug amount 2.7g, obeys crude drug amount 8.1g at every turn, obeys crude drug amount 24.3g every day.
Description of drawings
Fig. 1 Radix Astragali thin-layer chromatogram;
Fig. 2 Radix Salviae Miltiorrhizae thin-layer chromatogram;
Fig. 3 Radix Puerariae thin-layer chromatogram;
Fig. 4 Rhizoma Chuanxiong thin-layer chromatogram;
Fig. 5 positive reference substance chromatogram;
Fig. 6 test sample chromatogram;
Fig. 7 negative control product chromatogram.
The specific embodiment
Further describe the present invention by the following examples, it should be understood that these embodiment only are used for the purpose of illustration, never limit the scope of the invention.
The preparation of [embodiment 1] tablet
Take by weighing each raw material by following weight portion:
Radix Polygoni Multiflori Preparata 350g, Radix Astragali 350g, Radix Salviae Miltiorrhizae 300g, Radix Puerariae 300g, Folium Ginkgo 300g, Rhizoma Chuanxiong 300g, Rhizoma Alismatis 300g, Rhizoma Gastrodiae 250g, Ramulus Uncariae Cum Uncis 250g;
More than nine the flavor, give as one thinks fit cataclasm, get Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae, Radix Puerariae, Folium Ginkgo and Rhizoma Alismatis with the alcohol heating reflux of 8 times of weight 75% 2 hours, collect extracting solution, residue adds the alcohol heating reflux 1.5 hours of 6 times of weight 75%, collects extracting solution, merge extracted twice liquid, filter, decompression filtrate recycling ethanol also is concentrated into the clear paste that relative density is about 1.10 (80 ℃), and is standby; Get the water that Rhizoma Chuanxiong adds 8 times of weight, the water vapour distillation extracts volatile oil, and the volatile oil beta-cyclodextrin inclusion compound of collection is standby; The residue and the Radix Astragali after ethanol extraction and volatile oil extract, Rhizoma Gastrodiae, Ramulus Uncariae Cum Uncis decocts with water secondary, adds 10 times of weight water for the first time, decocts 2 hours, for the second time add 8 times of weight water, decocted collecting decoction 1.5 hours, filter, filtrate decompression is concentrated into the clear paste that relative density is about 1.15 (80 ℃), adds ethanol and makes and contain the alcohol amount and reach 65%, stir, left standstill 48 hours, filter, decompression filtrate recycling ethanol also is concentrated into the clear paste that relative density is about 1.10 (80 ℃), with alcohol extraction cream and water extraction cream mixing, add 2% dextrin, mixing, spray drying, add the about 180g of starch, mixing is made granule, 60～80 ℃ of dryings, add volatile oil clathrate compound, mixing adds magnesium stearate, mixing, be pressed into 1000, the bag film-coat, promptly.
The preparation of [embodiment 2] tablet
Take by weighing each raw material by following weight portion:
Radix Polygoni Multiflori Preparata 350g, Radix Astragali 350g, Radix Salviae Miltiorrhizae 300g, Radix Puerariae 300g, Folium Ginkgo 300g, Rhizoma Chuanxiong 300g, Rhizoma Alismatis 300g, Rhizoma Gastrodiae 250g, Ramulus Uncariae Cum Uncis 250g;
More than nine flavors, give as one thinks fit cataclasmly, get Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae, Radix Puerariae, Folium Ginkgo and Rhizoma Alismatis and use alcohol heating reflux, the collection extracting solution, residue adds alcohol heating reflux, collects extracting solution, merges extracted twice liquid, filter, decompression filtrate recycling ethanol also is condensed into clear paste, and is standby; Get Rhizoma Chuanxiong water vapour distillation and extract volatile oil, the volatile oil beta-cyclodextrin inclusion compound of collection, standby; Residue and the Radix Astragali, Rhizoma Gastrodiae, Ramulus Uncariae Cum Uncis after ethanol extraction and volatile oil extract decoct with water, and collecting decoction filters, filtrate decompression is concentrated into clear paste, adds ethanol, stirs, leave standstill, filter, decompression filtrate recycling ethanol also is concentrated into clear paste, with alcohol extraction cream and water extraction cream mixing, add 2% dextrin, mixing, spray drying, add the about 180g of starch, mixing is made granule, 60～80 ℃ of dryings, add volatile oil clathrate compound, mixing adds magnesium stearate, mixing, be pressed into 1000, the bag film-coat, promptly.
The preparation of [embodiment 3] capsule
Take by weighing each raw material by following weight portion:
Radix Polygoni Multiflori Preparata 300g, Radix Astragali 300g, Radix Salviae Miltiorrhizae 250g, Radix Puerariae 250g, Folium Ginkgo 250g, Rhizoma Chuanxiong 250g, Rhizoma Alismatis 250g, Rhizoma Gastrodiae 200g, Ramulus Uncariae Cum Uncis 200g;
More than nine the flavor, give as one thinks fit cataclasm, get Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae, Radix Puerariae, Folium Ginkgo and Rhizoma Alismatis with 8 times of amount alcohol heating reflux of 75% 2 hours, collect extracting solution, residue adds the alcohol heating reflux 1.5 hours of 6 times of amounts 75%, collects extracting solution, merge extracted twice liquid, filter, decompression filtrate recycling ethanol also is concentrated into the clear paste that relative density is about 1.10 (80 ℃), and is standby; Get the water that Rhizoma Chuanxiong adds 8 times of amounts, the water vapour distillation extracts volatile oil, and the volatile oil beta-cyclodextrin inclusion compound of collection is standby; 3 flavors such as the residue after ethanol extraction and volatile oil extract and the Radix Astragali decoct with water secondary, add 10 times of water gagings for the first time, decoct 2 hours, for the second time add 8 times of water gagings, decocted collecting decoction 1.5 hours, filter, filtrate decompression is concentrated into the clear paste that relative density is about 1.15 (80 ℃), adds ethanol and makes and contain the alcohol amount and reach 65%, stir, left standstill 48 hours, filter, decompression filtrate recycling ethanol also is concentrated into the clear paste that relative density is about 1.10 (80 ℃), with alcohol extraction cream and water extraction cream mixing, add 2% dextrin, mixing, spray drying, it is an amount of to add microcrystalline Cellulose, and mixing adds volatile oil clathrate compound, mixing, incapsulate, make 1000, promptly.
