CN112691113A - Pharmaceutical composition for preventing and treating hypertensive inflammatory response and application thereof - Google Patents
Pharmaceutical composition for preventing and treating hypertensive inflammatory response and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of traditional Chinese medicine research and development, and particularly relates to a pharmaceutical composition for preventing and treating hypertensive inflammatory response and application thereof. The medicine composition is prepared from 3.2-12.8 parts of gastrodin; 2.4-9.6 parts of hesperidin; 2.5-10 parts of pachymic acid A; 5.3 to 21.2 parts of liquiritigenin and 4.5 to 18 parts of isoliquiritigenin. The titer of the pharmaceutical composition for preventing or relieving the hypertensive inflammatory reaction can reach 98.77%. The pharmaceutical composition does not contain pinellia ternate toxic components of calcium oxalate needle crystals and lectin protein, avoids the irritation harm to human bodies caused by the pinellia ternate, bighead atractylodes rhizome and gastrodia elata decoction original prescription, can be used safely, and has enhanced curative effect; finally, lays a foundation for further developing novel active ingredient composition preparations.
Description
Technical Field
The invention belongs to the field of traditional Chinese medicine research and development, and particularly relates to a pharmaceutical composition for preventing and treating hypertensive inflammatory response and application thereof.
Background
Hypertension is a systemic, low grade inflammatory disease. In recent years, there is increasing evidence that aberrant immune activation is an important factor in the development of the blood pressure rise and hypertensive pathology. Under the change of blood flow rate and pressure of hypertension, red blood cells are excited to actively release a large amount of ATP molecules, ATP is bound to dendritic cells in the immune system, and a large amount of abnormal activation of T cells is manifested as inflammation. Blood pressure homeostasis is maintained by co-regulation of the cardiovascular, autonomic nervous systems, kidneys, etc., but the development of inflammation impairs the regulatory function of these systems, causing elevated blood pressure.
The decoction is prepared from 6 traditional Chinese medicines of pinellia ternate, gastrodia elata, poria cocos, exocarpium citri rubrum, bighead atractylodes rhizome and liquorice, mainly comprises phenolic acid, flavone, saponin, alkaloid, polysaccharide, protein and other macromolecules as main chemical components, has the effects of eliminating dampness and phlegm and calming liver and calming wind, is mainly used for treating dizziness and headache, chest distress and nausea, white and greasy tongue fur, wiry and smooth pulse and other symptoms caused by wind-phlegm disturbance, and is a representative prescription for clinically treating phlegm-dampness accumulation type hypertension in traditional Chinese medicine. Pinellia ternate, bighead atractylodes rhizome and gastrodia elata decoction is recorded in the ancient classic famous-square catalog (first batch) published by the national traditional Chinese medicine administration of 2018, is one of the 100 classic famous-square published in the first batch, and no modern Chinese patent medicine varieties are found on the market at present.
Network pharmacology is a new subject developed on the basis of single-target drug research in recent years, integrates subjects such as system biology, network biology and chemical biology, integrates research methods such as calculation prediction and experimental verification, gradually becomes a leading-edge cross subject in modern medical research, emphasizes integrity, systematicness and traditional Chinese medicine theory, is fit for academic characteristics and practice of traditional Chinese medicine, and can well explain deep connotation of traditional Chinese medicine, including analysis of traditional Chinese medicine action mechanism, search of pharmacodynamic substances, explanation of compatibility mechanism and the like.
Disclosure of Invention
The invention provides a pharmaceutical composition for preventing and treating hypertension inflammatory reaction, which consists of gastrodin, hesperidin, pachymic acid A, glycyrrhizic acid and isoglycyrrhizic acid. Pharmacodynamic experiments prove that the 5 components have the effect of synergistically preventing or relieving the hypertensive inflammatory response together, and the synergy is remarkable.
The technical scheme of the invention is as follows:
a pharmaceutical composition for preventing and treating hypertension inflammatory reaction is prepared from the following components in parts by weight: 3.2-12.8 parts of gastrodin; 2.4-9.6 parts of hesperidin; 2.5-10 parts of pachymic acid A; 5.3 to 21.2 parts of liquiritigenin and 4.5 to 18 parts of isoliquiritigenin.
Preferably, the pharmaceutical composition is prepared from the following components in parts by weight: 12.8 parts of gastrodin; 9.6 parts of hesperidin; 10 parts of pachymic acid A; 5.3 parts of glycyrrhizic acid and 4.5 parts of isoglycyrrhizic acid.
The preparation of the pharmaceutical composition for preventing and treating the hypertensive inflammatory response comprises tablets, capsules, granules, oral liquid, syrup, dropping pills, sustained-release tablets, pellets, aerosol, suppositories or plasters.
The application of the preparation of the pharmaceutical composition for preventing and treating the hypertensive inflammatory response in preparing the medicine for preventing and treating the hypertensive inflammatory response.
