CN114642707A

CN114642707A - A Chinese medicinal composition comprising herba Erigerontis, Ginseng radix, radix Ophiopogonis, and fructus Schisandrae

Info

Publication number: CN114642707A
Application number: CN202011517641.6A
Authority: CN
Inventors: 林艳和
Original assignee: Yunnan Biovalley Pharmaceutical Co ltd
Current assignee: Yunnan Biovalley Pharmaceutical Co ltd
Priority date: 2020-12-21
Filing date: 2020-12-21
Publication date: 2022-06-21
Also published as: WO2022135329A1

Abstract

The invention belongs to the field of medicines, and discloses a pharmaceutical composition containing erigeron breviscapus, ginseng, dwarf lilyturf tuber and schisandra chinensis extracts, which comprises common oral dosage forms such as capsules, tablets, oral liquid, dropping pills or granules.

Description

Medicinal composition containing erigeron breviscapus, ginseng, ophiopogon root and schisandra chinensis

Technical Field

The invention relates to the field of medicines, in particular to an erigeron breviscapus and pulse-activating effective part extract, a preparation method and application thereof, and especially application in preparing medicines for treating cardiovascular and cerebrovascular diseases.

Background

In recent years, with the aging of the population of China accelerating, the urbanization degree deepening and the gradual change of life style, the disease spectrum also changes greatly. Chronic non-infectious diseases such as hypertension, coronary heart disease, diabetes and the like are widely prevalent, and the incidence of various diseases (including cardiovascular and cerebrovascular diseases, lower limb arteriosclerosis, vascular dementia and the like) caused by vascular embolism also tends to increase rapidly.

The prescription for treating cardiovascular and cerebrovascular diseases is formed by screening and optimizing, is added on the basis of the traditional classic prescription of pulse-activating powder, takes erigeron breviscapus, ginseng, schisandra chinensis and ophiopogon japonicus as raw materials, and the Chinese patent medicine generally has folk medicine history, but the drug effect of the Chinese patent medicine is different due to the change of medicine taste. Wherein, breviscapine (capable of dilating arteriole, reducing blood viscosity, improving brain circulation) and caffeic acid ester (antioxidant, antiinflammatory, antiviral, anti-fibrosis, inhibiting smooth muscle contraction, and reducing blood lipid) contained in herba Erigerontis are enriched; lignanoid in fructus Schisandrae has antiinflammatory, antioxidant, antiviral, blood vessel dilating, nerve protecting, and ulcer inhibiting effects; the high isoflavone compounds in the ophiopogon root have the activity of resisting myocardial ischemia; the ginsenoside in Ginseng radix has effects of treating neurodegenerative diseases in nervous system, improving memory function, protecting brain tissue, resisting arrhythmia, myocardial hypertrophy, myocardial ischemia and myocardial apoptosis in cardiovascular system, inducing apoptosis, inhibiting tumor cell proliferation, regulating signal path, and regulating immunity.

Disclosure of Invention

The invention aims to provide a medicinal composition of erigeron breviscapus, ginseng, dwarf lilyturf tuber and schisandra chinensis, which has controllable quality and high stability. Meanwhile, the composition is a composition of each effective component obtained by refining each medicine.

The invention is implemented by the following technical scheme.

The invention provides a medicinal composition containing erigeron breviscapus, ginseng, dwarf lilyturf tuber and schisandra chinensis, which is characterized in that: the weight ratio of the erigeron breviscapus in the raw materials of the composition is 70 percent and less than or equal to 90 percent, and the total weight of the ginseng, the dwarf lilyturf tuber and the Chinese magnoliavine fruit in the raw materials of the composition is 10 to 30 percent. Preferably, 70 percent of erigeron breviscapus is less than or equal to 90 percent, 1.5 to 7.5 percent of ginseng, 1.5 to 7.5 percent of Chinese magnoliavine fruit and 2 to 15 percent of dwarf lilyturf tuber; wherein the ginseng, the dwarf lilyturf tuber and the Chinese magnoliavine fruit are prepared from the following raw materials in parts by weight: schisandra chinensis: the ratio of radix Ophiopogonis to radix Ophiopogonis is 1:1: 2.

At present, similar technologies of similar erigeron breviscapus extracts supplemented with pulse-activating effective parts exist in the market, but the process of the erigeron breviscapus extracts is obviously different from that of the invention, so that the obtained effective parts have large component and content difference. The invention has the advantages that the effective components in the four medicines can be better gathered to remove harmful components and inactive components due to the upgrading of the extraction technology, and the effective component composition has better effect on various diseases caused by thrombus, in particular chronic cerebral ischemic diseases.

In the preferred embodiment of the invention, the composition is prepared from the following raw material medicines, by weight, 70.5% -90% of erigeron breviscapus, 3% -7.3% of ginseng, 3% -7.3% of schisandra chinensis and 4% -14.9% of radix ophiopogonis. More preferably, the composition is prepared from the following raw material medicines, by weight, 71% -85% of erigeron breviscapus, 4.5% -7.2% of ginseng, 4.5% -7.2% of schisandra chinensis and 6-14.6% of radix ophiopogonis.

More preferably, the composition is prepared from the following raw material medicines, by weight, 71.4% -80% of erigeron breviscapus, 5% -7.15% of ginseng, 5% -7.15% of schisandra chinensis and 10% -14.3% of radix ophiopogonis.

More preferably, the composition is prepared from (by weight ratio) herba Erigerontis 71.4-75%, Ginseng radix 6-7.15%, fructus Schisandrae 6-7.15%, and radix Ophiopogonis 13-14.3%.

The content of each component of the composition of the invention is selected within the above proportioning range and the sum is 100%.

The medicinal composition is prepared by the following steps:

extracting herba Erigerontis with 10-90% aqueous ethanol, and concentrating the extractive solution under reduced pressure to obtain extract; dissolving the extract in water, adjusting the pH value to 7-9, filtering, adjusting the pH value to 1-3 by adding acid, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with ethanol, adjusting the pH value to 7-8 by adding alkali, filtering, and spray-drying to obtain powder 1; adjusting the pH value of the acidified filtrate to 7-9, clarifying with a ceramic microfiltration membrane, concentrating the clarified liquid obtained after clarification with an organic nanofiltration membrane, passing the concentrated liquid through a polyamide chromatographic column, eluting with water, eluting with ethanol, collecting ethanol eluate, adjusting the pH value to 7-9 after concentration, filtering, and spray-drying the filtrate to obtain powder 2;

extracting Ginseng radix with ethanol under reflux, filtering, mixing filtrates, concentrating under reduced pressure to obtain fluid extract, adding 3-15 times of purified water to obtain Ginseng radix clear solution, clarifying with ceramic microfiltration membrane, concentrating the clear solution with organic nanofiltration membrane, and collecting the concentrated solution. Extracting radix Ophiopogonis with ethanol under reflux, filtering, mixing filtrates, concentrating under reduced pressure to obtain extract, adding water into the extract for precipitation, removing water layer, and collecting precipitate;

decocting fructus Schisandrae with water, removing water solution, adding ethanol, reflux-extracting, filtering, mixing filtrates, concentrating under reduced pressure to obtain extract, adding water to obtain fructus Schisandrae clear liquid, clarifying with ceramic microfiltration membrane, concentrating clarified liquid with organic nanofiltration membrane to obtain fructus Schisandrae clear paste, extracting with ethyl acetate, collecting ethyl acetate extractive solution, and concentrating under reduced pressure to obtain extract;

mixing and dissolving the ginseng concentrated solution, the dwarf lilyturf tuber precipitate and the schisandra chinensis extract, spray-drying to obtain powder 3, and combining the powder 1, the powder 2 and the powder 3 to obtain the pharmaceutical composition.