The preparation of [embodiment 4] oral liquid
Take by weighing each raw material by following weight portion:
Radix Polygoni Multiflori Preparata 400g, Radix Astragali 400g, Radix Salviae Miltiorrhizae 350g, Radix Puerariae 350g, Folium Ginkgo 350g, Rhizoma Chuanxiong 350g, Rhizoma Alismatis 350g, Rhizoma Gastrodiae 300g, Ramulus Uncariae Cum Uncis 300g;
More than nine the flavor, give as one thinks fit cataclasm, get Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae, Radix Puerariae, Folium Ginkgo and Rhizoma Alismatis with 8 times of amount alcohol heating reflux of 75% 2 hours, collect extracting solution, residue adds the alcohol heating reflux 1.5 hours of 6 times of amounts 75%, collects extracting solution, merge extracted twice liquid, filter, decompression filtrate recycling ethanol also is concentrated into the clear paste that relative density is about 1.10 (80 ℃), and is standby; Get the water that Rhizoma Chuanxiong adds 8 times of amounts, the water vapour distillation extracts volatile oil, and the volatile oil of collection adds emulsifying agent emulsifying, and is standby; 3 flavors such as the residue after ethanol extraction and volatile oil extract and the Radix Astragali decoct with water secondary, add 10 times of water gagings for the first time, decoct 2 hours, add for the second time 8 times of water gagings, decocted 1.5 hours, collecting decoction filters, filtrate decompression is concentrated into the clear paste that relative density is about 1.15 (80 ℃), add ethanol and make and contain alcohol amount and reach 65%, stir, left standstill 48 hours, filter, decompression filtrate recycling ethanol also is concentrated into the clear paste that relative density is about 1.10 (80 ℃), with alcohol extraction cream and water extraction cream mixing, merges with emulsive volatile oil, add edible essence 1.5ml, add sweeting agent 1.5g, add water and regulate total amount, stir evenly to 3000ml, filter, promptly.
The quality inspection of [test example 1] medicinal tablet of the present invention
Test sample: the embodiment of the invention 1 and 2 prepared tablets, be divided into 10 batch samples at random, be numbered 020701,020702,020801,020802,020803,020901,020902,021001,021002,021003 respectively.
Inspection content:
One, character: be Film coated tablets, remove and show yellowish-brown behind the film-coat; Mildly bitter flavor is puckery.
Two, differentiate
1, the thin layer of the Radix Astragali is differentiated:
The preparation of need testing solution: get 5 of test samples, remove film-coat, porphyrize adds methanol solution 30ml, and supersound process 30 minutes filters, and filtrate evaporate to dryness, residue add water 20ml makes dissolving, uses extracted with diethyl ether 2 times, each 30ml, the D of water layer by having handled well
101Type macroporous adsorptive resins (internal diameter 1cm, high 15cm) on, water 50ml eluting, discard water elution liquid,, discard 10% ethanol elution with 10% ethanol 50ml eluting, water 50ml eluting continues, discard water elution liquid, reuse 1% sodium hydroxide 50ml eluting discards sodium hydroxide eluting liquid, the water that continues is eluted to eluent and is neutral, with 40% ethanol 30ml eluting, discard 40% ethanol elution, with 70% ethanol 50ml eluting, collect 70% ethanol elution, evaporate to dryness, residue is with methanol 2ml dissolving, as need testing solution.
The preparation of reference substance solution: it is an amount of to get the astragaloside reference substance, adds methanol and makes the solution that every 1ml contains 1mg, in contrast product solution.
The preparation of negative controls: the negative controls that does not contain Milkvetch Root by the preparation method preparation of need testing solution.
Immobile phase: silica gel g thin-layer plate
Developing solvent: chloroform-methanol-water (13: 7: 2) lower floor.
The point sample amount: need testing solution 5 μ l, reference substance solution 2 μ l,
Developer: 10% ethanol solution of sulfuric acid, 105 ℃ dry by the fire to speckle colour developing clear.
Inspect: daylight and put under the ultra-violet lamp (365nm) and inspect.
The result: in the test sample chromatograph, with the corresponding position of reference substance chromatograph on, the speckle of apparent same color under the daylight; Put under the ultra-violet lamp (365nm) again and inspect, show the fluorescence speckle of same color, negative control does not have identical speckle, and warp detects 10 batch samples, this method specificity, and favorable reproducibility the results are shown in Figure 1.
2, the thin layer of Radix Salviae Miltiorrhizae is differentiated:
The preparation of need testing solution: get 5 of this product, remove film-coat, porphyrize, the 30ml that adds diethyl ether flooded 30 minutes, and supersound process 5 minutes filters, and filtrate evaporate to dryness, residue add methanol 1ml makes dissolving, as need testing solution.
The preparation of reference substance solution: get Tanshinone I I
AReference substance is an amount of, adds ethanol and makes the solution that every 1ml contains 2mg, in contrast product solution.
The preparation of negative controls: preparation does not contain the sample of red rooted salvia, prepares negative controls by the preparation method of need testing solution.
Immobile phase: silica gel g thin-layer plate
Developing solvent: with toluene-ethyl acetate (19: 1) is developing solvent
Point sample amount: need testing solution, each 2～5 μ l of reference substance solution
Inspect: inspect under the daylight
The result: in the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of identical color.Negative control does not have identical speckle, and warp detects 10 batch samples, this method specificity, and favorable reproducibility the results are shown in Figure 2.
