WO2022135329A1 - Composition pharmaceutique contenant erigerontis herba, ginseng radix et rhizoma, ophiopogonis radix et schisandrae chinensis fructus - Google Patents
Composition pharmaceutique contenant erigerontis herba, ginseng radix et rhizoma, ophiopogonis radix et schisandrae chinensis fructus Download PDFInfo
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- WO2022135329A1 WO2022135329A1 PCT/CN2021/139599 CN2021139599W WO2022135329A1 WO 2022135329 A1 WO2022135329 A1 WO 2022135329A1 CN 2021139599 W CN2021139599 W CN 2021139599W WO 2022135329 A1 WO2022135329 A1 WO 2022135329A1
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- extract
- ginseng
- schisandra chinensis
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Definitions
- the invention relates to the field of medicine, in particular to an extract of Dengzhan Asarum plus effective parts of Shengmai and a preparation method and application thereof, especially the application in the preparation of medicines for treating cardiovascular and cerebrovascular diseases.
- the prescription for treating cardiovascular and cerebrovascular diseases of the present invention is formed through screening and optimization. It is based on the traditional classical prescription Shengmai Powder with added flavor, and uses Dengzhan Asarum, ginseng, Schisandra, and Ophiopogon japonicus as raw materials. Chinese patent medicines generally have a history of folk medicine, but Its medicinal effect is often different due to the change of medicinal taste. In the present invention, all four raw materials are extracted, purified and micronized to be prepared. active ingredients, while removing toxic and inactive ingredients, allowing for improved efficacy without increasing oral doses.
- breviscapine can dilate arterioles, reduce blood viscosity, improve cerebral circulation
- caffeic acid antioxidant, anti-inflammatory, antiviral, anti-fibrosis, inhibit smooth muscle
- the lignans in Schisandra chinensis have anti-inflammatory, antioxidant, antiviral, vasodilating, nerve-protecting and ulcer-inhibiting effects; the high isoflavones in Ophiopogon japonicus have anti-myocardial ischemia activity; Ginsenosides in ginseng have the effects of treating neurodegenerative diseases, improving memory function, and protecting brain tissue in the nervous system.
- anti-tumor it has the effects of inducing apoptosis, inhibiting tumor cell proliferation, regulating signaling pathways, and regulating immune function.
- the purpose of the present invention is to provide a medicinal composition of Dengzhan Asarum, Panax ginseng, Ophiopogon japonicus and Schisandra chinensis with controllable quality and high stability. At the same time, it is a composition of each active ingredient obtained by refining each herbal medicine.
- the present invention is implemented through the following technical solutions.
- the invention provides a medicinal composition containing Dengzhan Asarum, ginseng, Ophiopogon japonicus and Schisandra chinensis, which is characterized in that: the weight ratio of Dengzhan Asarum medicinal materials in the raw materials of the composition is 70% ⁇ Dengzhan Asarum ⁇ 90% %, the total weight of ginseng, Ophiopogon japonicus and Schisandra in the raw materials of the composition is 10-30%.
- the composition is prepared from the following raw materials by weight: 70.5%-90% of Asarum radix, 3%-7.3% of ginseng, 3%-7.3% of Schisandra chinensis, 4% of Ophiopogon japonicus -14.9%. More preferably, the composition is prepared from the following raw materials by weight: 71%-85% of Asarum sinensis, 4.5%-7.2% of ginseng, 4.5%-7.2% of Schisandra chinensis, and 6-14.6% of Ophiopogon japonicus.
- the composition is prepared from the following raw materials by weight: 71.4%-80% of Asarum sinensis, 5%-7.15% of ginseng, 5%-7.15% of Schisandra chinensis, and 10-14.3% of Ophiopogon japonicus.
- the composition is prepared from the following raw materials by weight: 71.4%-75% of Asarum brevis, 6%-7.15% of ginseng, 6%-7.15% of Schisandra chinensis, and 13-14.3% of Ophiopogon japonicus.
- each component of the composition of the present invention should be selected within the above-mentioned ratio range and the sum should be 100%.
- composition of the present invention is prepared by the following method:
- ginseng Take ginseng, add ethanol for reflux extraction, filter, combine the filtrates, concentrate under reduced pressure to form a clear paste, add 3-15 times purified water to the ginseng clear paste to prepare adult ginseng clear liquid, use ceramic microfiltration membrane for clarification, and use organic
- the nanofiltration membrane is concentrated, and the concentrate is used for later use.