Compared with the effect achieved by the existing process, the beneficial effect of the product obtained by the process method has outstanding characteristics and remarkable progress. The erigeron breviscapus extract containing scutellarin and caffeoylquinic acid has high chlorophyll content, and the present invention adopts the said technological process and ceramic micro filtering film to eliminate great amount of insoluble macromolecular impurity chlorophyll, tannin, protein, etc. to clarify the extracted liquid. The clear liquid is concentrated by an organic nanofiltration membrane, so that the concentration cost can be reduced, most pyromeconic acid can be removed, and water-soluble small molecular impurities and inactive related substances are removed to the maximum extent; further utilizes column chromatography to remove the impurities which are difficult to remove such as pyromeconic acid, etc. and harmful to human body, and retains the active component caffeic acid ester, specially dicaffeic acid ester, so that the purity and yield of effective component can be raised.

The invention also provides a preparation method of the composition, which comprises the following steps: extracting herba Erigerontis with 10-90% ethanol, and concentrating the extractive solution under reduced pressure to obtain extract; dissolving the extract in water, adjusting the pH value to 7-9, filtering, adjusting the pH value to 1-3 by adding acid, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with ethanol, adjusting the pH value to 7-8 by adding alkali, filtering, and spray-drying to obtain powder 1; adjusting the pH value of the acidified supernatant to 7-9, clarifying with a ceramic microfiltration membrane, concentrating the clarified liquid obtained after clarification with an organic nanofiltration membrane, passing the concentrated liquid through a polyamide chromatographic column, eluting with water, eluting with ethanol, collecting ethanol eluate, concentrating, and spray-drying to obtain powder 2; extracting Ginseng radix with 80-85% ethanol under reflux twice, filtering, mixing filtrates, concentrating under reduced pressure to obtain fluid extract, adding 3-15 times of purified water into Ginseng radix fluid extract to obtain Ginseng radix clear solution, clarifying with ceramic membrane, concentrating the clear solution with organic nanofiltration membrane, and collecting the concentrated solution. Reflux-extracting radix Ophiopogonis with 80-85% ethanol twice, filtering, mixing filtrates, concentrating under reduced pressure to obtain extract, precipitating with 15 times of water, removing water layer, and collecting precipitate;

decocting fructus Schisandrae with water, removing water solution, adding ethanol, reflux-extracting, filtering, mixing filtrates, concentrating under reduced pressure to obtain extract, adding water to obtain fructus Schisandrae clear liquid, clarifying with ceramic microfiltration membrane, concentrating clarified liquid with organic nanofiltration membrane to obtain fructus Schisandrae clear paste, extracting with ethyl acetate, collecting ethyl acetate extractive solution, and concentrating under reduced pressure to obtain extract; mixing the Ginseng radix concentrated solution, radix Ophiopogonis precipitate, and fructus Schisandrae chinensis extract, dissolving, spray drying to obtain powder 3, mixing powder 1, powder 2, and powder 3 to obtain the pharmaceutical composition, adding appropriate amount of adjuvants, and making into oral solid preparation (oral compound preparation such as hard capsule, soft capsule, tablet, dripping pill, oral liquid or granule).

The membrane separation technology is used for directly clarifying, purifying by stages and concentrating traditional Chinese medicine and plant water extract, the clarified membrane can directly remove impurities such as boot-like substances, colloid, plant fibers, bacteria for macromolecular protein and the like, the permeate liquid is clarified and has high purity, and the concentrated membrane can remove salt and water to obtain high-purity concentrated solution. The method has the advantages of 1, reducing investment and construction cost of production hardware, 2, reducing working procedures and shortening production period, 3, no need of heating in the separation of physical process, reducing degradation and loss of effective components, 4, high separation precision and capability of effectively removing suspended particles, thalli, tannin, colloid, protein, starch and other impurities. And the concentration membrane can effectively remove water, inorganic salts and small molecules.

According to the pore size, the method can be divided into micro-filtration (pore size is larger than 50nm), ultra-filtration (pore size is 2-50 nm, molecular weight cut-off is 1000-million), nano-filtration (pore size is 0.5-5nm, molecular weight cut-off is 100-1000) and other types.

The clarifying membrane is a microfiltration membrane in a ceramic membrane, and the ceramic membrane is an asymmetric membrane formed by preparing a ceramic material through a special process. Most of ceramic membranes used in the market are microfiltration membranes, and a few of the ceramic membranes can achieve the ultrafiltration level. When the separation is carried out, under the action of external force, the small molecular substances permeate the membrane, and the large molecular substances are intercepted by the membrane, thereby achieving the purposes of separation, concentration, purification, impurity removal, sterilization and the like. The ceramic membrane also has the characteristics of low regeneration cost, long service life, stable process, simple operation and the like, and the preferred aperture is 100nm-200 nm.

The concentration membrane used in the method is an organic nanofiltration membrane, preferably 300D-400D (D is dalton abbreviated). Molecules with a molecular weight of 300D or 400D can be retained. Water and other small molecular substances permeate the membrane to achieve certain separation and concentration effects.

The preparation method of the medicinal composition of erigeron breviscapus, ginseng, dwarf lilyturf tuber and schisandra chinensis is mainly characterized in that the medicaments are respectively extracted and refined:

the main purpose of respectively extracting and refining is to enrich the active ingredients according to the properties of different types of active ingredients and remove harmful ingredients and inactive ingredients, so that the substances entering the body have stronger activity and better treatment effect. The prior purification method has the following technical problems:

firstly, the proposed erigeron breviscapus extract has high chlorophyll content and is not easy to be processed cleanly, thereby not only affecting the color of the extract, but also affecting the yield and the medicinal effect of other medicinal extracts even if the extract is processed.

Then, and more importantly, the extract contains a significant amount of the harmful component pyromeconic acid, which needs to be removed. Due to the existence of a large amount of chlorophyll, the chlorophyll is attached to the resin when the chlorophyll is loaded on the column, is not easy to elute, and increases the regeneration time and difficulty of the resin. This is also an important factor affecting the efficacy and safety of the drug.

In the prior art, only flavonoid ingredients in erigeron breviscapus are used as medicines, namely acidified precipitates are used as medicines, and the other active ingredient caffeic acid ester is lost.

Therefore, the extraction by alcohol reflux alone and then alkali dissolution acidification are adopted, and only the acidified precipitate is used as the medicine, so that the method is a coarse extraction method, and the effective components in the erigeron breviscapus cannot be well used as the medicine.