3, the thin layer of Radix Puerariae is differentiated:
The preparation of need testing solution: get 4 of this product, remove film-coat, porphyrize, add methanol 25ml, supersound process 30 minutes filters, filtrate evaporate to dryness, residue add water 20ml makes dissolving, uses extracted with diethyl ether 2 times, each 20ml discards ether extracted liquid, water layer ethyl acetate extraction 2 times, each 20ml merges ethyl acetate extraction liquid, evaporate to dryness, residue adds dehydrated alcohol 1ml makes dissolving, as need testing solution.
The preparation of reference substance solution: get the puerarin reference substance, add dehydrated alcohol and make the solution that every 1ml contains 1mg, in contrast product solution.
The preparation of negative controls: preparation does not contain the sample of Radix Puerariae medical material, prepares negative controls by the preparation method of need testing solution.
Immobile phase: sodium carboxymethyl cellulose is on the silica gel g thin-layer plate of adhesive,
Developing solvent: chloroform-methanol-water (28: 10: 1)
The point sample amount: need testing solution 5 μ l, reference substance solution 2 μ l,
Inspect: put under the ultra-violet lamp (365nm) and inspect
The result: in the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the fluorescence speckle of same color.Negative control does not have identical speckle, and warp detects 10 batch samples, this method specificity, and favorable reproducibility the results are shown in Figure 3.
4, the thin layer of Rhizoma Chuanxiong is differentiated
The preparation of need testing solution: get 5 of this product, remove film-coat, porphyrize, 20ml adds diethyl ether, supersound process 5 minutes filters, and filtrate volatilizes, and adds dehydrated alcohol 1ml and makes dissolving, preparation as the molten need testing solution of test sample: get this product 10g, porphyrize adds ethanol 30ml, reflux 2 hours filters the filtrate evaporate to dryness, residue adds water makes dissolving, uses n-butanol extraction 2 times, each 20ml, n-butanol extracting liquid is evaporate to dryness after washing, and residue adds methanol 2ml makes dissolving, as need testing solution.
The preparation of control medicinal material solution: get Rhizoma Chuanxiong control medicinal material 1g, the 10ml that adds diethyl ether shines medical material solution in pairs with legal system.
The preparation of negative controls: preparation does not contain the sample of Rhizoma Chuanxiong medical material, prepares negative controls by the preparation method of need testing solution.
Immobile phase: silica gel g thin-layer plate
Developing solvent: n-hexane-ethyl acetate (9: 1)
Point sample amount: need testing solution, each 5 μ l of control medicinal material solution
Inspect: put under the ultra-violet lamp (365nm) and inspect
The result: in the test sample chromatograph, with control medicinal material chromatograph relevant position on, show identical sapphirine fluorescence speckle.Negative control does not have identical speckle, and warp detects 10 batch samples, this method specificity, and favorable reproducibility the results are shown in Figure 4.
Three, check
According to " an appendix VI of Chinese pharmacopoeia version in 2000 D tablet item requires down to check.
1, weight differential
According to " [weight differential] inspection technique under an appendix VI of Chinese pharmacopoeia version in 2000 the D tablet item is checked for test agent ten batches.The results are shown in Table 1:
The inspection of table 1 weight differential
2, disintegration
According to " an appendix XII of Chinese pharmacopoeia version in 2000 A inspection technique disintegration is checked ten batch samples.The results are shown in Table 2:
Table 2 is checked disintegration
3, limit test of microbe
According to " an appendix XIII of Chinese pharmacopoeia version in 2000 C microbial limit test is checked ten batch samples.Microbial limit standard bacterial population≤100/g, mycete and yeast count≤100/g, escherichia coli must not detect, and the demodicid mite that lives must not detect.Through ten batch samples are carried out limit test of microbe, the equal conformance with standard regulation of result the results are shown in Table 3:
Table 3 limit test of microbe
Four, assay
Radix Polygoni Multiflori Preparata is one of monarch drug in the drug regimen object space of the present invention, record in " one one of Chinese pharmacopoeia version in 2000 contains plurality of active ingredients, wherein 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside (C
20H
22O
9) be main effective ingredient, have active function.Earlier use 75% alcohol reflux among the preparation technology, the reuse water extraction can the better extract effective ingredient.Select to measure in the Radix Polygoni Multiflori Preparata 2,3,5,4 '-content of tetrahydroxystilbene-2-O-β-D-glucoside controls this product inherent quality.
" the Radix Polygoni Multiflori medical material assay item that records of Chinese pharmacopoeia one of version in 2000 adopts high effective liquid chromatography for measuring 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside content, Radix Polygoni Multiflori Preparata is the process of preparing Chinese medicine processed goods of Radix Polygoni Multiflori, on Radix Polygoni Multiflori content assaying method basis, according to this product characteristics, its quality standard assay item intends adopting high effective liquid chromatography for measuring 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside content, and methodology investigated, the result is as follows:
1, instrument, reagent reagent
High performance liquid chromatograph: Tianjin, island SPD-10A UV-detector, the LC-10AT pump, day island proper Tianjin (Wuxi) company produces.
Ultrasonic oscillator: AS-3120 type, AUTOSCIENCE.
Analytical balance: the AE-240 type, Mettler-Toledo Instrument (Shanghai) Co., Ltd. produces.
2, reagent and reagent
2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside reference substance: purchase in Chinese medicine bioassay institute.
Acetonitrile: chromatographically pure reagent, lot number on January 6th, 2002, Tianjin consonance medical science and technology company of the Chinese Academy of Medical Sciences produces.
Ethanol: chemically pure reagent, lot number 20011110, chemical reagent factory in Harbin produces.
3, chromatographic condition and system suitability
Chromatographic column: octadecylsilane chemically bonded silica is filler (VP-ODS, Shim-Paok, 5 μ m, 150 * 4.6mm I.D.).
Mobile phase: " in a Radix Polygoni Multiflori assay of Chinese pharmacopoeia version in 2000 item on the mobile phase basis, different acetonitriles of conversion and water ratio, definite at last mobile phase is acetonitrile-water (15: 85), and the separation of sample is met the requirements.
Detect wavelength: 320nm.
Number of theoretical plate by 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside peak calculates and should be not less than 2000.
