CN114377030B - Pharmaceutical composition of chicoric acid and echinacoside and application thereof - Google Patents
Pharmaceutical composition of chicoric acid and echinacoside and application thereof Download PDFInfo
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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Abstract
The invention provides a pharmaceutical composition of chicoric acid and echinacoside and application thereof in preparation of a medicament for treating hepatic fibrosis.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition of chicoric acid and echinacoside and application thereof.
Background
Chicoric Acid (CA), molecular formula C 22 H 18 O 12 The caffeic acid component with molecular weight of 474, also called dicaffeoyltartaric acid, is extracted and separated from Compositae plant (herba Cichorii, echinacea purpurea, caulis et folium Lactucae Sativae), wherein L-type chicoric acid is generally in the form of L-type chicoric acidTo about 80%. Research shows that chicoric acid has various pharmacological actions of resisting inflammation, resisting oxidation, resisting tumor, resisting virus, improving body immunity and the like, but the pharmacological action mechanism is not clear, and no related research is available for the application of chicoric acid in hepatic fibrosis.
Echinacoside (ECH) with molecular formula of C 35 H 46 O 20 The molecular weight is 786.72, the compound is phenylethanoid glycosides micromolecule compound, and the compound is widely present in natural plants such as echinacea, cistanche, rehmannia glutinosa and the like. Has antioxidant, antiinflammatory, neuroprotective, memory improving, antitumor, and hepatoprotective effects. Early studies show that echinacoside can inhibit the expression of Smad2 and Smad3 downstream of transforming growth factor-beta 1 (TGF-beta 1) promoting liver fibrosis and can also improve the expression of Smad7 with TGF-beta 1 pathway signal inhibition, so that the echinacoside can inhibit the activation of hepatic stellate cells and has a potential effect of resisting liver fibrosis, however, no clinical evidence exists at present.
Hepatic fibrosis is a chronic liver disease, the clinical etiology is complex, and viral, alcoholic, hepatitis, fatty liver and the like can cause hepatic fibrosis. Modern medicine considers that the essence of liver fibrosis is the repair reaction of the body to the liver when the liver is chronically injured, and the liver fibrosis can not intervene in time, so that the condition of the liver can be deteriorated into cirrhosis and even liver cancer, and therefore, the liver fibrosis is a hot spot of research in the field of liver diseases in recent years. Although the current treatments for hepatic fibrosis are causal treatment, anti-fibrotic drug treatment, orthotopic liver transplantation, and cell-based therapy, clinically significant effective therapeutic drugs are lacking.
There is therefore a need in the art for a medicament that is significantly effective in the treatment of liver fibrosis diseases.
Disclosure of Invention
In order to solve the above problems, in a first aspect, the present invention aims to provide a pharmaceutical composition comprising chicoric acid and echinacoside.
In a particular embodiment, said chicoric acid in the pharmaceutical composition of the present invention may be levorotatory chicoric acid or a mixture of levorotatory and dextrorotatory chicoric acids.
In a particular embodiment, the molar ratio of said chicoric acid and said echinacoside in the pharmaceutical composition of the invention may be 1.5 to 1.8, preferably may be 1.2 to 1.
In a specific embodiment, the chicoric acid in the pharmaceutical composition of the present invention may be a chemically synthetic compound or a natural plant extract; the natural plants include, but are not limited to, compositae plants; preferably it may be chicory, echinacea or lettuce.
In a specific embodiment, the echinacoside in the pharmaceutical composition of the present invention may be a chemically synthesized compound or a natural plant extract; the natural plants may include, but are not limited to, cistanche plants, rehmannia and echinacea; preferably, the cistanche plant can be cistanche tubulosa and cistanche deserticola.
In specific embodiments, the pharmaceutical composition of the present invention may be in the form of tablets, capsules, granules, syrups, oral liquids, dispersible tablets, rapidly disintegrating tablets, fast dissolving tablets, sustained release tablets, controlled release tablets; wherein the capsule can also contain a dispersing agent and an auxiliary material; the dispersing agent may be a conventional pharmaceutically acceptable dispersing agent such as polyethylene glycol; preferably polyethylene glycol 6000; the excipient may be a common pharmaceutical excipient, such as microcrystalline cellulose.
In a second aspect, the present invention aims to provide the use of a pharmaceutical composition as described in the first aspect in the preparation of a medicament for the treatment of liver fibrosis.
Compared with the prior art, the pharmaceutical composition has the following advantages:
(1) The pharmaceutical composition of the invention can effectively reverse carbon tetrachloride (CCl) in mice 4 ) Induced liver fibrosis;
(2) The treatment effect of the pharmaceutical composition on hepatic fibrosis is superior to that of echinacoside single drug;
(3) The active ingredients of the pharmaceutical composition are the main ingredients of the health food, so the safety degree is high;
(4) The pharmaceutical composition and the capsule have the advantages of easily available raw materials, simple preparation method and low cost.