- Get Ophiopogon japonicus add ethanol for reflux extraction, filter, merge filtrate, concentrate under reduced pressure into extract, extract add water to precipitate, discard water layer, collect precipitation for subsequent use;
- Schisandra chinensis Take Schisandra chinensis, add water to decoct, discard the aqueous solution, add ethanol to reflux for extraction, filter, combine the filtrates, concentrate under reduced pressure to form an extract, add water and prepare a clear liquid of Schisandra chinensis with ceramic microfiltration membrane for clarification, and the clarified liquid obtained after clarification
- the organic nanofiltration membrane is used for concentration again to obtain Schisandra chinensis clear paste, which is extracted with ethyl acetate, and the ethyl acetate extract is collected and concentrated under reduced pressure to form an extract for subsequent use;
- the beneficial effect of the product obtained by the above-mentioned process method has outstanding characteristics and remarkable progress.
- the scutellaria scutellariae extract comprising scutellarin and caffeoylquinic acid
- the scutellaria scutellariae extract obtained by the prior art extraction method has high chlorophyll content.
- Insoluble macromolecular impurities such as chlorophyll, tannin, protein, etc., make the extract clear.
- the clarified liquid is then concentrated with an organic nanofiltration membrane, which can reduce the concentration cost, and can also remove most of the pyroconic acid, maximizing the removal of water-soluble small molecular impurities and inactive related substances; further use column chromatography to remove Difficult to remove impurities such as pyroconic acid that are harmful to the human body are removed, and the active ingredient caffeic acid ester, especially dicaffeoate, is retained, and the purity and yield of the active ingredient are improved.
- the present invention also provides a method for preparing the above composition.
- the method includes: extracting Dengzhan Asarum and adding aqueous ethanol (10-90%), and concentrating the extract under reduced pressure into an extract; adding water to dissolve the extract, and adjusting the pH to 7- 9, filter, add acid to adjust pH 1 ⁇ 3, leave overnight, filter, collect filtrate and precipitate, precipitate with ethanol, add alkali to adjust pH value to 7 ⁇ 8, filter, spray-dry to obtain powder 1; the acidification The pH value of the supernatant is adjusted to 7-9, clarified with a ceramic microfiltration membrane, and the clarified liquid obtained after clarification is then concentrated with an organic nanofiltration membrane.
- Schisandra chinensis Take Schisandra chinensis, add water to decoct, discard the aqueous solution, add ethanol to reflux for extraction, filter, combine the filtrates, concentrate under reduced pressure to form an extract, add water and prepare a clear liquid of Schisandra chinensis with ceramic microfiltration membrane for clarification, and the clarified liquid obtained after clarification
- Concentrate with an organic nanofiltration membrane again to obtain Schisandra clear paste which is extracted with ethyl acetate, collect the ethyl acetate extract, and concentrate under reduced pressure to form an extract for subsequent use; mix the ginseng concentrate, Ophiopogon japonicus precipitation, and Schisandra extract Dissolve, spray-dry to obtain powder 3, combine powder 1, powder 2, and powder 3 to obtain the described pharmaceutical composition, add an appropriate amount of auxiliary materials, and prepare the described oral solid preparation (hard capsule, soft capsule, tablet, drop Oral compound medicines such as pills, oral liquids or granules).
- Membrane separation technology is used for direct clarification, fractional purification and concentration of traditional Chinese medicine and plant water extracts.
- the clarified membrane can directly remove impurities such as boot quality, colloids, plant fibers, and bacteria for macromolecular proteins.
- the permeate is clear and has high purity.
- the concentrating membrane can remove salt and water to obtain a high-purity concentrate. Its advantages are 1. Reduce the investment and construction cost of production hardware, 2. Reduce the process and shorten the production cycle, 3.
- the physical process separation does not require heating, reducing the degradation and loss of effective components, 4.
- the separation accuracy is high, and it can effectively remove suspended particles, bacteria, Tannin, colloid, protein, starch and other impurities. While concentrating membranes can effectively remove water, inorganic salts and small molecules.
- the pore size it can be divided into microfiltration (pore size greater than 50nm), ultrafiltration (pore size 2-50nm, molecular weight cut-off 1000-million), nanofiltration (pore size 0.5-5nm, molecular weight cut-off 100-1000) and other types.
- the clarification membrane in this patent adopts the microfiltration membrane in the ceramic membrane.
- the ceramic membrane is an asymmetric membrane formed by the preparation of ceramic materials through a special process. Work. Most of the ceramic membranes used on the market are microfiltration membranes, and a few can achieve ultrafiltration grades. During separation, under the action of external force, small molecular substances pass through the membrane, and macromolecular substances are retained by the membrane, so as to achieve separation, concentration, purification, impurity removal, sterilization and other purposes.
- the ceramic membrane also has the characteristics of low regeneration cost, long service life, stable process and simple operation, and the preferred pore size is 100nm-200nm.
- the concentration membrane used in this patent is an organic nanofiltration membrane, preferably 300D to 400D (D is the abbreviation of Dalton). Molecules ⁇ 300D or 400D can be retained. Allow water and other small molecules to pass through, so as to achieve a certain separation and concentration effect.