4, the preparation of sample
1) preparation of positive reference substance solution
Precision takes by weighing 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside reference substance is an amount of, and add Diluted Alcohol and make the solution that every 1ml contains 30 μ g, promptly.
2) preparation of need testing solution
Select L for use
4(2
3) orthogonal test investigates the influence to extraction effect of different solvents and different supersound extraction time, the factor level investigation table sees Table 4:
Table 4 need testing solution prepares extraction factor level design table
Get 20 of this product, remove film-coat, the accurate title, decided porphyrize, get 0.5g, 4 parts, accurate respectively title is fixed, puts in the tool plug conical flask, by the accurate respectively solvent 25ml that adds of EXPERIMENTAL DESIGN condition, claim to decide weight, supersound process is put cold, divide another name to decide weight again, supply the weight that subtracts mistake, shake up, filter with Diluted Alcohol, get subsequent filtrate, inject chromatograph of liquid respectively, measure 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside content, calculate.The results are shown in Table 5,6:
Table 5L
4(2
3) orthogonal test need testing solution preparation investigation result
Table 6 variance analysis
It can be seen from the table, extraction solvent is principal element (P＜0.05), should get horizontal B
1, the supersound process time is secondary cause (P＞0.05), and is not remarkable to the extraction effect influence, and two horizontal differences are less, select A
1, optimum extraction condition is for being solvent with Diluted Alcohol, supersound process prepared need testing solution in 15 minutes.
3) preparation of negative controls
Preparation does not contain the sample of Radix Polygoni Multiflori Preparata, prepares negative controls by the need testing solution preparation method.
5, algoscopy
Accurate respectively each 10～20 μ l of positive reference substance solution, need testing solution and negative controls that draw inject chromatograph of liquid, measure.High-efficient liquid phase chromatogram is seen Fig. 6～8.
In the positive reference substance chromatogram, 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside peak retention time is about 20 minutes; In the test sample chromatogram, 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside peak retention time is also about 20 minutes, and separate enough preferably with other peak energy, meet the requirement of high performance liquid chromatogram assay; In the negative controls chromatogram, in 2,3,5,4 '-tetrahydroxystilbene-2-O-β-corresponding retention time in D-glucoside peak place do not have absworption peak, and it is noiseless to show that this method is carried out assay.
6, set up standard curve
The reference substance solution of getting concentration and be 0.048mg/ml is drawn 1 μ l, 2 μ l, 4 μ l, 8 μ l respectively, 12 μ l, 16 μ l inject liquid phase and survey spectrometer, measures, and calculates.With content Y is abscissa, and peak area X is that vertical coordinate is set up the standard curve equation.The results are shown in Table 7:
The foundation of table 7 standard curve
7, precision test
Accurate respectively absorption 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside reference substance solution (0.024mg/ml) 10 μ l, inject chromatograph of liquid, continuous 5 sample introductions, the record peak area the results are shown in Table 8:
Table 8 Precision test result
8, repeatability test
Get same lot number sample, remove film-coat, get 5 parts respectively, every part of about 2g, the accurate title, decide, and prepares sample solution by the need testing solution preparation method, injects chromatograph of liquid respectively, measures, and calculates.The results are shown in Table 9:
Table 9 reproducible test results
9, stability test
Get each 20 of 3 duplicate samples respectively, remove film-coat, the accurate title, decide, get about 0.5g respectively, the accurate title, decide, and prepares need testing solution by the need testing solution preparation method respectively, each sample injected liquid phase respectively at 0 hour, 4 hours, 8 hours and surveys spectrometer, measured, and calculated.The results are shown in Table 10:
Table 10 stability test result
10, recovery test
Get same batch sample, remove film-coat, get 6 parts respectively, every part of accurate title of about 0.5g is fixed, and wherein 1 part of precision adds methanol 25ml, as raw sample solution; All the other 5 parts accurate respectively 2,3,5 of the 0.02736mg/ml that add, 4 '-tetrahydroxystilbene-2-O-β-D-glucoside reference substance solution 13ml, methanol 7ml prepares sample solution by the need testing solution preparation method, inject hplc determination respectively, calculate.The results are shown in Table 11:
Table 11 recovery test result
11, ten batch samples detect data
Get ten batch samples and reach condition respectively as stated above and prepare reference substance solution and need testing solution, and measure 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside content.
Table 12 ten batch sample assay results
According to above-mentioned ten batch samples 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside assay result, tentative every of this product contains Radix Polygoni Multiflori Preparata with 2,3,5,4 '-tetrahydroxystilbene-2-O-β-D-glucoside (C
20H
22O
9) must not count and be less than 0.40mg.
The pharmacodynamics test of [test example 1] pharmaceutical composition of the present invention
Results of pharmacodynamic test shows that pharmaceutical composition of the present invention has the pharmacological action of following several respects:
1, have the effect that obviously formation of anti-experimental character arteriosclerosis rabbit cerebral arteriosclerosis, aortosclerosis formation and common carotid artery sclerosis is formed, can obviously reduce the aortosclerosis plaque area, effect strengthens with dosage; Can obviously suppress cerebral tissue blood vessel and nervous lesion due to the cerebral arteriosclerosis, obviously suppress the blood vessel injury that arteriosclerosis such as aorta and common carotid artery intimal thickening, the infiltration of foam cell deposition of lipids cause.
2, has tangible effect for reducing blood fat: can significantly reduce hyperlipidemia model rabbit cholesterol, triglyceride and low-density lipoprotein white level, the trend of high density lipoprotein increasing content is arranged.
3, has the sedimentary effect in liver of the experimental arteriosclerosis rabbit of certain inhibition lipid.
4, to hemorheological influence: can reduce hyperlipidemia model rabbit whole blood viscosity, accelerate erythrocyte electrophoretic time, can obviously suppress the inductive platelet aggregation of rat adenosine diphosphate (ADP), effect strengthens with dosage.
5, has treating cerebral ischemia: can alleviate obviously that brain weight due to the rat cerebral ischemia increases and the degree of cerebral edema, can obviously prolong the decapitated mice breathing time, obviously increase frequency of respiration, the cerebral ischemia brain injury is had the certain protection effect.