In the prior art, ginseng, dwarf lilyturf tuber and Chinese magnoliavine fruit are mixed and extracted, and are used as medicines after n-butyl alcohol extraction. The n-butanol has high polarity, low extraction efficiency and high boiling point, and is not easy to be completely removed by concentration, and the spray-dried powder is easy to have residues. Affecting the safety and quality of the medicine. The method adopted by the invention is as follows:

extracting herba Erigerontis with aqueous alcohol (10-90%, preferably 40-60%, more preferably 45-55%, most preferably 50%), and concentrating under reduced pressure to obtain extract (relative density of 1.15-1.25, 75 deg.C); dissolving the extract in water, adjusting the pH value to 7-9, filtering, adjusting the pH value to 1-3 by adding acid, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with ethanol, adjusting the pH value to 7-8 by adding alkali, and spray-drying to obtain powder 1. The purpose of this step is to extract the flavone component in erigeron breviscapus, the main substance is scutellarin.

Adjusting the pH value of the filtrate to 7-9, and clarifying by using a ceramic microfiltration membrane to remove a large amount of insoluble macromolecular impurities under a neutral condition; the clarified supernatant is then concentrated with an organic nanofiltration membrane, which on the one hand reduces the cost of concentration, and on the other hand removes most of the pyromeconic acid, which is much more water-soluble than liposoluble and of lower molecular weight, only 112. Loading the membrane concentrated solution into 30-60 mesh amide chromatographic column at a ratio of 1:1, adsorbing overnight, eluting with water for 4 column volumes, eluting with 55-75% ethanol, collecting ethanol eluate, concentrating, and spray drying to obtain powder 2. The key point of the step is to further remove pyromeconic acid and enrich the required caffeic acid ester components, especially the dicaffeic acid ester components, so that the high pharmaceutical activity of the extract is ensured.

Extracting Ginseng radix with 80-85% ethanol under reflux twice, filtering, mixing filtrates, concentrating under reduced pressure to obtain fluid extract, adding 3-15 times of purified water into the fluid extract to obtain Ginseng radix clear solution, clarifying with ceramic microfiltration membrane, concentrating the clarified solution with organic nanofiltration membrane, and collecting the concentrated solution. This step effectively removes macromolecular insoluble impurities such as protein starch and the like and micromolecular water-soluble substances in the ginseng extract, and the enriched ginsenoside Rg1, Rb1, Re and other components. Extracting radix ophiopogonis twice with 80-85% ethanol under reflux, filtering, combining filtrates, concentrating under reduced pressure to obtain an extract, adding 15 times of water into the extract for precipitation, removing a water layer, and collecting the precipitate for later use. The flavanone and saponin components of the dwarf lilyturf tuber are enriched, polysaccharide components are removed, the influence of spray drying on the components in the later period is large, and if the components are too much, the powder spraying fails.

Decocting fructus Schisandrae with water once, removing water solution, removing organic acids, adding 80-85% ethanol, reflux-extracting twice, filtering, mixing filtrates, concentrating under reduced pressure to obtain extract, adding water to obtain fructus Schisandrae clear liquid, clarifying with ceramic microfiltration membrane, concentrating the clarified clear liquid with organic nanofiltration membrane to obtain fructus Schisandrae clear paste, extracting with ethyl acetate, collecting ethyl acetate extractive solution, and concentrating under reduced pressure to obtain extract. The ceramic membrane is firstly used for clarification to remove macromolecular impurities such as tannin, protein and the like, and then the organic membrane is used for concentration, so that the concentration cost can be reduced, and the membrane is used for removing small molecular water-soluble substances such as malic acid, tartaric acid, protocatechuic acid, quinic acid and the like, and then the extraction is carried out, so that the extraction efficiency can be improved, and the aim of enriching lignanoid components in the schisandra chinensis can be achieved.

Mixing the concentrated solution of Ginseng radix, radix Ophiopogonis extract and fructus Schisandrae extract, dissolving in water, spray drying to obtain powder 3, adding appropriate amount of adjuvants into the powder 1,2,3, and making into oral compound preparation such as hard capsule, soft capsule, tablet, dripping pill, oral liquid or granule.

The method comprises diluting with water by weight.

In the composition, the erigeron breviscapus extract powder 1 containing flavone and the erigeron breviscapus total caffeic acid ester extract powder 2 containing 4, 5-di-O-caffeoylquinic acid account for 50-55% by weight, and the erigeron breviscapus extract powder 3 containing ginseng, dwarf lilyturf tuber and Chinese magnoliavine fruit accounts for 44-49% by weight.

In the above-mentioned preparation method of components of medicinal composition, the described alkali can be used for regulating pH value of solution by using NaOH and Na₂CO₃,NaHCO₃、KOH、K₂CO₃Or KHCO₃(ii) a The pH value of the acid adjusting solution is HCl and H₂SO₄Or H₃PO₄(ii) a The concentration of ethanol eluted by the polyamide chromatographic column is 50-95%.

The invention also provides a preparation containing the medicinal composition, the preparation is an oral solid preparation, the preparation also contains pharmaceutically acceptable auxiliary materials, the medicinal composition accounts for 70-99% of the weight of the preparation, and the balance is the auxiliary materials. The oral preparation is preferably a capsule.

The invention also provides a pharmaceutical composition obtained by the following method:

extracting herba Erigerontis with aqueous ethanol (10-90%, preferably 40-60%, more preferably 45-55%, most preferably 50%), and concentrating under reduced pressure to obtain extract; dissolving the extract in water, adjusting the pH value to 7-9, filtering, adjusting the pH value to 1-3 by adding acid, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with ethanol, adjusting the pH value to 7-8 by adding alkali, filtering, and spray-drying to obtain powder 1; adjusting the pH value of the acidified supernatant to 7-9, clarifying with a clarifying membrane (a ceramic microfiltration membrane), concentrating the clarified liquid with a concentrating membrane (an organic nanofiltration membrane), passing the concentrated liquid through a polyamide chromatographic column, eluting with water, eluting with ethanol, collecting ethanol eluate, concentrating, and spray-drying to obtain powder 2;

extracting Ginseng radix with ethanol under reflux, filtering, mixing filtrates, concentrating under reduced pressure to obtain fluid extract, adding 3-15 times of purified water into Ginseng radix fluid extract to obtain Ginseng radix clear solution, clarifying with ceramic membrane, concentrating the clear solution with organic nanofiltration membrane, and collecting the concentrated solution. Extracting radix Ophiopogonis with ethanol under reflux, filtering, mixing filtrates, concentrating under reduced pressure to obtain extract, adding water into the extract for precipitation, removing water layer, and collecting precipitate;

decocting fructus Schisandrae with water, discarding water solution, adding ethanol, reflux-extracting, filtering, mixing filtrates, concentrating under reduced pressure to obtain extract, adding water to obtain fructus Schisandrae clear solution, clarifying with ceramic membrane, clarifying to obtain clarified solution, concentrating with organic membrane to obtain fructus Schisandrae fluid extract, extracting with ethyl acetate, collecting ethyl acetate extractive solution, concentrating under reduced pressure to obtain extract, respectively dissolving radix Ginseng concentrated solution and radix Ophiopogonis, respectively dissolving fructus Schisandrae extract, spray drying to obtain powder 3, and mixing powder 1, powder 2 and powder 3 to obtain the pharmaceutical composition.