- the main purpose of separate extraction and purification is to enrich the active ingredients according to the properties of different types of active ingredients, while removing harmful and inactive ingredients, so that the substances entering the body are more active and have better therapeutic effects.
- the existing purification method has the following technical problems:
- the chlorophyll content in the proposed Dengzhanhua extract is high, and it is not easy to handle cleanly, which not only affects the color of the extract, but also affects the yield and medicinal effect of other medicinal extracts even if handled.
- the extract contains a lot of the harmful ingredient pyroconic acid, which needs to be removed. Due to the presence of a large amount of chlorophyll, the chlorophyll adheres to the resin when the column is applied, which is not easy to elute, and increases the time and difficulty of resin regeneration. This is also an important reason that affects the efficacy and safety of the drug.
- ginseng, Ophiopogon japonicus and Schisandra chinensis are combined and extracted, and n-butanol is extracted and then used as medicine. Due to the high polarity of n-butanol, the extraction efficiency is low, and the boiling point is high. It is not easy to be completely removed by concentration, and it is easy to have residues in the spray-dried powder. Affect drug safety and quality.
- the method adopted in the present invention is:
- the pH of the filtrate is adjusted to 7-9, and clarified with a ceramic microfiltration membrane, which can remove a large number of macromolecular impurities that are insoluble under neutral conditions; the clarified liquid obtained after clarification is then concentrated with an organic nanofiltration membrane, which can reduce the concentration Second, most of the pyroconic acid can be removed, because the water solubility of pyroconic acid is much higher than the fat solubility, and the molecular weight is small, only 112.
- the membrane concentrate was applied to a 30-60 mesh amide chromatography column in an amount of 1:1 column volume. After overnight adsorption, eluted with water for 4 column volumes, eluted with 55-75% ethanol, collected the ethanol eluent and concentrated. After spray drying, powder 2 was obtained. This step is to further remove pyroconic acid and enrich the required caffeic acid esters, especially dicaffeoate.
- ginseng Take ginseng, add 80-85% ethanol for reflux extraction twice, filter, combine the filtrates, and concentrate under reduced pressure to form a clear paste.
- the clear paste of ginseng is added with 3-15 times purified water to prepare adult ginseng clear liquid, which is clarified with a ceramic microfiltration membrane. , the clarified solution is then concentrated with an organic nanofiltration membrane, and the concentrated solution is used for later use. This step effectively removes macromolecular insoluble impurities such as protein starch and small molecular water-soluble substances in the ginseng extract, as well as the enriched ginsenosides Rg1, Rb1 and Re and other components.
- Ophiopogon japonicus add 80-85% ethanol to reflux for extraction twice, filter, combine the filtrates, concentrate under reduced pressure to form an extract, add 15 times the amount of water to the extract for precipitation, discard the water layer, and collect the precipitation for subsequent use.
- Ophiopogon japonicus flavanones and saponins except for polysaccharides, which have a great impact on spray drying in the later stage. If there are too many, powder spraying will fail.
- schisandra Take schisandra, add water to decoct once, discard the aqueous solution, remove organic acids, add 80-85% ethanol for reflux extraction twice, filter, combine the filtrates, concentrate under reduced pressure into extract, add water to prepare schisandra clear liquid for use
- the ceramic microfiltration membrane is used for clarification, and the clarified liquid obtained after clarification is concentrated with an organic nanofiltration membrane to obtain the clear paste of Schisandra chinensis.
- the purpose of clarification with ceramic membranes is to remove macromolecular impurities, such as tannins, proteins, etc., and then concentrate with organic membranes.
- water-soluble substances of small molecules such as malic acid, Tartaric acid, protocatechuic acid, quinic acid, etc.
- ginseng concentrate Ophiopogon japonicus extract and Schisandra chinensis extract, dissolve in water, spray dry to obtain powder 3, add powders 1, 2, 3, and add appropriate amount of auxiliary materials to prepare hard capsules, soft capsules, tablets, drop pills, Oral compound medicines such as oral liquid or granules.
- the flavonoid-containing scutellaria scutellariae extract powder 1 and the 4,5-di-O-caffeoylquinic acid-containing scutellaria scutellariae total caffeic acid ester extract powder 2 account for 50-55 percent by weight.
- %, containing ginseng, Ophiopogon japonicus, and Schisandra chinensis extract powder 3 accounted for 44-49%.
- NaOH, Na 2 CO 3 , NaHCO 3 , KOH, K 2 CO 3 or KHCO 3 are used for the pH value of the alkali adjusting solution;
- the acid adjusting solution is The pH value is HCl, H 2 SO 4 or H 3 PO 4 ;
- the ethanol concentration of the polyamide chromatographic column used for elution is 50-95%.