6, has significant analgesia role: can obviously reduce the number of times that acetic acid causes the mouse writhing reaction.
The toxicologic study test of [test example 2] pharmaceutical composition of the present invention
One, acute toxicity test
The tablet of the medicine of the present invention that embodiment 1 is prepared is with 60% Cmax (g/ml), maximum volume (0.8ml/20g body weight), secondary is irritated stomach and given mice in 24 hours, observe once every day, observed 7 continuously, each 10 mice of male and female are all in good condition, the any discomfort phenomenon do not occur, fur light, color and luster are normal, and behavioral activity, diet drinking-water, two just reach color, the colour of skin, breathing and there is no unusually, also no abnormal secretions, no dead mouse situation in 7 days after the administration.Experimental result shows: the oral medicine of the present invention of mice is not measured LD
50, maximum tolerated dose (MTD) is equivalent to 25.92g crude drug/kg greater than 48g/kg, and more than 533 times of clinical every day of consumption are equivalent to be grown up.Show that drug oral administration of the present invention is safe.
Two, long term toxicity test result
The tablet of the medicine of the present invention that embodiment 1 is prepared with 9g/kg/ day (be equivalent to clinical adult's dosage 100 times), 4.5g/kg/ day (be equivalent to clinical adult's dosage 50 times), 1.2g/kg/ day (be equivalent to clinical adult's dosage 13.4 times) dosage irritated that stomach gives rat in continuous 90 days and after 2 weeks of drug withdrawal, each test group outward appearance sign, behavioral activity, urine color, feces character etc. there is no unusually, relatively, difference does not have significance meaning (p＞0.05) between food ration, body weight and matched group; Each administration group rat leukocyte counting, leukocyte differential count, red blood cell count(RBC), hemoglobin, hematological indices and ALTs (ALT) such as platelet count, aspartic acid aminotransferase (AST), alkali phosphatase (ALP), blood urea nitrogen (BUN), creatinine (Crea), blood glucose (GLU), total protein (TP), total bilirubin (T-BIL), T-CHOL (TCHO), albumin (ALB), globulin blood biochemicals such as (GLB) is learned index and matched group difference does not have significance meaning (p＞0.05); Rat is carried out gross anatomy, comprehensive gross necropsy, each administration group rat heart, liver, spleen, lung, kidney, brain, stomach, intestinal, thymus, the adrenal gland, thyroid, prostate, testis, the uterus, vitals no abnormality seens such as ovary change, each administration group rat main organs coefficient and matched group comparing difference do not have significance meaning (P＞0.05), reach convalescent period after the administration to the rat heart, liver, spleen, lung, kidney, brain, stomach, intestinal, thymus, the adrenal gland, thyroid, prostate, testis, the uterus, the ovary important organ carries out the pathological tissue morphological examination, and each administration group is not seen the pathological change relevant with medicine with matched group.Show that long-term oral medicine of the present invention does not have the overt toxicity reaction.
The clinical observation on the therapeutic effect test of [test example 3] medicine composite for curing cerebral arteriosclerosis of the present invention
One, physical data
Pharmaceutical composition of the present invention has benefiting QI for activating blood circulation, support that essence is filled out marrow, turbid expectorant function disappears.Be used for the dizziness and headache due to the mutual resistance of the expectorant stasis of blood, insomnia forgetfulness or drowsiness, heavy dusk expands, apathetic expression, breast gastral cavity painful abdominal mass is vexed, and numb limbs and tense tendons, cerebral arteriosclerosis are seen above-mentioned patient.
According to the requirement of " medicine registration management way " (trying) pertinent regulations,, and face fiber crops and observe by " new Chinese medicine clinical research guideline " " cerebral arteriosclerosis expectorant stasis of blood mutual resistance card " design.During clinical observation, the patient that will meet the case choice criteria is divided into treatment group and matched group at random by factors such as sex, age, case source, the state of an illness and the courses of disease.Clinical observation treatment group 31 examples, matched group 30 examples, wherein the oldest person is 72 years old, reckling 46 years old, the grouping situation is asked for an interview table 13:
The natural grouping situation of table 13
Treatment group and matched group compare there was no significant difference at aspects such as sex, age, the course of disease and the state of an illness, treatment group and matched group have comparability.
Two, case choice criteria
1 includes the case standard in
1.1 Chinese medical discrimination standard (with reference to " new Chinese medicine clinical research guideline ", " Chinese Internal Medicine " " practical traditional Chinese medical science presbyatrics ").
1.1.1 primary symptom
1. dizzy.
2. headache.
3. insomnia or drowsiness.
4. forgetful.
1.1.2 inferior card
1. heavy dusk expands.
2. apathetic expression.
3. breast gastral cavity painful abdominal mass is vexed.
4. numb limbs and tense tendons.
1. dimly red tongue or the petechia ecchymosis is arranged.
2. tongue is greasy in vain.
3. stringy and rolling pulse.
Possess 2 of primary symptoms, inferior card possesses 2 above persons at least and can make a definite diagnosis.
1.2 Western medicine diagnose standard (with reference to the tentative standard of " new Chinese medicine clinical research guideline ", the academic meeting revision of the 3rd the neural psychiatric department in the whole nation in 1981)
Slight cerebral arteriosclerosis: clinical manifestation be dizzy, has a headache, and head swells, numb, often with constriction and constriction, tinnitus, tired, drowsiness or insomnia and dreamful sleep, extremity are numb, emotional instability, and judgement goes down, sometimes anxiety, anxiety, fear, suspicious, apathetic expression, bradykinesia, hypomnesis etc.
1.2.1 the age is generally more than 45 years old.
1.2.2 just send out unsettled symptom of higher nervous activity and/or brain diffuse lesion symptom.
1.2.3 more than the ocular fundus arteriosclerosis II level
1.2.4 aortic arch broadening
1.2.5 it is harder that carotid artery or radial artery touch, the circumstantial evidence of GAS such as coronary heart disease.
