CN113144015A - Application of product of xianglian or combination of product of xianglian and antibiotic in anti-helicobacter pylori medicine - Google Patents
Application of product of xianglian or combination of product of xianglian and antibiotic in anti-helicobacter pylori medicine Download PDFInfo
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- CN113144015A CN113144015A CN202110581700.4A CN202110581700A CN113144015A CN 113144015 A CN113144015 A CN 113144015A CN 202110581700 A CN202110581700 A CN 202110581700A CN 113144015 A CN113144015 A CN 113144015A
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Abstract
The invention provides an application of a xianglian product or a xianglian product and antibiotics in combination in an anti-helicobacter pylori drug, aiming at the characteristics of poor safety, poor clinical compliance and the like of the existing xianglian product in Hp resistance or treatment or prevention of fatty liver, hepatic fibrosis, liver cirrhosis and liver cancer, and also relates to a preparation method of a super-concentrated xianglian product. The invention has better anti-Hp effect, and improves the safety of the medicine by combining with one antibiotic or two antibiotics. The invention also has the function of treating or preventing fatty liver, hepatic fibrosis, liver cirrhosis and liver cancer.
Description
Technical Field
The invention is applied to the technical field of traditional Chinese medicine preparations, and particularly relates to an application of a xianglian product or a xianglian product and an antibiotic in an anti-helicobacter pylori medicament.
Background
Huang Lian was recorded in Shen nong Ben Cao Jing, listed as the superior. Coptis root, rhizoma Coptidis is bitter in taste and cold in nature, and has the effects of purging pathogenic fire, removing toxic substance, clearing heat, and eliminating dampness. Can be used for treating dysphoria, coma, vexation, insomnia, damp-heat, abdominal distention, emesis, abdominal pain, dysentery, conjunctival congestion, toxic swelling, aphtha, eczema, scald, hematemesis, and epistaxis. A large number of research results show that the coptis has extremely strong anti-Helicobacter Pylori (HP) effect (Xuyi, etc. the research on the bacteriostatic action of single Chinese herbal medicine and compound Chinese herbal medicine on helicobacter pylori, Chinese and Western medicine combined with spleen and stomach J8 (5): 292.2000). Famous classics using coptis as main raw material include xianglian pill and zuojin pill. The xianglian pill is from li jiangtang jie fang (Li Jiang Bing Ji Fang) (from Ju Qi of political and materia Medica), is composed of 4 parts of coptis root and 1 part of costus root, has the functions of clearing heat, resolving dampness, promoting qi circulation and relieving pain, and is used for treating dysentery caused by damp-heat in large intestine, with symptoms of stool purulent blood, tenesmus, fever and abdominal pain, enteritis and bacillary dysentery with the symptoms.
Helicobacter pylori (Hp) is the first causative agent of various gastric diseases including gastric cancer, and the infection rate in our country is as high as about 50% (Chen W, oral. disorders by nature, age, and sex in site-specific cancer resistant to 23potential modified risk factors in the Chinese: a comprehensive risk assessment. Lancet Global Health,2019,7(2): e 257-69). Currently, methods for clinical clearance of Hp are mainly "triple therapy" and "quadruple therapy". With the widespread use and even abuse of antibiotics, bacteria develop various degrees of resistance, which poses serious threats to the health of human beings or animals; at present, the number of antibiotics for treating Hp is mainly 6 (clarithromycin, amoxicillin, furazolidone, levofloxacin, metronidazole and tetracycline), and the antibiotics have certain drug resistance, and some antibiotics cannot be used in practice because of serious drug resistance. The search for new anti-Hp drugs is the focus of future research on the treatment of Hp.