- the present invention also provides a preparation containing the above-mentioned pharmaceutical composition, the preparation is an oral solid preparation, the preparation also contains pharmaceutically acceptable excipients, the pharmaceutical composition accounts for 70-99% by weight of the preparation, and the balance for excipients.
- the oral formulation is preferably a capsule.
- the present invention also provides a pharmaceutical composition obtained by the following method:
- aqueous ethanol (10-90%, preferably 40-60%, more preferably 45-55%, most preferably 50%) to extract, and the extract is concentrated under reduced pressure to form an extract;
- the extract is dissolved in water and adjusted to pH 7 -9, filter, add acid to adjust pH 1 ⁇ 3, leave overnight, filter, collect filtrate and precipitate, precipitate with ethanol, add alkali to adjust pH value to 7 ⁇ 8, filter, spray dry to obtain powder 1;
- the acidified supernatant is adjusted to pH 7-9, clarified with a clarification membrane (ceramic microfiltration membrane), and the clarified solution obtained after clarification is concentrated with a concentrated membrane (organic nanofiltration membrane), and the concentrated solution is subjected to polyamide chromatography Column, eluted with water, eluted with ethanol, collected the ethanol eluent, concentrated and spray-dried to obtain powder 2;
- ginseng Take ginseng, add ethanol for reflux extraction, filter, combine the filtrates, concentrate under reduced pressure to form a clear paste, add 3-15 times purified water to the ginseng clear paste to prepare adult ginseng clear liquid, use ceramic membrane for clarification, and then use organic nanofiltration for the clear liquid The membrane is concentrated, and the concentrate is used for later use.
- Ophiopogon japonicus add ethanol for reflux extraction, filter, combine the filtrates, concentrate under reduced pressure into extract, add water to the extract for precipitation, discard the water layer, and collect the precipitation for subsequent use;
- Schisandra chinensis Take Schisandra chinensis, add water to decoct, discard the aqueous solution, add ethanol for reflux extraction, filter, combine the filtrates, concentrate under reduced pressure to form an extract, add water and prepare a clear liquid of Schisandra chinensis for clarification with a ceramic membrane, and the clarified liquid obtained after clarification is reused
- the organic membrane is concentrated to obtain the clear paste of Schisandra chinensis, the clear paste is extracted with ethyl acetate, the ethyl acetate extract is collected, and concentrated under reduced pressure into an extract for subsequent use. Powder 3 is obtained, and powder 1, powder 2, and powder 3 are combined to obtain the pharmaceutical composition.
- the proportions of the above raw materials are preferably 70.5%-90% of Asarum sinensis, 3%-7.3% of ginseng, 3%-7.3% of Schisandra chinensis, and 4%-14.9% of Ophiopogon japonicus. More preferably, 71%-85% of Asarum sinensis, 4.5%-7.2% of ginseng, 4.5%-7.2% of Schisandra, and 6-14.6% of Ophiopogon japonicus.
- the beneficial effects obtained by the process method of the present invention have significant characteristics and progress.
- the scutellaria scutellariae extract which includes scutellarin and caffeoylquinic acid
- the scutellaria extract obtained by the prior art extraction method has high chlorophyll content, chlorophyll is an inactive substance, and the caffeic acid ester part is discarded.
- the alcohol-extracted extract is acidified by alkali solution, the acidified precipitate is flavonoids, and then the pH of the acidified supernatant is adjusted to 7-9, which is clarified with a ceramic membrane, which can remove a large amount of large amount of large insoluble in neutral conditions.
- the clarified liquid obtained after clarification is concentrated with an organic membrane, which can reduce the cost of concentration and remove most of the pyroconic acid. This is because the water solubility of pyroconic acid is much higher than that of fat.
- the membrane concentrate is passed through a polyamide chromatography column, eluted with water, and then eluted with ethanol. The ethanol eluent is collected and subjected to gradient elution with a polyamide column to maximize the removal of water-soluble impurities and inactive related substances.
- the active ingredient caffeic acid ester especially dicaffeoate ester
- the extraction solvent uses hydrous alcohol
- the effective substances are extracted to the greatest extent, and most of the water-insoluble macromolecular impurities, such as chlorophyll, are removed through the ceramic membrane, and organic
- the membrane removes small water-soluble components, especially pyroconic acid.
- column chromatography is used to remove impurities such as pyroconic acid that are difficult to remove and harmful to human body, and the purity and yield of active ingredients are improved.
- the extracts of ginseng, Ophiopogon japonicus and Schisandra chinensis obtained by the prior art extraction method have the following disadvantages: all three flavors are extracted together and then extracted with n-butanol, n-butanol is extracted, and the extraction efficiency is low, due to the mutual solubility of n-butanol and water It is large and easy to emulsify, especially the recovered n-butanol has a large water content and low extraction efficiency, and the extracted components have many inactive components, that is, there are many impurities. Due to the high boiling point of n-butanol itself, the energy used during recovery is high. and easy to have residues.