Drawings
FIG. 1 shows the measurement results of the capsule component sample content of the composition of the present invention.
FIG. 2 shows the body weight changes of mice in the control group, echinacoside monotherapy group and capsule therapy group of the composition of the present invention.
FIGS. 3A-C show the ALT, AST and Tbil changes in the control group, echinacoside monotherapy group and the capsule therapy group of the present invention, respectively.
FIGS. 4A-D are quantitative analyses of liver weight change, liver weight/body weight ratio change, hepatitis activity and liver fibrosis in the control group, echinacoside monotherapy group and the composition capsule treatment group of the present invention.
FIGS. 5A-D are the pathological evaluation of liver fibrosis in the control group and the capsule treatment group of the composition of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention.
All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
The technical scheme of the invention is further explained by the specific implementation mode in combination with the attached drawings.
Example 1: preparation of a medicament
25％CCl 4 Solution preparation (carbon tetrachloride: olive oil): CCl is mixed 4 Mixing with olive oil according to the ratio of 1:3 in volume ratio. The preparation is fresh before each use, and is mixed evenly into a uniform solution by vortex.
Echinacoside single drug: drying and crushing cistanche, adding 75% ethanol, heating and refluxing at 70 ℃ for extraction for 2h, centrifuging for 10min at 3000r/min, taking the supernatant, concentrating, loading to an HPD-100 resin chromatographic column, performing gradient elution by using 30% ethanol aqueous solution, collecting eluent once per 0,5BV (column volume), and determining the purity of echinacoside by HPLC.
Chicoric acid single drug: freezing and pulverizing Echinacea purpurea, weighing plant powder, extracting with 40% ethanol entrainer and CO2 at 25kg/h under 30MPa at 60 deg.C for 2h, and determining echinacoside purity by HPLC.
Example 2: capsule preparation
The chicoric acid single drug and the echinacoside single drug are mixed in a molar ratio of 1. The content of each capsule is 0.47g, wherein the content of chicoric acid is not less than 18mg, and the content of echinacoside is not less than 31mg. The content of chicoric acid and echinacoside was determined by randomly extracting 7 capsules from 100 capsule products prepared, and the measurement results are shown in FIG. 1.
Example 3: animal experiments
Animal treatment process
30 BALB/c mice (6-7 weeks old, 6 spare) were purchased from Experimental animals technology, inc., vitonuli, beijing. At animal arrival, animal house personnel transfer the animals from shipping packages to squirrel cages and examine each animal. The examination range includes appearance, limbs, cavities and the like, and whether the animal is abnormally represented when the animal is static or in motion. The adaptation period is 7 days.
The mice were then placed in clear resin plastic squirrel cages (265 mm by 160mm by 127 mm) in the animal house, 2-5 per cage. The mouse cage padding is autoclaved corncob padding (Shandong Dezhou Gumei agriculture science and technology Co., china), and is replaced every 7-10 days. The room number where the animals were placed throughout the experiment was recorded in the experimental record. The animal room is equipped with high-efficiency air filter, and the ventilation frequency is 15-25 times per hour. The temperature is maintained between 20-26 deg.C (68-79 deg.F) and the relative humidity is 40-70%. Temperature and humidity were continuously observed and recorded. The lighting conditions were 12 hours (08 00-20) daylight lamp illumination and 12 hours no illumination per day.
At the beginning of the animal experiment, BALB/c (7-8 weeks old) mice were randomly divided into G1-G3 groups by BioBook random distribution function on day 0 according to animal body weight to achieve similar average weight of each group and reduce variation among groups. Starting on day 0, animals of groups G1-G3 were all given a 4-week CCl 4 Treatment (intraperitoneal injection of 25% CCl) 4 4mL/kg twice a week for 4 consecutive weeks) to establish a liver fibrosis model.
Meanwhile, the G1 group mice are used as a control group and are not treated by any administration, the G2 mice are administered with echinacoside single drug, and the G3 group mice are administered with the capsule of chicoric acid and echinacoside prepared in the example 2, and the specific administration scheme is detailed in the following Table 1.
TABLE 1 administration groups and dosing schedules
and a, administration according to the weight obtained by the last weighing.
The health status of the animals and the comprehensive response to the drugs were observed every day, and no appearance or behavioral abnormality was observed.
Pathological analysis and evaluation of mice
(1) Body weight level
The G1-G3 groups of mice were weighed twice weekly, see figure 2 and table 2 below.