In the prior art, the combination of the xianglian pill and triple therapy (omeprazole 20mg, clarithromycin 500mg and amoxicillin capsule 1000mg) is facilitated, and the Hp removing effect of the triple therapy can be improved (clinical research on treating helicobacter pylori related peptic ulcer by the combination of Zhangin and xianglian pill in a triple scheme, Shanxi Chinese medicine 2015,36 (3): 296.). However, the triple therapy is that a plurality of antibiotics are used in a large dose, and then a large dose of 'xianglian pills' or xianglian tablets are added for combined use, so that the oral dose is larger, more difficult and the clinical compliance is poor; meanwhile, the safety is poor when antibiotics and traditional Chinese medicines are used in large dose. Therefore, a drug combination for resisting helicobacter pylori is developed, the treatment effect of resisting helicobacter pylori can be ensured by using a small dose of drug, and the drug safety is improved.
According to the investigation of medical journal lancet, it is shown that by 2017, the Chinese obese population is the first world, with 4320 million obese men and 4640 million obese women accounting for 16.3% and 12.4% of the world, respectively. The obesity can cause diseases such as fatty liver and the like, and medical experts have conservative estimation, so that fatty liver patients in China currently have more than 2 hundred million fatty liver patients and have a trend of rising year by year. The long-term fatty liver will cause hepatic fibrosis, further cause the attack of coronary heart disease and arteriosclerosis diseases, and the prolonged time will cause hepatic fibrosis, even cirrhosis and liver cancer. At present, no ideal medicine for treating hepatic fibrosis and no medicine for treating and preventing liver cirrhosis caused by fatty liver exist in clinic. The research focus of the future is to find new drugs for preventing hepatic fibrosis and liver cirrhosis caused by fatty liver, and further drugs for preventing serious diseases such as liver cancer and the like. However, in the prior art, no precedent of treatment by using the products of xianglian is found in the treatment or prevention of fatty liver, hepatic fibrosis, liver cirrhosis and liver cancer, and the safety is poor.
Disclosure of Invention
The invention aims at the problems in the prior art and provides a xianglian product or an application of the xianglian product and an antibiotic in an anti-helicobacter pylori medicament.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
a preparation method of a super-concentrated xianglian product is characterized by comprising the following steps:
1) preparing a golden thread extract: weighing Cornus officinalis, percolating, neutralizing until pH is 2.0-7.0, and filtering; concentrating the filtrate under reduced pressure to 0.5-2g of Cornus officinalis/mL; adding halide salt into the filtrate, precipitating, and filtering to obtain extract I; adding halide salt and high-valence halide salt into the filtered mother liquor, precipitating and filtering to obtain an extract II; mixing the extract I and the extract II to obtain a Cornus officinalis extract;
2) preparation of an elecampane extract: weighing radix aucklandiae, and extracting volatile oil under reflux; filtering the extracted water solution, repeatedly refluxing and extracting the filtered residues for 1-2 times, and combining the filtered water solutions to obtain an extract III; concentrating the extracting solution III to 1-2g of elecampane/mL under reduced pressure; adding ethanol, and filtering to obtain an alcohol solution; recovering ethanol, and oven drying to obtain radix aucklandiae extract; mixing the volatile oil and the water-extraction and alcohol-precipitation extract of costus root to obtain an extract of costus root;
3) mixing the extract of the golden thread and the extract of the costus root, adding auxiliary materials, and granulating to obtain the super-concentrated xianglian product.
A preparation method of a super-concentrated xianglian product comprises the following steps:
1) preparing a golden thread extract: weighing Cornus officinalis, percolating with 0.1% -2% sulfuric acid solution, neutralizing percolate with lime or calcium hydroxide to pH 2.0-7.0, and filtering; concentrating the filtrate under reduced pressure to 0.5-2 g/mL of Corni fructus Coptidis rhizoma, cooling, and filtering; adding 1-20% of halide salt into the filtrate, standing at 0-25 deg.C for 1-96 hr, precipitating, and filtering to obtain extract I; adding 1-20% of halide salt and 0.1-2% of high-valence halide salt into the filtered mother liquor, standing at 0-25 deg.C for 1-96 hr, precipitating, and filtering to obtain extract II; mixing the extract I and the extract II to obtain a Cornus officinalis extract;
2) preparation of an elecampane extract: weighing radix aucklandiae, extracting with 5 times of water under reflux for 1-3 hr, and collecting volatile oil; filtering the extracted water solution, repeatedly refluxing and extracting the filtered residues for 1-2 times, and combining the filtered water solutions to obtain an extract III; concentrating the extracting solution III to 1-2g of elecampane/mL under reduced pressure; adding 1-3 times of ethanol, standing for 1-24 hours, and filtering to obtain an alcohol solution; recovering ethanol, and oven drying to obtain radix aucklandiae extract; mixing the volatile oil and the water-extraction and alcohol-precipitation extract of costus root to obtain an extract of costus root;
3) mixing the extract of the golden thread and the extract of the costus root, adding auxiliary materials, and granulating to obtain the super-concentrated xianglian product.