1.2.6 the nervous system positive sign: deep reflex is asymmetric, the palmomental reflex positive and/or the sucking reflex positive.
1.2.7 serum cholesterol increases.
1.2.8 get rid of other brain diseasess.
Possess in above-mentioned 85 promptly diagnosable.
1.3 include the case standard in
1.3.1 meet expectorant stasis of blood mutual resistance Chinese medical discrimination standard, and meet slight cerebral arteriosclerosis Western medicine diagnose standard person;
1.3.2 the age is between 40～75 years old;
1.3.3 aspiration is tried, and signature enters research notice person in the know;
1.3.4 do not participate in other clinical trial person.
1.4 get rid of the case standard
1.4.1 not meeting that Chinese medical discrimination belongs to expectorant stasis of blood mutual resistance card or do not meet Western medicine diagnose is slight cerebral arteriosclerosis person;
1.4.2 the age is person below 40 years old or more than 75 years old;
1.4.3 allergic constitution reaches this medicine allergy sufferers;
1.4.4 merge serious primary disease such as cardiovascular, liver, kidney and hemopoietic system and psychotic;
1.4.5 in, the severe cerebral arteriosclerosis, the cerebral arteriosclerosis mentally disturbed;
1.4.6 once suffered from patient behind acute myocardial infarction, cerebrovascular accident, severe trauma or the capital operation in half a year.
1.4.7 participate in other clinical trial person.
1.5 reject the case standard
1.5.1 by the medication of testing program regulation, drug compliance is not poor.
1.5.2 including the back in finds not meet to include standard person in.
Three, experimental observation group technology
1. case is originated and quantity
The test case is selected clinic case, and should strict control variable factor.31 examples are organized in treatment, matched group 30 examples.
2. observe the case grouping
The patient that will meet the case choice criteria follows principle at random, adopts the simple randomization method, reaches the state of an illness sequentially and is divided into treatment group and matched group.Except that medication was different, other may be by the factor of influence for therapeutic outcome, and were consistent as much as possible as sex, age, the state of an illness, the course of disease etc., make it have comparability between treatment group and the matched group.Viewing duration must not use any Chinese and western drugs relevant with primary disease.
3. Therapeutic Method
Treatment group: take the prepared tablet of the embodiment of the invention 1; Usage and dosage: oral, one time 3,3 times on the one; Specification: every heavy 0.5g.
Matched group: take NAODESHENG PIAN, function cures mainly: blood circulation promoting and blood stasis dispelling, dredging the meridian, consciousness-restoring and orifice-opening.Be used for cerebral arteriosclerosis, ischemia apoplexy and apoplexy sequela etc.Usage and dosage: oral, one time 6,3 times on the one.
The course of treatment: 30 days is a course of treatment.
Four, observation index
1. safety observation
1.1 general health check-up project.
1.2 blood, urine, just routine examination.
1.3 the heart, liver, kidney function test.
1.4 untoward reaction that may occur and coherent detection index thereof.
2. health giving quality index observation
2.1 main related symptoms
Expand dizziness and headache, insomnia forgetfulness or drowsiness, heavy dusk, other relevant syndromes performances such as apathetic expression, breast gastral cavity painful abdominal mass are vexed, numb limbs and tense tendons, observe its variation weekly.
2.2 mainly relevant sign
Tongue fur, pulse condition, blood pressure, heart rate are observed its variation weekly.
2.3 relevant physico-chemical examination index
Blood fat (cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, LDL) detection, examination of ocular fundus, rheoencephalogram, hemorheology, on-test, end are respectively surveyed 1 time.
Formulate syndrome observation index score standard according to symptom and sign etc., ask for an interview table 14:
Table 14 cerebral arteriosclerosis expectorant stasis of blood mutual resistance card symptom scalar quantization table and syndrome observation index score-sheet
| Observation item | Normally (0 minute) | Slightly (1 minute) | Moderate (2 minutes) | Severe (3 minutes) |
| Dizzy | No dizzy | Dizziness and blurred vision, in time, end when doing | Look the thing rotation, can not walk | Dizzy desire is fallen forward, and can not stand |
| Headache | No headache | Slight headache, in time, end when doing | Headache can be born, and continues more than | Have a headache unbearably upper punch volume top |
| Insomnia | There is not insomnia | Sleep has minimizing slightly, easily wakes up | The time see insomnia, difficulty falling asleep | Can not fall asleep |
| Or it is drowsiness | No drowsiness | Sleep was more than 10 hours every days, and that exhales can wake up | Sleep was more than 15 hours every days, and that exhales can wake up | Sleep was more than 10 hours every days, and that exhales can wake up, and woke up and slept again |
| Forgetful | No forgetful | Forget things once in a while, still can recall | The time and forget things, be difficult for recalling | Promptly forget in a twinkle, can not recall |
| Heavy dusk expands | Do not have and expand heavy dusk | Little feel dusk expands, and upstairs the chronognosis lower limb are heavy | Light when weighing when dusk expands, lower limb are stranded heavy during the stride level land | Dusk expands significantly, and taking a step, lower limb are stranded obviously heavy when lifting lower limb |
| Apathetic expression | Amimia indifferent | The thoughts and feelings and send out, mild symptoms, spontaneous remission is fast | Have or not thoughts and feelings all can occur, or be interrupted when occurring heavy when light | Do not have thoughts and feelings and send out longer duration, severe symptoms |
| Breast gastral cavity painful abdominal mass is vexed | No breast gastral cavity painful abdominal mass is vexed | The indistinct painful abdominal mass of breast gastral cavity is vexed | Sensation obviously, in time, end when doing | Sensation significantly continues more than |
| Numb limbs and tense tendons | No numb limbs and tense tendons | Idol has numbness, and degree is slight | Numbness can be born, and time ends when doing | Numbness continues more than unbearably |
| Picture of the tongue | Light red tongue, white and thin fur | Tongue is dark red, and tongue is greasy in vain | Tongue is dark red, and the petechia ecchymosis is arranged, and tongue is greasy in vain | |
| Pulse condition | Normal pulse | Stringy and rolling pulse |
Five, curative effect determinate standard
The therapeutic evaluation of 1 cardinal symptom (separately dizzy, headache, insomnia forgetfulness of symptom or drowsiness, heavy dusk expands, apathetic expression, vexed, the numb limbs and tense tendons of breast gastral cavity painful abdominal mass).