The preparation is orally taken or injected by intravenous, intramuscular, subcutaneous or other injection modes, or absorbed by oral cavity, rectum, vagina and skin or inhaled by nasal cavity, or is in the form of pharmaceutical preparation containing active ingredients and is administered in the form of pharmaceutically acceptable preparation.
Pharmacodynamic experiments and results
1. Screening active ingredients of the pinellia ternate, bighead atractylodes rhizome and gastrodia elata decoction for treating hypertension inflammation reaction:
1.1 analysis of chemical Components of ban Xia Bai Zhu Tian Tang
1.1.1 sample solution of 9g of pinellia ternate, 6g of rhizoma gastrodiae, 6g of poria cocos, 6g of exocarpium citri rubrum, 15g of rhizoma atractylodis macrocephalae and 4g of liquorice, adding 500mL of water, decocting (boiling with strong fire and slowly decocting with slow fire) for 2 times, each time for 0.5h, and combining filtrates. Concentrating by rotary evaporator to 2.30g/mL crude drug mass concentration. According to the method, the Chinese medicinal materials in the table 1 are expressed as L18 (3)7) And (4) arranging and combining orthogonal tables to prepare 18 batches of pinellia ternate, bighead atractylodes rhizome and gastrodia elata soup.
Taking 2mL of pinellia ternate, bighead atractylodes rhizome and gastrodia elata soup, adding methanol to a constant volume of 25mL, sealing, dissolving for 30min by ultrasonic waves (250W and 40 kHz), standing, cooling, weighing the constant mass, supplementing the lost mass with methanol, shaking up, filtering, taking the subsequent filtrate, and filtering through a 0.45-micrometer filter membrane to obtain the traditional Chinese medicine.
TABLE 1 Place of production and lot number of decoction pieces of ban Xia Bai Zhu Tian Ma Tang medicinal materials
1.1.2 Single-medicine test solution 9g of pinellia ternate, 6g of gastrodia elata, 6g of poria cocos, 6g of exocarpium citri rubrum, 15g of bighead atractylodes rhizome and 4g of liquorice are weighed and respectively operated according to the method of '1.1.1'.
1.1.3 study of finger-print of ban Xia Bai Zhu Tian Tang
1.1.3.1 establishment of fingerprint
Respectively and precisely sucking 10 mu L of 18 batches of pinellia ternate, bighead atractylodes rhizome and gastrodia elata soup sample solutions, carrying out sample injection measurement, sequentially introducing fingerprints of 18 batches of samples into a traditional Chinese medicine chromatogram fingerprint similarity evaluation system (2012) in a CDF format, taking an S18 sample spectrum as a reference spectrum, adopting a median method, wherein the time window width is 0.10, carrying out multi-point correction on chromatographic peaks, and then automatically matching to generate a reference fingerprint. A total of 24 common peaks were normalized.
1.1.3.2 common peak attribution analysis and identification
Precisely absorbing 10 μ L of test solution (S1), each single test solution and corresponding negative control test solution, performing sample injection measurement according to high performance liquid chromatography, and recording chromatogram, as shown in figure 1.
And numbering the common peaks according to the chromatogram results, and comparing the retention time with the ultraviolet absorption spectrogram to analyze and identify the attribution of each common peak. The results show that in 24 matched common peaks, the peaks 4 and 5 are from pinellia ternate, the peak 8 is from gastrodia elata, the peaks 6, 7, 21, 22, 23 and 24 are from bighead atractylodes rhizome, the peaks 9, 12, 15, 16, 17 and 18 are from chrysoidine, the peaks 10 and 11 are from chrysoidine, and the peaks 13, 14, 19, 20 and 25 are from liquorice, wherein the sources of the 2 common peaks cannot be clarified.
1.2 network pharmacological analysis of pharmacodynamic substances
Extracting chemical component molecular fingerprints of the decoction of pinellia ternate, white atractylodes rhizome and tall gastrodia tuber by Open source software Open Babel 2.4.1, comparing chemical fingerprint characteristics of a two-dimensional structure (mol) with medicines on the market of the Food and Drug Administration (FDA), performing similarity scoring by a similarity measuring method defined by a Tanimoto coefficient, taking a medicine target with the scoring coefficient more than 0.8 as a potential target required by the research, and establishing a medicine candidate target information database. Through enrichment analysis of functions and pathways in which the candidate targets of the drugs participate, chemical components of tumor necrosis factor signal pathway targets AKT1, MAPK14, MMP3, MMP9, PIK3R1, MAPK1, MAPK3, PTGS2 and TNF which are key pathological links of preventing or slowing down the inflammatory reaction of the hypertension disease are excavated, and the results comprise gastrodine (No. 8 peak), pachymic acid A (No. 10 peak), liquiritin (No. 14 peak), hesperidin (No. 16 peak) and isoliquiritin (No. 19 peak), which are shown in figure 2.