- the present invention adopts a fractionation method, wherein ginseng is filtered and concentrated by alcohol extraction membrane, mainly to enrich ginsenoside components;
- Ophiopogon japonicus adopts alcohol extraction and water precipitation method to mainly enrich high isoflavones and Ophiopogon saponins components and remove oligosaccharides
- Schisandra chinensis is first extracted with water to remove organic acids, and then extracted with alcohol.
- the macromolecular components are removed through a clarifying membrane, and the water-soluble acidic components are removed by an organic concentrating membrane, and then extracted with ethyl acetate. It contains lignans.
- the spray-dried powder obtained in the refining process has clearly improved content of active ingredients, improved purity and purity of active substances, and it is easy to control the content of active ingredients, which greatly improves batch-to-batch consistency and drug stability.
- the present invention also provides pharmaceutical preparations prepared from the above-mentioned pharmaceutical compositions, such as capsules, tablets, oral liquids, etc., with reference to conventional preparation techniques, adding and appropriate amount of auxiliary materials, such as capsules, the added auxiliary materials account for 1-1% of the total weight of the capsule. 30%, through a conventional encapsulation process, a capsule containing the pharmaceutical composition of the present invention is obtained.
- the present invention also provides the application of the above-mentioned medicinal composition in the preparation of medicines for the treatment of ischemic cardiovascular and cerebrovascular diseases, especially chronic ischemic cardiovascular and cerebrovascular diseases, these diseases include cardiovascular and cerebrovascular diseases, lower extremity arteriosclerosis, brain Infarction, stroke, coronary heart disease, hyperlipidemia, vascular dementia, other cognitive dysfunction, etc., can be used to prevent and treat ischemic cardiovascular and cerebrovascular diseases, lower extremity arteriosclerosis obliterans, vascular cognitive dysfunction and other cognitive impairments .
- inventive process administration group-Example 1 By improving the existing preparation process (existing process administration group-Dengzhan Shengmai Pharmacopoeia method and formula (existing process), inventive process administration group-Example 1)
- mice Male SD rats, 200, weighing 300g ⁇ 25g, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. The animals were reared in the special pathogen-free animal experimental center of the Institute of Materia Medica, Chinese Academy of Medical Sciences, with a 12-hour light/dark cycle, under the conditions of constant temperature and humidity (23 ⁇ 2°C, 55 ⁇ 5%). They were reared for two weeks before the experiment. The experimental animals can drink water and eat freely, and the research abides by the regulations established by the Animal Experiment Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences.
- the rat model of chronic cerebral ischemic injury was prepared by bilateral common carotid artery ligation (2VO).
- the experimental rats were fasted for 12 hours and water for 4 hours before operation.
- the anesthetic was 2% sodium pentobarbital aqueous solution, and the administration dose was 60 mg/kg.
- the rats were anesthetized by intraperitoneal injection.
- the anesthetized rats were fixed in the supine position on the rat board. After disinfection with alcohol cotton balls, the skin in the middle of the neck was incised, and the layers of tissues were bluntly separated, especially to avoid damage to the vagus nerve and trachea.
- the bilateral common carotid arteries were exposed and separated, ligated with No. 5 silk thread, and sutured with No. 0 silk thread.
- the Morris water maze positioning and navigation training experiment was carried out 3 weeks after the operation, which lasted for 5 days to check whether the model was established successfully, and the model rats were screened.
- the screening criteria are: (average latency - reference value)/average latency > 0.2 (where the reference value is the average latency of the sham-operated rats, and the average latency refers to the average latency of the model rats), that is, the rat is considered to appear Cognitive impairment, modeling success.
- Rats with successful modeling were randomly divided into model group and model administration group, plus sham operation group, a total of 3 groups. There were 14 rats in each group, of which 10 were used for lipidomic and polar small molecule metabolomics analysis, and 4 were used for pathological section analysis.
- the model administration group was continuously given Dengzhan Shengmai spray dry powder (0.72g/kg, i.g.) by gavage for 30 days, and the Morris water maze test was performed on the last 5 days of the administration period to determine whether Dengzhan Shengmai had medicinal effect.
- Morris water maze test includes positioning navigation training experiment for 5 days, and space exploration experiment is carried out after the positioning navigation training experiment on the last day.
- the Morris water maze device used was developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the model is DMS-2.
- the water maze is 1.2m in diameter, 0.5m in height, cylindrical, with black inner wall. It is divided into 4 quadrants. There is a black platform with a diameter of 10cm inside, which is located 1cm below the water in the third quadrant.
- the internal water temperature is controlled at 22-25°C.
- the P value is the result of t test, the P value of the model group is the model group vs the sham operation group; the P value of the medication group is the Dengzhan Shengmai group vs the model group
- the platform was removed on the 6th day to record the time from entering the water to the first time the rats reached the platform, the number of times they crossed the platform, and the stay time in the target quadrant within 60s, that is, the effective stay time, as an index to measure their spatial learning and memory ability. , and the results are shown in Table 2.