Further, the total alkaloids of coptis chinensis in the percolated liquid obtained in the step 1) are more than 95% of the total alkaloids of coptis chinensis.
Further, the halide salt in step 1) refers to a monovalent salt of a halogen, and is preferably sodium chloride, potassium chloride, sodium bromide, potassium bromide, sodium iodide, potassium iodide, sodium fluoride or potassium fluoride.
The higher halide salt is a metal salt of a divalent or higher halogen, and is preferably iron chloride, manganese chloride, or zinc chloride.
Further, the granules prepared in the step 3) are respectively prepared into pills, tablets or capsules.
Further, the content of the coptis total alkaloids in the super-concentrated xianglian product is 50-90%.
An application of a Chinese medicine 'xianglian' in preparing the medicines for preventing and treating fatty liver, hepatic fibrosis, hepatocirrhosis and liver cancer is disclosed, which features that said Chinese medicine 'xianglian' is prepared from coptis root and aucklandia root, and said Chinese medicine 'xianglian' contains said hyperconcentrated Chinese medicine. Preferably, the xianglian product comprises at least one of xianglian pills, xianglian tablets, xianglian capsules, concentrated xianglian pills and super-concentrated xianglian products.
Preferably, the application of the xianglian capsule, the concentrated xianglian pill or the super concentrated xianglian product in the medicines for preventing and treating fatty liver, hepatic fibrosis, liver cirrhosis and liver cancer.
An application of a Chinese medicinal composition comprising Coptidis rhizoma and radix aucklandiae as main ingredients in a Chinese medicinal preparation for preventing and/or treating helicobacter pylori, wherein the Chinese medicinal composition comprises the hyperconcentrated Chinese medicinal product. Preferably, the xianglian product comprises at least one of xianglian pills, xianglian tablets, xianglian capsules, concentrated xianglian pills and super-concentrated xianglian products.
In the invention, the xianglian pills, the xianglian tablets, the xianglian capsules and the concentrated xianglian pills are traditional Chinese medicine products which are sold in the market or prepared according to a known method. In the invention, the super-concentrated xianglian product is prepared by the preparation method.
An application of a Coptis chinensis Franch product and one or two antibiotics in combination in a medicine for preventing and/or treating helicobacter pylori is disclosed, wherein the Coptis chinensis Franch product is a traditional Chinese medicine composition taking golden thread and costus root as main components, and the Coptis chinensis Franch product comprises the super-concentrated Coptis chinensis Franch product. Preferably, the xianglian product comprises at least one of xianglian pills, xianglian tablets, xianglian capsules, concentrated xianglian pills and super-concentrated xianglian products.
Further, the antibiotic is one or two of clarithromycin, amoxicillin, furazolidone, levofloxacin, metronidazole, tetracycline, omeprazole and other PPI.
Preferably, the two antibiotics are one of omeprazole and clarithromycin, omeprazole and amoxicillin, omeprazole and metronidazole, omeprazole and levofloxacin, omeprazole and furazolidone.
Further, the use of a capsule of coptidis rhizoma or a super-concentrated product of coptidis rhizoma in combination with an antibiotic in a medicament for the prevention and/or treatment of helicobacter pylori.
Further, the antibiotic is one of clarithromycin, amoxicillin, furazolidone, levofloxacin and metronidazole.