The preferred proportion of the raw materials is 70.5-90% of erigeron breviscapus, 3-7.3% of ginseng, 3-7.3% of schisandra chinensis and 4-14.9% of radix ophiopogonis. More preferably, the breviscapine is 71-85%, the ginseng is 4.5-7.2%, the schisandra fruit is 4.5-7.2%, and the ophiopogon root is 6-14.6%.

Compared with the effect achieved by the existing process, the beneficial effect obtained by the process method has obvious characteristics and progress. The erigeron breviscapus extract comprises scutellarin and caffeoylquinic acid, the content of chlorophyll in the erigeron breviscapus extract obtained by the extraction method in the prior art is high, the chlorophyll is an inactive substance, and the caffeic acid ester part is discarded, after the alkali dissolution and acidification of the aqueous alcohol extract, an acidified precipitate is a flavonoid component which is firstly precipitated, then the pH of the acidified supernatant is adjusted to 7-9, and the supernatant is clarified by a ceramic membrane, so that a large amount of macromolecular impurities which are not dissolved under a neutral condition can be removed; the clarified liquid is concentrated by organic membrane to reduce the cost and remove most pyromeconic acid because its water solubility is much higher than liposolubility. Passing the membrane concentrated solution through polyamide chromatographic column, eluting with water, eluting with ethanol, collecting ethanol eluate, performing gradient elution with polyamide column to remove water soluble impurities and inactive related substances to the maximum extent, and retaining active ingredient caffeic acid ester, especially dicaffeoic acid ester; the extraction solvent uses aqueous alcohol to extract effective substances to the maximum extent, so that most of macromolecular impurities which are insoluble in water, such as chlorophyll, are removed by a ceramic membrane, and small-molecular water-soluble components, particularly pyromeconic acid, are removed by an organic membrane. Further utilizes column chromatography to remove the impurities which are difficult to remove and are harmful to human body, such as pyromeconic acid, etc. so as to raise the purity and yield of effective component. The extracts of ginseng, dwarf lilyturf tuber and Chinese magnoliavine fruit obtained by the extraction method in the prior art have the following defects: all the three ingredients are extracted together and then extracted by using n-butyl alcohol, the n-butyl alcohol is used for extraction, the extraction efficiency is low, the n-butyl alcohol is easy to emulsify due to large intersolubility with water, particularly, the recovered n-butyl alcohol is large in water content and low in extraction efficiency, extracted components are more in inactive components, namely more in impurities, and the n-butyl alcohol is high in energy source used during recovery due to high boiling point and easy to have residues. The invention adopts a separation and extraction method, wherein ginseng is filtered and concentrated by adopting an alcohol extraction membrane, and ginsenoside components are mainly enriched; radix Ophiopogonis adopts alcohol extraction and water precipitation method to mainly enrich high isoflavone and radix Ophiopogonis saponin components and remove oligosaccharide components; the schisandra chinensis is extracted by water once to remove organic acid substances, then is extracted by alcohol, macromolecular components are removed by a clarifying membrane, water-soluble acidic components are removed by an organic concentrating membrane, and then the schisandra chinensis is extracted by ethyl acetate to mainly enrich lignanoid components. The content of the definite active ingredients of the spray-dried powder obtained in the refining process is improved, the purity of the active substances is improved, and the content of the active ingredients is easy to control, so that the batch consistency and the stability of the medicine are greatly improved.

The invention also provides a medicinal preparation prepared from the medicinal composition, such as capsules, tablets, oral liquid and the like, and a proper amount of auxiliary materials, such as capsules, are added according to the conventional preparation process, wherein the added auxiliary materials account for 1-30% of the total weight of the capsules, and the capsules containing the medicinal composition are obtained through the conventional capsule filling process.

The invention also provides the application of the medicinal composition in preparing medicaments for treating ischemic cardiovascular and cerebrovascular diseases, in particular chronic ischemic cardiovascular and cerebrovascular diseases, wherein the diseases comprise cardiovascular and cerebrovascular diseases, lower limb arteriosclerosis, cerebral infarction, stroke, coronary heart disease, hyperlipidemia, vascular dementia, other cognitive dysfunction and the like, and the medicinal composition can be used for preventing and treating ischemic cardiovascular and cerebrovascular diseases, lower limb arteriosclerosis obliterans, vascular cognitive dysfunction and other cognitive disorders.

By improving the existing preparation process (existing process administration group-erigeron pulse-activating pharmacopoeia method and prescription (existing process), the invention process administration group-example 1)

1.1 Experimental animals

Male SD rats, 200, weighing 300 g. + -. 25g, were purchased from Experimental animals technology, Inc. of Wei Tong Hua, Beijing. The animal is bred in the animal experiment center without special pathogen of the institute of medicine of Chinese medical science, under the conditions of 12-hour light/dark cycle, constant temperature and humidity (23 +/-2 ℃ and 55 +/-5 percent), and is bred and adapted for two weeks before the experiment. The experimental animals can be freely drunk, and the research complies with the regulations specified by animal experiment ethics committee of the institute of medicine of Chinese academy of medicine.

1.2 standards and reagents

Water, deionized water, a product of Hangzhou Wahaha company; sodium pentobarbital, product of Sigma-Aldrich, analytical grade; chloral hydrate, national pharmaceutical group chemical reagent limited, analytically pure; formaldehyde, national chemical group chemical reagent limited, analytically pure; superoxide dismutase (SOD) and Malondialdehyde (MDA) determination kit, purchased from Nanjing reagent company; BCA protein quantification kit, purchased from Thermo Fisher Scientific; normal saline, science, ltd, kawa; the breviscapine pulse-activating spray dry powder (batch number: 20150110) is provided by Yunnan biological grain pharmaceutical industry GmbH.

1.3 instrumentation

The Morris water maze device (model DMS-2) is developed by the institute of medicine of Chinese academy of medical sciences; light-absorbing microplate reader, products of TECAN corporation; a METTLER TOLEDO ten-thousandth electronic balance, a product of METTLER corporation, switzerland.

The rats began the animal experiment two weeks after acclimation. A rat model with chronic cerebral ischemic injury is prepared by a bilateral common carotid artery ligation (2VO) method. The experimental rats are fasted for 12 hours before operation, water is forbidden for 4 hours, the anesthetic is 2% sodium pentobarbital aqueous solution, the administration dose is 60mg/kg, and the rats are anesthetized by intraperitoneal injection. The anesthetized rat is fixed on a rat board in a supine position, the skin in the middle of the neck is cut after the alcohol cotton ball is sterilized, and tissues of all layers are separated in a blunt manner, so that the vagus nerve and the trachea are particularly prevented from being damaged. The bilateral common carotid arteries were exposed and separated, ligated with 5.0 silk thread, and sutured with 0 silk thread. The sham group only performed "common carotid artery exposure and dissection" without ligation, followed by suture with 0 gauge silk. And performing a Morris water maze positioning navigation training experiment 3 weeks after the operation, continuing for 5 days, inspecting whether the model is successfully established, and screening the model-making rats. The screening criteria were: (mean latency-reference value)/mean latency >0.2 (wherein the reference value is the mean of the latencies of the rats in the sham operation group, and the mean latency is the mean of the latencies of the model-making rats), that is, the rat is considered to have cognitive impairment and the model-making is successful.