2 optimized proportion of active ingredients
2.1 cell culture HUVECs were suspended in DMEM containing 10% fetal bovine serum and placed at 37 ℃ in sterile CO2Culturing in an incubator, changing the culture solution 1 time every 2-3 days, carrying out passage 2 times every week, and carrying out experiment after passage 4.
2.2 grouping and processing according to L16（45) Orthogonal design, with 4 dose levels (high dose 1/10 at half lethal concentration LC 50) set forth in table 2, resulted in 16 different compatibility groups of 5 active ingredients. In addition, a normal group and a model group are set. The passaged HUVECs cells were seeded at an appropriate density in 96-well plates, 3 duplicate wells per group, and the cells were synchronized to G0 phase using serum-free medium. The cells were grouped and added with different drug ingredients for 2h, and then added with ox-LDL to a final concentration of 200. mu.g/mL for 24 h. And detecting absorbance (A) with the wavelength of 450nm by using an enzyme-labeling instrument to reflect the cell activity, and determining the compatible concentration of each active component. Cell viability = (drug-treated group a value-blank group a value)/(normal group a value-blank group a value) × 100%. The test arrangement and results are shown in tables 3 and 4, and the analysis of variance is shown in table 5. Analysis of variance showed dayThe influence of ephedrine and pachymic acid A on drug effect is significantly different (P)<0.01 or P<0.05). The visual analysis shows that the influence sequence of each factor on the comprehensive drug effect is A>C>B>D = E, the degrees of influence of the factor levels on the results are in the order of A4 > A2 > A3 > A1, B4 > B2 > B3 > B1, C4 > C3 > C2 > C2, D2 > D3 > D4 > D1, E2 > E3 > E4 > E1. Comprehensive analysis determines that the optimal component compatibility is A4B4C4D2E2, namely, gastrodin is 12.8uM, hesperidin is 9.6uM, pachymic acid A is 10uM, liquiritigenin is 5.3uM, and isoliquiritigenin is 4.5 uM.
TABLE 2 design of factor level
TABLE 3 analysis of orthogonal experiments
TABLE 4 analysis of variance
Note:F 0.05（3，3）=9.28。
2.3 verifying that the potency (E) of the pharmaceutical composition which is screened out by the experiment and consists of the optimal mixture ratio and is used for preventing or slowing the hypertensive inflammatory reaction is obviously enhanced; the drug effect of the pharmaceutical composition can reach or even exceed the whole formula of the pinellia ternate, bighead atractylodes rhizome and gastrodia elata decoction, and the dosage of the drug is obviously reduced, which shows that gastrodin, hesperidin, pachymic acid A, glycyrrhizic acid and isoglycyrrhizic acid are drug effect substances of the pinellia ternate, bighead atractylodes rhizome and gastrodia elata decoction for regulating the inflammatory reaction of hypertension; the drug effect of the drug composition is obviously larger than that of each monomer component, and gastrodin, hesperidin, pachymic acid A, glycyrrhizic acid and isoglycyrrhizic acid have compatibility and synergism. The results are shown in Table 5.
Table 5 verification of experimental results (
，n=3）
Note: the normal group was compared with the model group,1) P<0.01; the treatment group was compared with the model group,2) P<0.01，3) P<0.05。
drawings
FIG. 1 shows the common peak assignment of ban Xia Bai Zhu Tian Tang;
FIG. 2 is a multi-dimensional network relationship of "Chinese medicinal materials-chemical components-core targets-key pathways" of ban Xia Bai Zhu Tian Tang for treating hypertension; green represents the Chinese medicine, purple represents the ingredients, blue represents the key target, and red represents the pathway.
Has the advantages that:
1. has good effect of treating hypertension inflammatory reaction
The invention excavates the effective components of the pinellia ternate, bighead atractylodes rhizome and gastrodia elata decoction for treating the hypertension inflammatory reaction based on network pharmacological data, optimizes the optimal compatibility dosage of the effective components through the research of orthogonal design and optimization of the compatibility formula of the effective components, and exerts the drug effect of the pinellia ternate, bighead atractylodes rhizome and gastrodia elata decoction for treating the hypertension inflammatory reaction to the maximum extent. The titer of the inflammatory reaction for treating hypertension by adopting the pharmaceutical composition can reach 98.77 percent, which is far higher than 80.52 percent of the decoction of pinellia tuber, white atractylodes rhizome and tall gastrodia tuber.
2. Has no toxic components and side effects
Compared with the traditional Chinese medicine compound decoction containing pinellia ternate, bighead atractylodes rhizome and gastrodia elata, the medicine composition provided by the invention has the advantages that pinellia ternate toxic components (calcium oxalate needle crystals and lectin protein) are removed, the medicine taking dosage is reduced, the potential irritant toxicity and hepatotoxicity harm of the original formula of the decoction containing pinellia ternate, bighead atractylodes rhizome and gastrodia elata to a human body are avoided, no side effect is caused, the decoction can be used safely, and the curative effect is enhanced.