Further, the use of the xianglian capsule or the super-concentrated xianglian product in combination with two antibiotics in the preparation of a medicament for preventing and/or treating helicobacter pylori. Preferably, the super-concentrated xianglian product is prepared by the preparation method.
Further, the two antibiotics are one of omeprazole and clarithromycin, omeprazole and amoxicillin, omeprazole and metronidazole, omeprazole and levofloxacin, omeprazole and furazolidone. The total coptis alkaloid in the invention refers to the sum of alkaloids in coptis, such as berberine, palmatine, coptisine, epiberberine, jateorhizine and the like.
The effective usage amount of the xianglian product in the medicines for preventing and treating fatty liver, hepatic fibrosis, liver cirrhosis and liver cancer and the medicines for preventing and/or treating helicobacter pylori is the common usage amount in the application field of the xianglian product at present.
Compared with the prior art, the invention has the beneficial effects that:
(1) the product of the invention has better Hp resistance, and the Hp resistance effect is obviously improved compared with the product of the invention which is used independently when the product of the invention is used together with an antibiotic; when the antibiotic is combined with two antibiotics, the anti-Hp effect is consistent with that of the common combined use of a triple method, and the antibiotic has an ideal anti-Hp effect.
(2) The traditional Chinese medicine composition is combined with the antibiotics, so that the antibacterial activity of the antibiotics is obviously improved, the drug resistance of the antibiotics is obviously inhibited, compared with the conventional triple therapy, the drug resistance of the antibiotics and the toxic and side effects of the triple therapy are reduced or even eliminated, and the safety of the medicine is improved.
(3) The invention selects the super-concentrated rhizoma coptidis product, has high rhizoma coptidis alkaloid content and small volume of the traditional Chinese medicine preparation, only accounts for about 15 percent of the crude drug amount of the original formula, and is easier to take orally; less impurities and higher safety.
(4) The invention selects the super-concentrated xianglian product, the preparation process of the super-concentrated xianglian product is simple, the prepared traditional Chinese medicine preparation has small volume, is convenient to be processed into capsules, tablets (coatings), pills (coatings) and the like, can effectively improve the taste of the preparation, and obviously improves the clinical compliance; the utilization rate of the coptis alkaloid is high, the transfer rate of the total alkaloid is more than 95%, and the precipitation rate of the total alkaloid in the solution is more than 95%.
(5) The product of the invention has better functions of preventing and treating fatty liver, hepatic fibrosis and liver cirrhosis, etc.
Drawings
FIG. 1 shows the result of Masson's liver fibrosis staining in the application of the product of xianglian of the present invention or its combination with antibiotic in the anti-helicobacter pylori medicine.
FIG. 2 shows the results of HE staining and Masson staining of cirrhosis in the application of the product of the invention or its combination with antibiotics in anti-helicobacter pylori drugs.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
In addition, unless otherwise specifically indicated, various starting materials, reagents, instruments and equipment used in the present invention may be commercially available or prepared by existing methods.
Example 1:
weighing 80g of Cornus officinalis rhizoma Coptidis, percolating with 0.5% sulfuric acid solution until the color of percolate is light (HPLC analysis extracting total alkaloids in raw materials above 95%); neutralizing the percolate with calcium hydroxide to pH 3.0, and filtering; concentrating the filtrate under reduced pressure to 1 g/mL of Corni fructus Coptidis rhizoma, cooling, and filtering; adding 10% sodium chloride into the filtrate, standing at 5 deg.C for 24 hr, precipitating, and filtering to obtain extract I; adding 10% sodium chloride and 0.5% zinc chloride into the filtered mother liquor, standing at 5 deg.C for 5 hr, precipitating, and filtering to obtain extract II; and mixing the extract I and the extract II to obtain the Cornus officinalis extract.
Weighing 20g of costustoot, extracting for 1 hour by using 5 times of water under reflux, and collecting volatile oil; filtering the extracted water solution, extracting the filtered residue with appropriate amount of water under reflux for 1 time, filtering, and mixing the filtered water solutions to obtain extract III; concentrating the extracting solution III to 1g of costustoot/mL under reduced pressure; adding 2 times of ethanol, standing for 5 hours, and filtering to obtain an alcohol solution; recovering ethanol, and oven drying to obtain radix aucklandiae extract; mixing the volatile oil and the water-extraction and alcohol-precipitation extract of radix aucklandiae to obtain radix aucklandiae extract.