Rats successfully modeled were randomly divided into a model group and a model administration group, and 3 groups were added to the sham operation group. Each group of rats had 14 rats, 10 of which were used for lipidomics and polar small molecule metabolomics analysis and 4 for pathological section analysis. The model administration group continuously injects the erigeron breviscapus pulse-activating spray dry powder (0.72g/kg, i.g.) for 30 days, and Morris water maze test is carried out on the last 5 days of the administration period to judge whether the erigeron breviscapus pulse-activating spray dry powder has drug effect. The Morris water maze test is carried out for 5 days including the positioning navigation training experiment, and the space exploration experiment is carried out after the last day of the positioning navigation training experiment is finished.

Morris Water maze test

The Morris water maze device is developed by the institute of medicine of Chinese academy of medical sciences, and has the model of DMS-2. The diameter of the water maze is 1.2m, the height is 0.5m, the water maze is cylindrical, the inner wall is black, the water maze is divided into 4 quadrants, a black platform with the diameter of 10cm is arranged inside the water maze, the water maze is positioned at the underwater 1cm position of the third quadrant, and the internal water temperature is controlled to be 22-25 ℃.

(1) Positioning navigation experiment: the experimental rats were trained once a day in the morning and afternoon. In the morning, the rat is placed at the edge 1/2 of the first quadrant, heading towards the pool wall and recording the time to reach the platform. If not after 60s, it is guided to the platform and left for 20 s; rats found the platform by themselves and allowed to remain on the platform for 20 s. In the afternoon, the rats were placed at the edge 1/2 of the fourth quadrant and the other experiments were as described above.

(2) Space exploration experiment: the platform was removed and the rat was placed at the edge 1/2 of the first quadrant, and the water was introduced head towards the pool wall, and the time at which the rat first reached the platform position was recorded. If the rat does not reach the platform, the retention time of the rat in the target quadrant within 60s, namely the effective retention time, is recorded to measure the spatial learning and memory ability of the rat. The external environment is kept consistent in the whole experiment process, such as light, article placement and the like in an experiment room, and experiment operators are controlled not to exceed 2 persons, so that the interference of external factors is eliminated.

In the water maze positioned navigation experiment, the influence of the erigeron breviscapus pulse on the incubation period of the rats after the Morris water maze training test is shown in Table 1. The model group has significant difference (P <0.001) compared with the incubation period of the sham operation group, which indicates that the model is successfully made; the incubation period time of the erigeron breviscapus pulse-activating administration group and the model group has significant difference (P is less than 0.001), which shows that the erigeron breviscapus pulse-activating administration group has good drug effect of improving the learning and memory abilities of rats compared with the model group.

Table 1. influence of Erigerontis pulse on the incubation period of rats after Morris water maze training test

Note: the P value is a t test result, and the P value of the model group is a model group vs sham operation group; p value of dosing group is V s model group of breviscapine pulse group

The space exploration experiment is that the platform is removed on day 6, the time from the water entering of the rat to the first time reaching of the platform position, the times of passing through the platform and the residence time of the rat in a target quadrant within 60s, namely the effective residence time are recorded and used as indexes for measuring the space learning and memory capacity of the rat, and the result is shown in table 2. The effective residence time, the first platform finding time and the platform finding times of the model group and the false operation group are compared, and the significant differences (P <0.01) indicate that the model is successfully made; the effective residence time, the time for finding the platform for the first time and the frequency for finding the platform of the erigeron breviscapus pulse-activating administration group and the model group are all significantly different (P is less than 0.05), which shows that the erigeron breviscapus pulse-activating administration group has good drug effect for improving the learning and memory abilities of rats compared with the model group.

TABLE 2. influence of Breviscaping pulse-activating capsule on the ability of space exploration after removal of the platform in Morris Water maze test

Note: the P value is a t test result, and the P value of the model group is a vs sham operation group; model group with dosage group P value of vs

The spatial navigation training is a combined learning known by looking up related documents, the formed memory is spatial reference memory, and when the rodent completes the tasks of spatial learning and memory, a large number of brain areas and nerve conduction paths are involved, at least the hippocampus, the cortex, the striatum, the basal forebrain and the cerebellum are involved. The hippocampal cells are considered as the original basis of spatial learning and memory in a directional navigation experiment, the postsynaptic potential enhancement (LTP) of the dentate gyrus of the hippocampus can be kept for a plurality of weeks at most, which is needed by learning and memory, and the hippocampal cells play an important role in the early memory formation process; in the space exploration experiment, cells in parts such as hippocampus, cortex region and the like are required to act together, and the damage of the cortex has great influence on the storage of long-term memory. The incubation periods of the erigeron breviscapus pulse administration group and the model group in a positioning navigation experiment are significantly different, which shows that the medicament has a certain repairing effect on the injured cells of the hippocampus; in a space exploration experiment, the erigeron breviscapus pulse-activating administration group and the model group data have significant difference, which shows that the erigeron breviscapus pulse-activating administration group and the model group data have good drug effect.

Analysis of biochemical index data

Test method

Rat plasma and brain tissue samples were thawed at 4 ℃, brain tissue samples were homogenized with physiological saline, and Superoxide dismutase (SOD) activity and Malondialdehyde (MDA) content were measured according to the instructions, respectively. The SOD determination adopts xanthine oxidase, the MDA determination adopts thiobarbituric acid precipitation, and the specific operation is carried out according to the kit specification.

Chronic cerebral ischemia is a complex injury process including oxidative stress, inflammatory response, abnormal energy metabolism, neurotransmitter disturbance, neuronal damage, and the like. Oxidative stress is mainly characterized by increased production of Reactive Oxide Species (ROS) and reduced ability to scavenge free radicals, which causes a large amount of free radicals to accumulate in tissues and cause damage to tissues and cells. Under physiological conditions, the oxidation and anti-oxidation systems of the body are in dynamic balance. SOD is the main antioxidant enzyme in the organism, can protect cells from being damaged by active oxides, and the content of SOD can reflect the ability of the organism to remove free radicals and active oxides. MDA is a product of lipid peroxidation of organisms, the content of MDA can reflect the damage degree of tissue cells attacked by free radicals, so that the determination of SOD and MDA can evaluate the drug effects of a 2VO chronic cerebral ischemia rat model and a breviscapine pulse.

Biochemical index measurement data (table 3) show that the MDA content of brain tissue and plasma is highest in a 2VO rat cerebral ischemia model group, the model administration group has a downward trend, the model group has a significant difference (P <0.05) compared with a pseudo-operation group, and the model administration group has a significant difference (P <0.05) compared with the model group. The SOD activity values are all the lowest in a model group, the SOD activity values have an ascending trend after administration, and the model group has significant difference (P is less than 0.05) compared with a sham operation group; the model group had significant differences compared to the model group (P < 0.05). The biochemical index measurement data show that after the bilateral common carotid artery is permanently ligated and modeled, the brain tissue of the rat generates obvious oxidative stress injury, the MDA content of the model after administration is reduced compared with that of the model group, and the SOD activity is obviously improved, which shows that the erigeron breviscapus pulse-activating has certain function of improving the oxidative stress injury.