- the P value is the result of the t test, the P value of the model group vs the sham operation group; the P value of the medication group vs the model group
- spatial navigation training is a type of joint learning, and the memory formed is spatial reference memory.
- the memory formed is spatial reference memory.
- a large number of brain regions and neural conduction pathways are involved, at least hippocampus, Involvement of cortex, striatum, basal forebrain, cerebellum.
- Hippocampal cells are considered to be the original basis of spatial learning and memory in directional navigation experiments.
- Postsynaptic potentiation (LTP) in the hippocampal dentate gyrus can be maintained for up to several weeks, which is exactly what is required for learning and memory.
- the rat plasma and brain tissue samples were thawed at 4°C, and the brain tissue samples were homogenized with normal saline.
- the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) were determined according to the instructions respectively.
- SOD superoxide dismutase
- MDA malondialdehyde
- the xanthine oxidase method was used for the SOD measurement, and the thiobarbituric acid precipitation method was used for the MDA measurement. The specific operation was carried out according to the kit instructions.
- Oxidative stress is mainly manifested in the increase of reactive oxide species (ROS) generation and the decrease in the ability to scavenge free radicals, resulting in the accumulation of a large number of free radicals in tissues, causing damage to tissues and cells.
- ROS reactive oxide species
- SOD is the main antioxidant enzyme in the body, which can protect cells from the damage of reactive oxides. The level of SOD can reflect the body's ability to scavenge free radicals and reactive oxides.
- MDA is the product of lipid peroxidation in the body, and its content can reflect the degree of damage to tissue cells by free radical attack. Therefore, the determination of SOD and MDA can evaluate the efficacy of 2VO in the rat model of chronic cerebral ischemia and Dengzhan Shengmai.
- the biochemical index measurement data (Table 3) showed that the MDA content in brain tissue and plasma was the highest in the 2VO rat cerebral ischemia model group, while the model administration group showed a downward trend. Compared with the sham operation group, the model group was significantly The difference (P ⁇ 0.05), the model administration group was significantly different from the model group (P ⁇ 0.05). The SOD activity values of the model group were the lowest, and there was an upward trend after administration. There was a significant difference between the model group and the sham operation group (P ⁇ 0.05); there was a significant difference between the model administration group and the model group (P ⁇ 0.05). P ⁇ 0.05).
- the measurement data of biochemical indicators showed that after permanent ligation of bilateral common carotid arteries, the rat brain tissue was significantly damaged by oxidative stress. Pulse has a certain effect on improving oxidative stress injury.
- the rat model of chronic cerebral ischemia was established by permanent ligation of bilateral common carotid arteries (2VO).
- the rats were divided into four groups: sham operation, model, administration by the existing technology and administration by the invention process.
- the model administration group continued After 30 days of oral administration of Dengzhan Shengmai (DZSM), pharmacodynamic evaluation was performed.
- DZSM Dengzhan Shengmai
- pharmacodynamic evaluation was performed.
- the cells in the hippocampal CA1 area of the brain tissue were significantly damaged, and the cell damage was significantly improved after the administration of Dengzhan Shengmai, and the invention technology group was superior to the existing technology group; the behavioral test data of the water maze showed that Dengzhan Shengmai could improve chronic cerebral ischemia injury.
- the invention technology group is better than the existing technology group; biochemical index analysis data show that the rat cerebral ischemic injury produces a certain oxidative stress injury, and there is a certain improvement after Dengzhan Shengmai administration The effect of oxidative stress damage, the invention technology group is better than the existing technology group.
- the evaluation results of behavioral, biochemical indicators and pathological slices showed that the model was successfully established and remained stable during the administration period, and Dengzhan Shengmai administration had a significant improvement on cerebral ischemia injury, and the invention technology group was better than the existing technology group.
- the content of chemical active ingredients and impurities obtained by this method is very different even if the same proportion of the composition is used, especially the active ingredients, such as scutellarin, 4,5-di-O -Indices such as caffeoylquinic acid, ginsenosides and schisandrin A in the total mixed powder are all increased by more than 20%, and various impurities, such as chlorophyll, pyroconic acid, polysaccharides and tannins A minimum of 90% of the class can be removed.
- active ingredients such as scutellarin, 4,5-di-O -Indices such as caffeoylquinic acid, ginsenosides and schisandrin A in the total mixed powder are all increased by more than 20%
- various impurities such as chlorophyll, pyroconic acid, polysaccharides and tannins A minimum of 90% of the class can be removed.