Mixing the extract of the golden thread and the extract of the costus root, adding a proper amount of dextrin, granulating and encapsulating to obtain the super-concentrated xianglian product. HPLC analysis shows that the content of total alkaloids in the super-concentrated rhizoma coptidis product is 61% (berberine 30%, coptisine 12%, palmatine 9%, epiberberine 8%, jateorhizine 2%). The product has a volume of only 15% of the volume of the xianglian pill, has the function of resisting helicobacter pylori (Hp), is combined with antibiotics, and has better Hp resisting effect.
Example 2:
weighing 80g of Cornus officinalis rhizoma Coptidis, percolating with 2% sulfuric acid solution until the color of percolate is light (HPLC analysis shows that total alkaloids in raw materials are more than 95%); neutralizing the percolate with calcium hydroxide to pH 7.0, and filtering; concentrating the filtrate under reduced pressure to 2 g/mL of Corni fructus Coptidis rhizoma, cooling, and filtering; adding 1% potassium bromide into the filtrate, standing at 25 deg.C for 96 hr, precipitating, and filtering to obtain extract I; adding 20% potassium bromide and 0.1% ferric bromide into the filtered mother liquor, standing at 25 deg.C for 1 hr, precipitating, and filtering to obtain extract II; and mixing the extract I and the extract II to obtain the Cornus officinalis extract.
Weighing 20g of costustoot, extracting for 1 hour by using 5 times of water under reflux, and collecting volatile oil; filtering the extracted water solution, extracting the filtered residue with appropriate amount of water under reflux for 1 time, filtering, and mixing the filtered water solutions to obtain extract III; concentrating the extract III under reduced pressure to 0.5g radix aucklandiae/mL; adding 3 times of ethanol, standing for 24 hours, and filtering to obtain an alcohol solution; recovering ethanol, and oven drying to obtain radix aucklandiae extract; mixing the volatile oil and the water-extraction and alcohol-precipitation extract of radix aucklandiae to obtain radix aucklandiae extract.
Mixing the extract of Cornus officinalis and the extract of Costus root, adding a proper amount of microcrystalline cellulose, granulating, and encapsulating to obtain the super-concentrated rhizoma Coptidis product. HPLC analysis shows that the content of total alkaloids in the super-concentrated rhizoma coptidis product is 50% (berberine 25%, coptisine 10%, palmatine 9%, epiberberine 5%, jateorhizine 1%). The product has a volume of only 16% of the volume of the xianglian pill, has the function of resisting helicobacter pylori (Hp), is combined with antibiotics, and has better Hp resisting effect.
Example 3:
weighing 80g of Cornus officinalis rhizoma Coptidis, percolating with 1% sulfuric acid solution until the color of percolate is light (HPLC analysis shows that total alkaloids in raw materials are more than 95%); neutralizing the percolate with calcium hydroxide to pH 5.0, and filtering; concentrating the filtrate under reduced pressure to 1 g/mL of Corni fructus Coptidis rhizoma, cooling, and filtering; adding 10% sodium iodide into the filtrate, standing at 10 deg.C for 48 hr, precipitating, and filtering to obtain extract I; adding 10% sodium iodide and 0.5% magnesium iodide into the filtered mother liquor, standing at 10 deg.C for 10 hr, precipitating, and filtering to obtain extract II; and mixing the extract I and the extract II to obtain the Cornus officinalis extract.
Weighing 20g of costustoot, extracting for 1 hour by using 5 times of water under reflux, and collecting volatile oil; filtering the extracted water solution, extracting the filtered residue with appropriate amount of water under reflux for 1 time, filtering, and mixing the filtered water solutions to obtain extract III; concentrating the extracting solution III to 1g of costustoot/mL under reduced pressure; adding 2 times of ethanol, standing for 12 hours, and filtering to obtain an alcohol solution; recovering ethanol, and oven drying to obtain radix aucklandiae extract; mixing the volatile oil and the water-extraction and alcohol-precipitation extract of radix aucklandiae to obtain radix aucklandiae extract.