TABLE 2 weight changes in mice from different administration groups
It can be seen that echinacoside single drug (LCH) and composition capsules had no significant effect on mouse body weight average compared to the control.
(2) ALT, AST and TBIL levels in serum
Animal blood samples were collected before modeling, on day 11, and on day 27, respectively (whole blood was collected through the orbit after anesthesia with 1-4% isoflurane inhalation for 3-5 min), EDTA-K2 was anticoagulated, after standing for 2 hours at room temperature, centrifuged at 2000x g for 10min at 4 ℃, plasma was separated, liver function indices ALT, AST, and TBIL were analyzed using a full-automatic blood biochemical analyzer, and the measurement results are shown in fig. 3A-C.
Compared with a control group, the echinacoside single-drug group G2 and the composition capsule group G3 can reduce ALT and AST, wherein the influence of the echinacoside single-drug on the ALT and the AST is not obviously different from the control group, and the composition capsule can obviously reduce the ALT (p < 0.01) and the AST (p < 0.01) of mice. Meanwhile, the detection of the total bilirubin level (Tbil) shows that both the echinacoside single drug and the composition capsule can reduce the total bilirubin of the mice, wherein the composition capsule has obvious difference (p is less than 0.05) in the regulation and control of the total bilirubin and the control group.
(3) Liver weight, hepatitis activity score analysis, quantitative analysis of liver tissue fibrosis (Sirius red staining) (see fig. 4A-D);
after the end of week 4 blood draw (typically at the last CCl administration) 4 After 48 hours), animals were exposed to CO 2 After suffocation, the cervical vertebra is taken off and euthanized. The whole liver tissue was removed, rapidly washed with pre-cooled PBS, blotted to dry and weighed. It can be seen that the liver weight of the capsule group of the composition was significantly reduced, and the liver weight of the echinacoside monotherapy group was not significantly different from that of the control group (fig. 4A). Analysis of liver weight/body weight ratio shows that the liver weight/body weight ratio of the capsule group of the composition is significantly smaller than that of the control group, and the liver weight/body weight ratio of the echinacoside single-drug treatment group is not significantly different from that of the control group (fig. 4B).
Freezing and reserving liver middle lobe, immersing liver left lobe into 10% formalin for fixing for at least 48 hours, carrying out histopathological analysis, and observing histopathological change of liver. The method comprises the following steps:
a. dehydrating the tissue by using a tissue dehydrator, wherein the process comprises the following steps: gradient alcohol dehydration, xylene transparency, paraffin infiltration and embedding;
b. preparing the embedded wax block into 5 μm slices by a Leica automatic slicer;
c. sections were stained as needed for analysis.
Hepatitis activity score analysis (see figure 4C for results): taking H & E stained sections, observing left upper, right upper, left lower, right lower and middle 5 liver tissue visual fields in a single blind mode under a 200-fold microscope (see figures 5A and B), and scoring according to an inflammation activity semi-metric system, wherein the scoring standard is as follows (see table 3):
TABLE 3 semi-quantitative scoring system for inflammation activity
The echinacoside single drug and the composition capsule can both obviously reduce the liver inflammation, have obvious difference (p is less than 0.05) compared with a control, and the curative effect of the composition capsule is superior to that of the echinacoside single drug.
Quantitative analysis of liver fibrotic tissue (sirius red staining quantification) (results see fig. 4D): liver 4 μm thin sections were deparaffinized and stained with sirius red for 15 min at room temperature. Sections were dehydrated in 95% and 100% ethanol and xylene in that order and then mounted. Liver fibrosis tissues and total liver tissues were determined using sirius red stained sections. Tissue morphology measurements were performed using the Aperio ImageScope analysis software program (Aperio ImageScope v 12.4.3.5008). The histomorphometer is unaware of the specimen information at the time of measurement. Aperio Imagescope software program Total measured area (mm) of each section 2 ) Set to 100%, and the measured sirius red positive staining area (mm) 2 ) Set as a percentage of the total area. The total area measurement is done by manually tracing the projected image on the computer display by moving the stylus mouse over the associated tablet. Total area is defined as the total area of the liver lobe minus the area of the lumen of the blood vessel (null), the area of sirius red positive staining is measured by adjusting the Aperio assay to detect chromogens in the tissue sample, and the tissue is marked by operator adjustment of the intensityClassification, including strong (red), medium (orange), weak (yellow), or negative (blue) staining (see fig. 5C and D). The measurements for each sample are digitized and can be exported to an EXCEL spreadsheet for statistical analysis.
It can be seen that both echinacoside single drug and composition capsule can significantly reduce the hepatic fibrosis score (p < 0.05), wherein the composition capsule has better effect than echinacoside single drug.