3. Great research significance
The drug effect of the drug composition is obviously larger than that of each monomer component, and gastrodin, hesperidin, pachymic acid A, glycyrrhizic acid and isoglycyrrhizic acid have compatibility and synergism; meanwhile, the invention lays a foundation for further developing a novel active ingredient composition preparation with clear medicine components, clear action targets, clear action links and mechanisms and optimized dose-effect relationship among medicines.
Detailed Description
The pharmaceutical compositions and the preparation methods thereof are further illustrated by the following examples, but the present invention is not limited to the contents contained in the following examples.
Example 1
Preparing the syrup for preventing and treating the hypertension inflammation:
taking 110g of gastrodin, 30g of hesperidin, 40g of pachymic acid A40g, 100g of liquiritigenin and 150g of isoliquiritigenin, adding a proper amount of water for dissolving, stirring, standing, filtering, adding 250g of cane sugar and 5g of sodium benzoate, adding 1000ml of water, stirring uniformly, filling and sterilizing to obtain the traditional Chinese medicine.
Example 2
Preparing the dropping pill for preventing and treating the hypertensive inflammation:
heating 45g of gastrodin, 80g of hesperidin, 92g of pachymic acid A92g, 180g of liquiritigenin, 160g of isoliquiritigenin and 500g of polyethylene glycol to melt, mixing well, transferring to a liquid reservoir of a pill dropping machine, keeping the temperature at 90 ℃, dropping into cooled dimethicone, and preparing into 1000g of pills.
Example 3
Preparing the capsule for preventing and treating hypertension inflammatory reaction:
taking 55g of gastrodin, 75g of hesperidin, 50g g of pachymic acid, 100g of liquiritigenin and 170g of isoliquiritigenin, adding a proper amount of starch, uniformly mixing, and encapsulating to prepare 1000 granules.
Example 4
Preparing an injection for preventing and treating hypertension inflammation:
taking 100g of gastrodin, 95g of hesperidin, 85g of pachymic acid, 140g of liquiritigenin and 100g of isoliquiritigenin, adding 1800ml of water for injection, stirring to dissolve, adjusting the pH value to 7.0-7.5 by using a saturated sodium hydroxide solution, adding 10g of active carbon for injection, adding the water for injection to 2000ml, uniformly mixing, boiling for 30 minutes, refrigerating, filtering, adding the water for injection to 5000ml, filtering by using 0.45 mu m and 0.22 mu m microporous filter membranes respectively, subpackaging, 5ml per bottle, filling nitrogen, sealing, and sterilizing by flowing steam for 30 minutes to obtain 1000 injection concentrated solutions.
Claims (5)
1. A pharmaceutical composition for preventing and treating hypertensive inflammatory response is characterized by being prepared from the following components in parts by weight: 3.2-12.8 parts of gastrodin; 2.4-9.6 parts of hesperidin; 2.5-10 parts of pachymic acid A; 5.3 to 21.2 parts of liquiritigenin and 4.5 to 18 parts of isoliquiritigenin.
2. The pharmaceutical composition for preventing and treating hypertensive inflammatory response as defined in claim 1, wherein the pharmaceutical composition is prepared from the following components in parts by weight: 12.8 parts of gastrodin; 9.6 parts of hesperidin; 10 parts of pachymic acid A; 5.3 parts of glycyrrhizic acid and 4.5 parts of isoglycyrrhizic acid.
3. The formulation of the pharmaceutical composition for preventing and treating hypertensive inflammatory response of claim 1 or 2, comprising tablets, capsules, granules, oral liquids, syrups, drop pills, pellets, aerosols, suppositories, or plasters.
4. The preparation of the pharmaceutical composition for preventing and treating hypertensive inflammatory response of claim 3, wherein the preparation is used for preparing a medicament for preventing and treating hypertensive inflammatory response.
5. The formulation of pharmaceutical composition for the prevention and treatment of hypertensive inflammatory responses according to claim 3 or 4, wherein the administration is performed orally or by intravenous, intramuscular, subcutaneous or other injection, or by oral, rectal, vaginal, cutaneous absorption or nasal inhalation, or in the form of pharmaceutical preparations containing the active ingredient, in the form of pharmaceutically acceptable preparations.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115876936A (en) * | 2022-12-01 | 2023-03-31 | 上海交通大学 | Screening method and application of Sijunzi decoction components based on network pharmacology and molecular docking |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115876936A (en) * | 2022-12-01 | 2023-03-31 | 上海交通大学 | Screening method and application of Sijunzi decoction components based on network pharmacology and molecular docking |
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