- Dengzhan Shengmai Capsule described in the pharmacopoeia process of Dengzhan Asarum is separately extracted from other three herbs, wherein Dengzhan Asarum is only extracted by ethanol, then alkali-dissolved and acidified to obtain precipitation. And only the precipitation is used as medicine, another type of active ingredient caffeic acid esters in Dengzhan Xixin is directly discarded, and the content of 4,5-di-O-caffeoylquinic acid needs to be determined in the content determination, which also exists. unreasonable factors.
- the preparations prepared by the new technology preparation method are enriched in active ingredients, reduce impurities, can better improve drug efficacy, save resources, improve the controllability of drug quality, and increase the number of drugs. effectiveness and safety.
- 50% ethanol extraction and 75% ethanol extraction have the highest content, and 50% ethanol extraction is selected from cost considerations.
- the concentrate was passed through a 30-60 mesh polyamide chromatography column (diameter to length ratio 1:4), eluted with water for 3 column volumes, eluted with 65% ethanol for 4 column volumes, and collected the ethanol eluent, After concentration, spray drying to obtain powder 2;
- Schisandra chinensis Take 200g of Schisandra chinensis, add water to decoct once, and pour out the water once to remove most of the organic acids, otherwise the extract is too much, which is not conducive to enriching lignin, discard the aqueous solution, add 80-85% ethanol to reflux for extraction twice, Filtration, combined filtrates, concentrated under reduced pressure into extract, added water to prepare Schisandra clear liquid and clarified with 100nm ceramic membrane, the clarified clear liquid was then concentrated with 350D organic membrane to obtain Schisandra clear paste, clear paste with ethyl acetate Ester extraction, the ethyl acetate extract was collected, and concentrated under reduced pressure to form an extract for later use.
- the ginseng concentrate, Ophiopogon japonicus precipitation, and Schisandra chinensis extract were mixed and dissolved, and after spray drying, powder 3 was obtained, and powders 1, 2, and 3 were mixed uniformly to obtain 144 g of brown raw material extract.
- the content of baicalin in the obtained powder 1 is 520 mg/g, and the powder 1, 34 g is obtained; the powder 2 contains 35 mg/g of 4,5-di-O-caffeoylquinic acid, and the powder 2, 43 g is obtained; the powder 3 contains ginsenosides Rg1+Re 5.5mg/g, schisandrin methyl 3.8mg/g, to obtain powder 3,67g.
- the content of scutellarin is 129mg/g, 4,5-di-O-caffeoylquinic acid 12.8mg/g, ginsenoside Rg1+Re 2.4mg/g, schisandrin 3.9mg /g.
- the acidified filtrate was adjusted to pH 7-9, clarified with a 200nm ceramic membrane, the clarified solution obtained after clarification was concentrated with a 400D organic membrane, and the concentrated solution passed through a 30-60 mesh polyamide chromatography column (diameter to length ratio of 1). : 4), eluted with 3 column volumes of water, eluted with 3 column volumes of 70% ethanol, collected the ethanol eluent, concentrated and spray-dried to obtain powder 2;
- Schisandra chinensis Take 200g of Schisandra chinensis, add water to decoct once, discard the aqueous solution, add 80-85% ethanol for reflux extraction twice, filter, combine the filtrates, concentrate under reduced pressure into extract, add water to prepare Schisandra chinensis clear liquid with 200nm ceramic membrane for clarification , the clarified clear liquid is then concentrated with 400D organic membrane to obtain Schisandra chinensis clear paste, the clear paste is extracted with ethyl acetate, the ethyl acetate extract is collected, and concentrated under reduced pressure to form an extract for later use.
- the ginseng concentrate, Ophiopogon japonicus precipitation, and Schisandra chinensis extract were dissolved in water, and after spray drying, powder 3 was obtained, and powders 1, 2, and 3 were mixed uniformly to obtain 171 g of brown raw material extract.
- the content of baicalin in the obtained powder 1 is 478 mg/g, and the powder 1, 42 g is obtained; the powder 2 contains 36 mg/g of 4,5-di-O-caffeoylquinic acid, and the powder 2: 53 g; the powder 3 contains ginsenoside Rg1 +Re 5.1mg/g, schisandrin methyl 4.2mg/g, get powder 3,76g.
- the content of scutellarin is 117mg/g, 4,5-di-O-caffeoylquinic acid 16mg/g, ginsenoside Rg1+Re2.3mg/g, schisandrin 1.9mg /g.