TABLE 3 Biochemical index results in rat plasma and brain tissue

And (4) conclusion:

a rat model with chronic cerebral ischemia is established by adopting a bilateral common carotid artery permanent ligation method (2VO), the rat is divided into a pseudo operation model and a pseudo model, four groups of drug delivery are carried out by the prior art and the invented process, and pharmacodynamic evaluation is carried out 30 days after the model drug delivery group continuously injects stomach and delivers breviscapine pulse (DZSM). After the model is made, the cells in the hippocampus CA1 area of the brain tissue are obviously damaged, the cell damage is obviously improved after the administration of the erigeron breviscapus pulse activating drug, and the process set of the invention is superior to the prior process set; the water maze behavioural test data shows that the erigeron breviscapus pulse-activating has the effect of improving the learning and memory abilities of rats with chronic cerebral ischemia injury, and the process group of the invention is superior to the prior process group; the analysis data of biochemical indexes shows that the rat produces certain oxidative stress injury after cerebral ischemia injury, the erigeron breviscapus has certain effect of improving the oxidative stress injury after pulse-activating administration, and the process set of the invention is superior to the prior process set. The evaluation results of the behavioral indexes, the biochemical indexes and the pathological sections show that: the model is successfully established and is kept stable in the administration period, the brain ischemic injury is obviously improved after the administration of the breviscapine pulse generating drug, and the process set of the invention is superior to the prior process set.

Compared with the conventional method, the method has the advantages that even if the composition with the same proportion is used, the contents of the obtained chemical active ingredients and impurities are greatly different, particularly, the contents of the active ingredients such as scutellarin, 4, 5-di-O-caffeoylquinic acid, ginsenoside, schisandrin and the like in the total mixed powder are increased by more than 20 percent, and various impurities such as chlorophyll, pyromeconic acid, polysaccharide and tannin can be removed by more than 90 percent at the lowest. The extraction process of herba Erigerontis and other three medicines are respectively extracted, wherein the herba Erigerontis is extracted with ethanol, and then is subjected to alkali dissolution and acidification to obtain precipitate. And only the precipitate is used as the medicine, the caffeic acid esters as the other active ingredients in the erigeron breviscapus are directly discarded, and unreasonable factors exist in the determination of the content of the 4, 5-di-O-caffeoylquinic acid in the determination of the content.

Therefore, the preparation prepared by the new preparation method, such as capsules and the like, enriches active ingredients, reduces impurities, can better improve the drug effect, saves resources, improves the controllability of the drug quality, and increases the effectiveness and the safety of the drug.

TABLE 4 comparison of scutellarin content in erigeron breviscapus extracted with ethanol of different concentrations

The extraction content of 50% ethanol and 75% ethanol is the highest from the content of scutellarin in the extraction liquid, and the extraction content of 50% ethanol is selected from the cost consideration.

TABLE 5 ingredient content change table after membrane filtration after pH adjustment of acidified supernatant of erigeron breviscapus

As can be seen from table 5, after adjusting pH of erigeron acid supernatant to be close to neutral, dicaffeonate, an effective substance, is better retained after passing through a clarification membrane and a nanofiltration concentration membrane, while pyromeconic acid, a harmful substance, is removed by 84%.

TABLE 6 Schizandra chinensis extract content variation before and after membrane filtration

Name of article	Typical quantity (L)	Content (mg/ml)	Total amount (g)
				Fructus Schisandrae chinensis extractive solution	100	0.27	27.00
After the microfiltration and clarification membrane treatment	125	0.17	21.25
				After the nanofiltration concentration membrane treatment	32.1	0.57	18.30

As can be seen from Table 6, the total schizandrol A content after passing through the clarifying membrane and the concentrating membrane is kept above 67%.

TABLE 7 ginsenoside content changes before and after passing through membrane

As can be seen from Table 7, the ginsenosides Rg1, Rb1 and Re in the ginseng extract are greatly retained after being clarified and concentrated by a membrane, and are respectively retained by 95%, 89% and 96%.

The specific implementation mode is as follows:

example 1: preparation of crude drug extract

Decocting herba Erigerontis 2000g with 50% aqueous ethanol twice, each for 2 hr, filtering, mixing filtrates, and concentrating under reduced pressure to obtain extract (relative density of 1.15-1.25, 75 deg.C); dissolving the extract with 5 times of water, adding 5% sodium hydroxide solution while stirring, adjusting the pH value to 7.5-8.5, filtering, adding 10% sulfuric acid solution to adjust the pH value to 1-3, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with ethanol, adding 5% sodium hydroxide to adjust the pH value to 7-8, and spray-drying to obtain powder 1; adjusting the pH value of the acidified filtrate to 7-9, clarifying with a 100nm ceramic membrane, concentrating the clarified liquid with a 350D organic membrane, passing the concentrated liquid through a 30-60-mesh polyamide chromatographic column (the diameter and length ratio is 1:4), eluting with water for 3 column volumes, eluting with 65% ethanol for 4 column volumes, collecting ethanol eluate, concentrating, and spray-drying to obtain powder 2;

taking 200g of ginseng, adding 80-85% ethanol for reflux extraction twice, filtering, combining filtrates, concentrating under reduced pressure to obtain an extract, adding 10 times of water for dilution, clarifying with a 100nm ceramic membrane, and concentrating the clarified liquid with a 350D organic membrane to obtain a concentrated solution for later use.

Taking 400g of radix ophiopogonis, adding 80-85% ethanol for reflux extraction twice, filtering, combining filtrates, concentrating under reduced pressure to obtain an extract, adding 12-15 times of water into the extract for precipitation, removing a water layer, and collecting the precipitate for later use.

Taking 200g of schisandra chinensis, adding water for decocting once, pouring out once water extraction in order to remove most of organic acid, otherwise, too much extract is not beneficial to enriching lignin, discarding the water solution, adding 80-85% ethanol for reflux extraction twice, filtering, combining the filtrates, concentrating under reduced pressure to obtain an extract, adding water to prepare a schisandra chinensis clear solution, clarifying with a 100nm ceramic membrane, concentrating the clarified clear solution with a 350D organic membrane to obtain a schisandra chinensis clear paste, extracting the clear paste with ethyl acetate, collecting an ethyl acetate extract, and concentrating under reduced pressure to obtain an extract for later use. Mixing the concentrated solution of Ginseng radix, radix Ophiopogonis precipitate, and fructus Schisandrae chinensis extract, dissolving, spray drying to obtain powder 3, and mixing powder 1,2, and 3 uniformly to obtain brown material extract 144 g.

The scutellarin content in the obtained powder 1 is 520mg/g, and powder 1, 34g is obtained; the powder 2 contains 35mg/g of 4, 5-di-O-caffeoylquinic acid to obtain 2, 43g of powder; the powder 3 contains ginsenoside Rg1+ Re 5.5mg/g and schizandrol A3.8 mg/g to obtain powder 3, 67 g. After the powder 1, the powder 2 and the powder 3 are mixed, the content of scutellarin is 129mg/g, the content of 4, 5-di-O-caffeoylquinic acid is 12.8mg/g, the content of ginsenoside Rg1+ Re is 2.4mg/g and the content of schizandrol A is 3.9 mg/g.