1.1 clinic control: after finishing the course of treatment, transference cure.
1.2 produce effects: after finishing the course of treatment, the symptom classification reduces 2 grades.
1.3 effectively: after finishing the course of treatment, the symptom classification reduces 1 grade.
1.4 it is invalid: as not reach above-mentioned standard person.
2 tcm syndrome efficacy determinations
2.1 clinical cure: tcm clinical practice symptom, sign disappear or basic the disappearance, and the syndrome integration reduces 〉=95%.
2.2 produce effects: tcm clinical practice symptom, sign are obviously improved, and the syndrome integration reduces 〉=70%.
2.3 effectively: tcm clinical practice symptom, sign all take a favorable turn, the syndrome integration reduces 〉=30%.
2.4 invalid: tcm clinical practice symptom, sign all do not have obvious improvement, even increase the weight of, the syndrome integration reduces＜30%.Annotate: computing formula (nimodipine method) is [integration before (integration before the treatment-treatment back integration) ÷ treatment] * 100%.
3 relevant physico-chemical examination indexs
According to main its meaning of physico-chemical examination index mutation analysis before and after the treatment.
Six, clinical observation result
During clinical observation, situations of change such as the symptom behind the recording medicine, picture of the tongue, pulse condition.After observe finishing, sum up comprehensively and accurately, enumeration data is with Ridit and X
2Check, continuous data is checked with T.Itemized record are wanted in action method, dosage, indication and untoward reaction to medicine, and make correct evaluation.Efficacy evaluation will have two above attending doctors to participate in, and writes out the observation brief summary.
1. health giving quality observed result
1.1 clinical treatment cerebral arteriosclerosis expectorant stasis of blood mutual resistance card efficacy analysis is asked for an interview table 15:
Table 15 traditional Chinese medical science disease efficacy analysis
1.2 two groups of cardinal symptom situations of change see Table 16 before and after the treatment:
Cardinal symptom situation of change before and after table 16 treatment
1.3 table 17 is asked for an interview in the influence of picture of the tongue, pulse condition:
Situation of change before and after table 17 picture of the tongue, the pulse condition treatment
1.4 the influence to blood fat, hemorheology index, blood pressure, rheoencephalogram and examination of ocular fundus before and after the treatment sees Table 18,19,20,21:
Blood Lipid situation before and after table 18 treatment
Hemorheology index situation of change before and after table 19 treatment
Blood pressure situation before and after table 20 treatment
Rheoencephalogram, examination of ocular fundus and electrocardiogram situation of change before and after table 21 treatment
1.5 treatment group and matched group onset time relatively ask for an interview table 22:
The comparison of table 22 treatment group and matched group onset time
By The above results as seen, pharmaceutical composition of the present invention has curative effect preferably to treatment cerebral arteriosclerosis expectorant stasis of blood mutual resistance card, to expand its dizziness and headache, insomnia forgetfulness or drowsiness, heavy dusk, symptom such as apathetic expression, breast gastral cavity painful abdominal mass are vexed, numb limbs and tense tendons and picture of the tongue, pulse condition improve significantly; Obviously blood fat reducing, blood pressure improve hemorheology index, rheoencephalogram and ocular fundus arteriosclerosis degree, improve electrocardiogram.The treatment group is imitated and is better than the matched group NAODESHENG PIAN, and onset time treatment group obviously shortens than matched group; Rheoencephalogram improves and ocular fundus arteriosclerosis alleviates degree treatment group relatively there were significant differences (P＜0.05) with matched group, all the other every index two group difference not statistically significants (equal P＞0.05).
2. safety observed result
Before and after the treatment treatment group is partly observed case and carry out routine blood test, routine urinalysis, the inspection of liver function kidney merit, no abnormality seen.The results are shown in Table 23:
Routine blood test, routine urinalysis situation of change before and after table 23 treatment
During clinical observation, treatment group and matched group are observed case and are not found untoward reaction.
Observe conclusion: pharmaceutical composition of the present invention is to develop according to Traditional Chinese medical theory and in conjunction with modern Chinese medicine Chinese medicine research achievement, has benefiting QI for activating blood circulation, supports that essence is filled out marrow, the turbid expectorant effect that disappears, and is used for the treatment of cerebral arteriosclerosis.During 10～December in 2003, invention medicine composite for curing cerebral arteriosclerosis expectorant stasis of blood mutual resistance card is carried out clinical efficacy and safety is observed, and compare with NAODESHENG PIAN.Clinical patient's 61 examples that meet the mutual resistance of the case choice criteria cerebral arteriosclerosis expectorant stasis of blood of observing altogether, wherein 31 examples are organized in treatment, matched group 30 examples, treatment group clinic control rate is 16.1%, and obvious effective rate is 35.5%, and total effective rate is 93.5%; Matched group clinic control rate is 10.0%, and obvious effective rate is 26.7%, and total effective rate is 83.3%.
Pharmaceutical composition of the present invention to expand dizziness and headache, insomnia forgetfulness or drowsiness, heavy dusk, symptom such as apathetic expression, breast gastral cavity painful abdominal mass are vexed, numb limbs and tense tendons and picture of the tongue, pulse condition improve significantly; Obviously blood fat reducing, blood pressure improve the blood flow table and learn index, rheoencephalogram and ocular fundus arteriosclerosis degree, improve electrocardiogram.Treatment group curative effect is better than the matched group NAODESHENG PIAN, and onset time treatment group obviously shortens than matched group; Rheoencephalogram improves and ocular fundus arteriosclerosis alleviates degree treatment group relatively there were significant differences (P＜0.05) with matched group, all the other every index two group difference not statistically significants (equal P＞0.05).