- Extract 5 Dissolve twice the amount of water, add 5% sodium hydroxide solution with stirring, adjust pH to 7.5-9.0, filter, add 10% sulfuric acid solution to adjust pH to 1-3, leave overnight, filter, collect filtrate and precipitate, precipitate with ethanol for purification , adding 5% sodium hydroxide to adjust the pH value to 7-8, spray drying to obtain powder 1;
- the acidified filtrate was adjusted to pH 7-9, clarified with a 100nm ceramic membrane, and the clarified solution obtained after clarification was then concentrated with a 300D organic membrane, and the concentrated solution passed through a 30-60 mesh polyamide chromatography column (diameter to length ratio 1: 4), eluted with 3.5 column volumes of water, eluted with 3 column volumes of 75% ethanol, collected the ethanol eluent, concentrated and spray-dried to obtain powder 2;
- Schisandra chinensis Take 200g of Schisandra chinensis, add water to decoct once, discard the aqueous solution, add 80-85% ethanol to reflux for extraction twice, filter, combine the filtrates, concentrate under reduced pressure into extract, add water to prepare Schisandra chinensis clear liquid with 100nm ceramic membrane for clarification , the clarified clear liquid is then concentrated with a 300D organic membrane to obtain the clear paste of Schisandra chinensis, the clear paste is extracted with ethyl acetate, the ethyl acetate extract is collected, and concentrated under reduced pressure into an extract for later use.
- the ginseng extract, Ophiopogon japonicus precipitation, and Schisandra extract were dissolved in water, and after spray drying, powder 3 was obtained, and powders 1, 2, and 3 were mixed uniformly to obtain 166 g of brown raw material extract.
- the content of scutellarin in the obtained powder 1 530 mg/g, the powder 1, 38 g is obtained, the powder 2 contains 38 mg/g of 4,5-di-O-caffeoylquinic acid, and the powder 2, 47 g is obtained; the powder 3 contains ginsenosides Rg1+Re 5.2mg/g, schisandrin methyl 6.3mg/g, to obtain powder 3,81g.
- the content of scutellarin is 121mg/g, 4,5-di-O-caffeoylquinic acid 10.8mg/g, ginsenoside Rg1+Re 2.5mg/g, schisandrin 3.1 mg/g.
- the inventor also used 10%, 30%, 40%, 45%, 50%, 55%, 60%, 75%, 90% of different concentrations of aqueous ethanol to extract Asarum sinensis, and other steps were the same as in Example 1.
- spray dry powder is obtained.
- 10-90% ethanol extraction can obtain lampshade extract, but from the yield, membrane passing rate, impurity content, powder bulk density and uniformity, industrial Measured by indicators such as production cost, the extract obtained with more than 40% ethanol is relatively better than the ethanol extract with less than 40%, and the ethanol extract with 40-60% is obviously better and more suitable for the process of the present invention, and 50% is the most preferred.
- % ethanol to extract Asarum sinensis is the extract obtained with more than 40% ethanol is relatively better than the ethanol extract with less than 40%, and the ethanol extract with 40-60% is obviously better and more suitable for the process of the present invention, and 50% is the most preferred.
- % ethanol to extract Asarum sinensis is the extract obtained with more than 40% ethanol
- Embodiment 9 the preparation of oral liquid
- Example 2 Take 20 g of the extract prepared in Example 1, mix it with 300 g of honey, 50 g of sucrose, 2 g of sodium benzoate and 300 ml of distilled water, heat to dissolve, and filter for heat preservation.
- Example 1 of the pharmaceutical composition is not only because of the composition ratio, but also because the present invention provides a novel preparation method of medicine. ,
- the n-butanol extraction method carries out technical comparison, and the data obtained are as follows:
- the new method reduces the total extract powder without reducing the content of active ingredients, but further uses the active ingredients caffeic acid esters in Dengzhan Asarum. Since the conventional method does not use caffeic acid esters, and the hepatotoxic pyroconic acid is contained in the caffeic acid esters (in the acidified supernatant), the conventional methods cannot detect pyroconic acid.
- the proportion of the active ingredients in the spray-dried powder has been increased by more than 40% due to the reduction of impurity components, and the impurities have been reduced by more than 30%, which has a significant technical progress, and will definitely improve the efficacy and safety of drugs. To obtain unexpected technical effects, the preparation method is innovative.
- the preparations prepared by this method can be made smaller on the basis of preparing the same amount of preparations, thereby increasing the compliance of the medicines.
- Using the same amount of powder for dispensing can increase the proportion of active ingredients and make the drug more effective.
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Abstract
La présente invention relève du domaine de la médecine. La présente invention concerne une composition pharmaceutique contenant des extraits d'Erigerontis herba, de Ginseng radix et rhizoma, d'Ophiopogonis radix et de Schisandrae chinensis fructus. La composition pharmaceutique comprend des formes galéniques orales courantes telles que des gélules, des comprimés, un liquide oral, des pilules ou des granules. Le procédé de préparation selon l'invention permet de tirer pleinement parti des principes actifs de l'ester d'acide caféique de l'Erigerontis herba et de réduire la proportion d'autres substances nocives et inefficaces, d'améliorer l'effet pharmaceutique et de fournir une médecine traditionnelle chinoise plus pratique, plus efficace et plus moderne, avec un meilleur contrôle de la qualité pour une application clinique.
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