Example 2: preparation of crude drug extract

Decocting herba Erigerontis 3000g with 50-60% aqueous ethanol twice, each for 2 hr, filtering, mixing filtrates, and concentrating under reduced pressure to obtain extract (relative density of 1.15-1.25, 75 deg.C); dissolving the extract with 5 times of water, adding 5% sodium hydroxide solution while stirring, adjusting the pH value to 7-9, filtering, adding 10% hydrochloric acid solution to adjust the pH value to 1-3, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with ethanol, adding 5% sodium hydroxide to adjust the pH value to 7-8, and spray-drying to obtain powder 1;

adjusting the pH value of the acidified filtrate to 7-9, clarifying with a 200nm ceramic membrane, concentrating the clarified liquid with a 400D organic membrane, passing the concentrated liquid through a 30-60-mesh polyamide chromatographic column (the diameter to length ratio is 1:4), eluting with 3 column volumes of water, eluting with 3 column volumes of 70% ethanol, collecting the ethanol eluate, concentrating, and spray-drying to obtain powder 2;

taking 200g of ginseng, adding 80-85% ethanol for reflux extraction twice, filtering, combining filtrates, concentrating under reduced pressure to obtain clear paste, adding 6 times of water for dilution, clarifying with a 200nm ceramic membrane, and concentrating the clarified liquid with a 400D organic membrane to obtain a concentrated solution for later use. Taking 400g of radix ophiopogonis, adding 80-85% ethanol for reflux extraction twice, filtering, combining filtrates, concentrating under reduced pressure to obtain an extract, adding 15 times of water into the extract for precipitation, removing a water layer, and collecting the precipitate for later use. Taking 200g of schisandra chinensis, adding water for decocting once, removing an aqueous solution, adding 80-85% ethanol for reflux extraction twice, filtering, combining filtrates, concentrating under reduced pressure to obtain an extract, adding water to prepare a schisandra chinensis clear liquid, clarifying with a 200nm ceramic membrane, concentrating the clarified clear liquid with a 400D organic membrane to obtain a schisandra chinensis clear paste, extracting the clear paste with ethyl acetate, collecting an ethyl acetate extract, and concentrating under reduced pressure to obtain an extract for later use. Dissolving Ginseng radix concentrated solution, radix Ophiopogonis precipitate and fructus Schisandrae chinensis extract in water, spray drying to obtain powder 3, and mixing powder 1,2,3 to obtain brown material extract 171 g.

The scutellarin content in the obtained powder 1 is 478mg/g, and powder 1, 42g is obtained; powder 2 contains 36mg/g of 4, 5-di-O-caffeoylquinic acid, and powder 2: 53g of a soybean milk powder; the powder 3 contains ginsenoside Rg1+ Re 5.1mg/g and schizandrol A4.2 mg/g to obtain powder 3, 76 g. After the powder 1, the powder 2 and the powder 3 are mixed, the content of scutellarin is 117mg/g, the content of 4, 5-di-O-caffeoylquinic acid is 16mg/g, the content of ginsenoside Rg1+ Re2.3mg/g and the content of schizandrol A is 1.9 mg/g.

Example 3: preparation of crude drug extract

Adding 2500g of herba Erigerontis into 40-50% aqueous ethanol, decocting twice for 2 hr each time, filtering, mixing filtrates, and concentrating under reduced pressure to obtain extract (relative density of 1.15-1.25, 75 deg.C); dissolving the extract with 5 times of water, adding 5% sodium hydroxide solution while stirring, adjusting the pH value to 7.5-9.0, filtering, adding 10% sulfuric acid solution to adjust the pH value to 1-3, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with ethanol, adding 5% sodium hydroxide to adjust the pH value to 7-8, and spray-drying to obtain powder 1;

adjusting the pH value of the acidified filtrate to 7-9, clarifying with a 100nm ceramic membrane, concentrating the clarified liquid with a 300D organic membrane, passing the concentrated liquid through a 30-60-mesh polyamide chromatographic column (the diameter-length ratio is 1:4), eluting with 3.5 column volumes of water, eluting with 3 column volumes of 75% ethanol, collecting the ethanol eluate, concentrating, and spray-drying to obtain powder 2;

taking 200g of ginseng, adding 80-85% ethanol for reflux extraction twice, filtering, combining filtrates, concentrating under reduced pressure to obtain an extract, adding 8 times of water for dilution, clarifying with a 100nm ceramic membrane, and concentrating the clarified liquid with a 300D organic membrane to obtain a concentrated solution for later use.

Taking 400g of radix ophiopogonis, adding 80-85% ethanol for reflux extraction twice, filtering, combining filtrates, concentrating under reduced pressure to obtain an extract, adding 15 times of water into the extract for precipitation, removing a water layer, and collecting the precipitate for later use. Taking 200g of schisandra chinensis, adding water for decocting once, removing a water solution, adding 80-85% ethanol for reflux extraction twice, filtering, combining filtrates, concentrating under reduced pressure to obtain an extract, adding water to prepare a schisandra chinensis clear solution, clarifying with a 100nm ceramic membrane, concentrating the clarified clear solution with a 300D organic membrane to obtain schisandra chinensis clear paste, extracting the clear paste with ethyl acetate, collecting an ethyl acetate extract, and concentrating under reduced pressure to obtain an extract for later use. Dissolving Ginseng radix extract, radix Ophiopogonis precipitate and fructus Schisandrae extract in water, spray drying to obtain powder 3, and mixing powder 1,2, and 3 to obtain brown material extract 166 g. The content of scutellarin in the obtained powder 1 is as follows: 530mg/g to obtain powder 1, 38g, and powder 2 contains 38mg/g of 4, 5-di-O-caffeoylquinic acid to obtain powder 2, 47 g; the powder 3 contains ginsenoside Rg1+ Re 5.2mg/g and schizandrol A6.3 mg/g to obtain powder 3, 81 g. After the powder 1, the powder 2 and the powder 3 are mixed, the content of scutellarin is 121mg/g, the content of 4, 5-di-O-caffeoylquinic acid is 10.8mg/g, the content of ginsenoside Rg1+ Re is 2.5mg/g and the content of schizandrol A is 3.1 mg/g.

The inventor also simultaneously and respectively uses 10%, 30%, 40%, 45%, 50%, 55%, 60%, 75% and 90% of aqueous ethanol to extract erigeron breviscapus, other steps are the same as the example 1, spray dry powder is obtained after acidification and membrane concentration, experiments prove that the erigeron breviscapus extract can be obtained by 10-90% of ethanol extraction, but the extract obtained by ethanol with the concentration of more than 40% is relatively better than the ethanol extract with the concentration of less than 40%, the ethanol extract with the concentration of 40-60% is obviously better and more suitable for the process of the invention, and the erigeron breviscapus is extracted by ethanol with the concentration of 50% most preferably.

Example 4: preparation of capsules

And (3) adding 52g of starch into 128g of the extract prepared in the example 1, uniformly mixing, and filling into capsules to obtain the capsule.

Example 5: preparation of capsules

And (3) taking 151g of the extract prepared in the example 2, adding 29g of starch, uniformly mixing, and filling into capsules to obtain the capsule.

Example 6: preparation of capsules

And (3) taking 142g of the extract prepared in the example 1, adding 34g of starch and 4g of magnesium stearate, uniformly mixing, and filling into capsules to obtain the capsule.