The above experimental data are expressed as mean ± standard error (mean ± s.e.m.). Data were analyzed by Graphpad Prism 6 or SPSS using the corresponding statistical methods, the specific analysis protocol being indicated in the legend. A significant difference was considered to be p < 0.05.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (26)
1. Use of a pharmaceutical composition for the manufacture of a medicament for the treatment of liver fibrosis, wherein the pharmaceutical composition comprises chicoric acid and echinacoside in a molar ratio of 1.2 to 1.
2. Use according to claim 1, wherein chicoric acid is a chemically synthetic compound or a natural plant extract.
3. The use according to claim 2, wherein the natural plant includes but is not limited to a plant of the Asteraceae family.
4. Use according to claim 3, wherein the Asteraceae plant is chicory, echinacea or lettuce.
5. The use according to claim 1, wherein the echinacoside is a chemically synthesized compound or a natural plant extract.
6. The use of claim 5, wherein said natural plants include, but are not limited to, cistanche plants, rehmannia and echinacea.
7. The use of claim 6, wherein the cistanche plant is cistanche tubulosa or cistanche deserticola.
8. Use according to claim 1, wherein the medicament is in the form of tablets, capsules, granules, syrups or oral liquids.
9. Use according to claim 8, wherein the tablet is a dispersible tablet, a rapidly disintegrating tablet, a rapidly dissolving tablet, a sustained release tablet or a controlled release tablet.
10. The use according to claim 8, wherein the capsule further comprises a dispersing agent and an adjuvant.
11. Use according to claim 10, wherein the dispersant is polyethylene glycol.
12. Use according to claim 10, wherein the dispersant is polyethylene glycol 6000.
13. The use according to claim 10, wherein the excipient is microcrystalline cellulose or PEG.
14. A pharmaceutical composition, characterized in that it comprises chicoric acid and echinacoside, and the molar ratio of chicoric acid to echinacoside is 1.2.
15. The pharmaceutical composition of claim 14 wherein said chicoric acid is a chemically synthetic compound or a natural plant extract.
16. The pharmaceutical composition of claim 15, wherein the natural plant includes, but is not limited to, compositae.
17. The pharmaceutical composition of claim 16, wherein the Asteraceae plant is chicory, echinacea or lettuce.
18. The pharmaceutical composition of claim 14, wherein the echinacoside is a chemically synthesized compound or a natural plant extract.
19. The pharmaceutical composition of claim 18, wherein said natural plants include, but are not limited to, cistanche, rehmannia and echinacea.
20. The pharmaceutical composition of claim 19, wherein the cistanche plant is cistanche tubulosa or cistanche deserticola.
21. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, syrup, or oral liquid.
22. The pharmaceutical composition of claim 21, wherein the tablet is a dispersible tablet, a rapidly disintegrating tablet, a rapidly dissolving tablet, a sustained release tablet, or a controlled release tablet.
23. The pharmaceutical composition of claim 21, wherein the capsule further comprises a dispersing agent and an excipient.
24. The pharmaceutical composition of claim 23, wherein the dispersing agent is polyethylene glycol.
25. The pharmaceutical composition of claim 23, wherein the dispersing agent is polyethylene glycol 6000.
26. The pharmaceutical composition of claim 23, wherein the excipient is microcrystalline cellulose or PEG.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113425764A (en) * | 2021-07-16 | 2021-09-24 | 北京大学 | Application of herba cistanches Deserticolae total glycosides and echinacoside in preparing medicine for preventing and treating alcoholic liver injury and intestinal injury |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113425764A (en) * | 2021-07-16 | 2021-09-24 | 北京大学 | Application of herba cistanches Deserticolae total glycosides and echinacoside in preparing medicine for preventing and treating alcoholic liver injury and intestinal injury |
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| 《Chicorid acid attenuate a nonalcoholic steatohepatitis by inhibiting key regulators of lipid metaboloism, fibrosis, oxidation, and inflammation in mice with methionine and choline deficiency》;Myungsuk Kim等;《Mol. Nutr. Food Res.》;20171231;第61卷(第5期);1-14页，第3.3节 * |
| 《Interaction of Phytocompounds of Echinacea purpurea with ABCB1 and ABCG2 Efflux Transporters》;Awortwe, C等;《MOLECULAR PHARMACEUTICS》;20211231;第18卷(第4期);1622-1633 * |
| 《Nutraceuticals with targeted functionality, valorizing different medicinal plants》;Socaciu，C等;《Hop and Medicinal Plants》;20081231;第16卷(第1/2期);94-98 * |
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| 肝损伤的分子机制及其中药药理研究进展;张红阳等;《中药新药与临床药理》;20160525(第03期);448-455 * |
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