Before and after the treatment part is observed the patient and detect routine blood test, routine urinalysis, hepatic and renal function, there is no unusually, do not find untoward reaction during the clinical observation.
Clinical test results shows: medicine composite for curing cerebral arteriosclerosis determined curative effect of the present invention has no side effect clinical practice safety.
Claims (9)
1. a pharmaceutical composition for the treatment of cerebral arteriosclerosis is made by following bulk drugs: Radix Polygoni Multiflori Preparata 30-40 part, Radix Astragali 30-40 part, Radix Salviae Miltiorrhizae 25-35 part, Radix Puerariae 25-35 part, Folium Ginkgo 25-35 part, Rhizoma Chuanxiong 25-35 part, Rhizoma Alismatis 25-35 part, Rhizoma Gastrodiae 20-30 part, Ramulus Uncariae Cum Uncis 20-30 part.
2. according to the pharmaceutical composition of claim 1, it is characterized in that the weight portion of each crude drug is: 35 parts of Radix Polygoni Multiflori Preparatas, 35 parts of the Radixs Astragali, 30 parts of Radix Salviae Miltiorrhizaes, 30 parts of Radix Puerariaes, 30 parts of Folium Ginkgos, 30 parts of Rhizoma Chuanxiongs, 30 parts of Rhizoma Alismatis, 25 parts in Rhizoma Gastrodiae, 25 parts of Ramulus Uncariae Cum Uncis.
3. according to the pharmaceutical composition of claim 1, it is characterized in that being prepared into oral formulations according to the Chinese medicine preparation conventional method.
4. according to the pharmaceutical composition of claim 3, it is characterized in that described oral formulations is oral liquid, pill, capsule, tablet, powder or granule.
5. according to the pharmaceutical composition of claim 4, it is characterized in that described oral formulations is a tablet.
6. method for preparing the pharmaceutical composition of claim 1 may further comprise the steps:
(1) take by weighing each raw material by following weight portion:
Radix Polygoni Multiflori Preparata 30-40 part, Radix Astragali 30-40 part, Radix Salviae Miltiorrhizae 25-35 part, Radix Puerariae 25-35 part, Folium Ginkgo 25-35 part, Rhizoma Chuanxiong 25-35 part, Rhizoma Alismatis 25-35 part, Rhizoma Gastrodiae 20-30 part, Ramulus Uncariae Cum Uncis 20-30 part;
(2) Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae, Radix Puerariae, Folium Ginkgo, Rhizoma Alismatis are used alcohol reflux respectively, and merge extractive liquid, filters, and reclaim under reduced pressure gets extractum A; Residual medicine dreg is standby;
(3) Rhizoma Chuanxiong extracts volatile oil, collects the volatile oil beta-cyclodextrin inclusion compound, and it is standby to get dry clathrate; Residual medicine dreg is standby;
(4) step (2) and (3) residual medicine dreg and the Radix Astragali, Rhizoma Gastrodiae, Ramulus Uncariae Cum Uncis are decocted with water; Filter, filtrate decompression adds ethanol precipitation after concentrating again, leaves standstill, and filters, and decompression filtrate recycling ethanol gets extractum B;
(5) extractum A, B and dry clathrate are merged, add adjuvant, spray drying is made finished product through preparations shaping technology.
7. according to the method for claim 6, it is characterized in that in the above-mentioned preparation method, in the step (2) with Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae, Radix Puerariae, Folium Ginkgo, Rhizoma Alismatis with 75% alcohol reflux 2 times, refluxing for the first time adds the ethanol of 8 times of weight of medical material, reflux, extract, 2 hours, and refluxing for the second time adds the ethanol of 6 times of weight, reflux, extract, 1.5 hours, merge extractive liquid, filters, and it is that 80 ℃ of relative densities when measuring are 1.10 pure extractum A that filtrate decompression is concentrated into temperature; When step (3) is extracted Rhizoma Chuanxiong volatile oil, Rhizoma Chuanxiong was added water retting 30 minutes, amount of water is 8 times of weight of Rhizoma Chuanxiong, and extraction time is 4 hours; When volatile oil was used beta-cyclodextrin inclusion compound, the beta-schardinger dextrin-addition was to be that 40 minutes, enclose temperature are 40 ℃ 6 times of weight, the enclose time of volatile oil; With step (2) and (3) residual medicine dreg and the Radix Astragali, Rhizoma Gastrodiae, when Ramulus Uncariae Cum Uncis decocts with water, decoct with water 2 times, decoct the water that adds 10 times of weight of medical material for the first time in the step (4), decocted 2 hours, decoction for the second time adds the water of 8 times of weight, decocts 1.5 hours; Collecting decoction filters, and it is that 80 ℃ of relative densities when measuring are 1.15 aqueous extract that filtrate decompression is concentrated into temperature, reuse 65% ethanol carries out precipitate with ethanol, left standstill 48 hours, and filtered, the filtrate pressurization is reclaimed ethanol and is concentrated into temperature is that 80 ℃ of relative densities when measuring are 1.10 extractum B.
8. by the method for quality control of the made tablet of the pharmaceutical composition of claim 1, comprise following content:
(1) character: be Film coated tablets, remove and show yellowish-brown behind the film-coat; Mildly bitter flavor is puckery;
(2) adopting thin layer chromatography that the Radix Astragali, Radix Puerariae, Rhizoma Chuanxiong and Radix Salviae Miltiorrhizae are carried out thin layer differentiates;
(3) adopt high effective liquid chromatography for measuring 2,3,5,4
/-tetrahydroxystilbene-2-O-β-D-glucoside content, every contains Radix Polygoni Multiflori Preparata with 2,3,5,4
/-tetrahydroxystilbene-2-O-β-D-glucoside meter must not be less than 0.40mg.
9. any pharmaceutical composition of claim 1-5 is preparing the purposes for the treatment of in the cerebral arteriosclerosis disease drug.
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| 脑动脉硬化症的中医药治疗进展. 封银曼等.河南中医，第21卷第3期. 2001 * |
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