Example 7: preparation of tablets

Taking 151g of the extract prepared in example 2, 100g of starch and 10g of dextrin, sieving with a 14-mesh sieve, granulating, carrying out ventilation drying at 60-70 ℃, and adding 3g of magnesium stearate. Making into tablet and coating.

Example 8: preparation of dropping pills

Taking 15g of the extract prepared in the embodiment 3, adding 45g of the extract and polyethylene glycol 4000, uniformly mixing, melting, dripping into low-temperature liquid paraffin, selecting pills, and removing the liquid paraffin to obtain the traditional Chinese medicine composition.

Example 9 preparation of oral liquid

Mixing 20g of the extract prepared in example 1 with 300g of honey, 50g of sucrose, 2g of sodium benzoate and 300ml of distilled water, heating for dissolving, and filtering at constant temperature to obtain the traditional Chinese medicine composition.

Example 10: preparation of granules

And (3) taking 9g of the extract prepared in the example 3, uniformly mixing with 40g of microcrystalline cellulose, adding a 3% povidone ethanol solution to prepare a soft material, sieving with a 18-mesh sieve to prepare granules, drying at 600 ℃ for 30-45 minutes, grading, adding 4g of talcum powder, uniformly mixing, grading and bagging to obtain the compound vitamin E tablet.

Example 11: quality standard test

The embodiment 1 of the pharmaceutical composition is not only due to the composition proportion, but also due to the fact that the invention provides a novel pharmaceutical preparation method, in order to further prove the high efficiency of the preparation method, the technical comparison is carried out with the conventional mixed alcohol reflux and n-butanol extraction method, and the obtained data are as follows:

TABLE 8 comparison of the extraction process of the formulation of example 1 used in the present invention

Therefore, according to the comparison, the content of the effective components is not reduced while the total extract powder is reduced by the novel method, but the active component caffeic acid esters in the erigeron breviscapus are further used. Pyromeconic acid is also undetectable by conventional methods because it is not a caffeic acid ester component, but rather the hepatotoxic pyromeconic acid is contained in the caffeic acid ester component (in the acidified supernatant). The proportion of each active ingredient in the spray-dried powder is improved by more than 40 percent due to the reduction of impurity ingredients, the impurity is reduced by more than 30 percent, the preparation method has obvious technical progress, the drug effect and the safety of the medicine are certainly improved, unexpected technical effects are obtained, and the preparation method has innovation. The same traditional Chinese medicine composition is used, and the preparation prepared by the method can be made smaller on the basis of preparing the same amount of preparations, so that the compliance of the medicine is improved. The dosage of the medicine powder with the same amount can increase the ratio of the effective components, so that the medicine effect is stronger.

Claims

1. A medicinal composition containing erigeron breviscapus, ginseng, dwarf lilyturf tuber and schisandra chinensis is characterized in that: the weight ratio of the erigeron breviscapus in the raw materials of the composition is 70 percent and less than or equal to 90 percent, and the weight ratio of the ginseng, the dwarf lilyturf tuber and the Chinese magnoliavine fruit in the raw materials of the composition is 10 percent and less than or equal to 30 percent.

2. The pharmaceutical composition of claim 1, wherein the composition is prepared from 70% of herba Erigerontis less than or equal to 90%, 1.5% -7.5% of Ginseng radix, 1.5% -7.5% of fructus Schisandrae chinensis, and 2% -15% of radix Ophiopogonis.

3. The pharmaceutical composition of claim 2, wherein the composition is prepared from (by weight ratio) erigeron breviscapus 70.5-90%, ginseng 3-7.3%, schisandra chinensis 3-7.3%, and ophiopogon root 4-14.9%.

4. The pharmaceutical composition of claim 3, wherein the composition is prepared from (by weight ratio) erigeron breviscapus 71-85%, ginseng 4.5-7.2%, schisandra fruit 4.5-7.2%, ophiopogon root 6-14.6%.

5. The pharmaceutical composition of claim 4, wherein the composition is prepared from (by weight ratio) erigeron breviscapus 71.4-80%, ginseng 5-7.15%, schisandra chinensis 5-7.15%, and ophiopogon root 10-14.3%.

6. The pharmaceutical composition of claim 5, wherein the composition is prepared from (by weight ratio) erigeron breviscapus 71.4-75%, ginseng 6-7.15%, schisandra chinensis 6-7.15%, and ophiopogon root 13-14.3%.

7. The pharmaceutical composition of any one of claims 1-6, wherein the ginseng, ophiopogon root, and schisandra fruit are in a weight ratio of ginseng: schisandra chinensis: the ratio of radix Ophiopogonis to radix Ophiopogonis is 1:1: 2.

8. The pharmaceutical composition of claim 6, wherein the composition is prepared from the following raw materials, by weight, 71.43% erigeron breviscapus, 7.14% ginseng, 7.14% schisandra chinensis and 14.29% ophiopogon japonicus.

9. A process for preparing a pharmaceutical composition according to claim 1, which process comprises:

extracting herba Erigerontis with 10-90% aqueous ethanol, and concentrating the extractive solution under reduced pressure to obtain extract; dissolving the extract in water, adjusting the pH value to 7-9, filtering, adjusting the pH value to 1-3 by adding acid, standing overnight, filtering, collecting filtrate and precipitate, refining the precipitate with ethanol, adjusting the pH value to 7-8 by adding alkali, filtering, and spray-drying to obtain powder 1;

adjusting the pH value of the acidified filtrate to 7-9, clarifying with a ceramic microfiltration membrane, concentrating the clarified liquid obtained after clarification with an organic nanofiltration membrane, passing the concentrated liquid through a polyamide chromatographic column, eluting with water, eluting with ethanol, collecting ethanol eluate, adjusting the pH value to 7-9 after concentration, filtering, and spray-drying the filtrate to obtain powder 2;

extracting Ginseng radix with ethanol under reflux, filtering, mixing filtrates, concentrating under reduced pressure to obtain fluid extract, adding 3-15 times of purified water to obtain Ginseng radix clear solution, clarifying with ceramic microfiltration membrane, concentrating the clarified solution with organic nanofiltration membrane, and keeping the concentrated solution;

extracting radix Ophiopogonis with ethanol under reflux, filtering, mixing filtrates, concentrating under reduced pressure to obtain extract, adding water into the extract for precipitation, removing water layer, and collecting precipitate;

decocting fructus Schisandrae with water, removing water solution, adding ethanol, reflux-extracting, filtering, mixing filtrates, concentrating under reduced pressure to obtain extract, adding water to obtain fructus Schisandrae clear liquid, clarifying with ceramic microfiltration membrane, concentrating the clarified liquid with organic nanofiltration membrane to obtain fructus Schisandrae clear paste, extracting with ethyl acetate, collecting ethyl acetate extractive solution, and concentrating under reduced pressure to obtain extract;

mixing and dissolving the ginseng concentrated solution, the dwarf lilyturf tuber precipitate and the Chinese magnoliavine fruit extract, spray-drying to obtain powder 3, and combining the powder 1, the powder 2 and the powder 3 to obtain the pharmaceutical composition.

10. The use of the pharmaceutical composition of claim 1 in the preparation of medicaments for treating ischemic cardiovascular and cerebrovascular diseases, especially chronic cerebral ischemic diseases.