Mixing the extract of the golden thread and the extract of the costus root, adding a proper amount of dextrin, granulating and encapsulating to obtain the super-concentrated xianglian product. HPLC analysis shows that the content of total alkaloids in the super-concentrated rhizoma coptidis product is 70% (berberine 35%, coptisine 15%, palmatine 12%, epiberberine 7%, jateorhizine 1%). The product has a volume of only 14% of the volume of the xianglian pill, has the function of resisting helicobacter pylori (Hp), is combined with antibiotics, and has better Hp resisting effect.
Example 4:
weighing 80g of Cornus officinalis rhizoma Coptidis, percolating with 0.1% sulfuric acid solution until the color of percolate is light (HPLC analysis extracting total alkaloids in raw materials above 95%); neutralizing percolate with lime to pH 2.0, and filtering; concentrating the filtrate under reduced pressure to 0.5 g/mL of Corni fructus Coptidis rhizoma, cooling, and filtering; adding 20% potassium fluoride into the filtrate, standing at 0 deg.C for 1 hr, precipitating, and filtering to obtain extract I; adding 1% of potassium fluoride and 2% of manganese fluoride into the filtered mother liquor, standing at 0 ℃ for 96 hours, precipitating and filtering to obtain an extract II; and mixing the extract I and the extract II to obtain the Cornus officinalis extract.
Weighing 20g of costustoot, extracting for 3 hours by using 5 times of water under reflux, and collecting volatile oil; filtering the extracted water solution, extracting the filtered residue with appropriate amount of water under reflux for 2 times, filtering, and mixing the filtered water solutions to obtain extract III; concentrating the extracting solution III to 2g of elecampane/mL under reduced pressure; adding 1 time of ethanol, standing for 1 hour, and filtering to obtain an alcohol solution; recovering ethanol, and oven drying to obtain radix aucklandiae extract; mixing the volatile oil and the water-extraction and alcohol-precipitation extract of radix aucklandiae to obtain radix aucklandiae extract.
Mixing the extract of Coptidis rhizoma and radix aucklandiae, adding appropriate amount of starch, granulating, and making into capsule to obtain the final product. HPLC analysis shows that the content of total alkaloids in the super-concentrated rhizoma coptidis product is 90% (berberine 50%, coptisine 16%, palmatine 14%, epiberberine 8%, jateorhizine 2%). The product has a volume of only 15% of the volume of the xianglian pill, has the function of resisting helicobacter pylori (Hp), is combined with antibiotics, and has better Hp resisting effect.
The super concentrated xianglian products prepared in examples 1 to 4 have excellent effects of preventing and treating fatty liver, liver fibrosis and liver cirrhosis.
Comparative example 1: comparison of extraction techniques of Total alkaloid from Coptidis rhizoma product
In this comparative example, compared with the conventional salting-out method, the total alkaloid extraction technology of patent technology 1(ZL200810069671.8) and the total alkaloid extraction technology of patent technology 2(ZL201310357973.6) (the total alkaloid in the comparative technology is equivalent to the yu huang lian extract in this application), the related precipitation efficiency and product purity are compared as follows:
conventional salting out methods: soaking Coptidis rhizoma decoction pieces 100g in dilute sulphuric acid (1%) for 24 hr, and extracting for 3 times to obtain extract No. 1 (0.2g Coptidis rhizoma tablet/mL). 500mL of the extract 1, 5 times of the extract (1g of coptidis rhizoma tablets/mL) is pre-concentrated, and then the extract is precipitated by 20% of sodium chloride for 24 hours; to obtain total alkaloids (calculated by berberine, coptisine, palmatine, epiberberine and jateorhizine) 14.11g with content of 48% and yield of 70.5%.
Patent technology 1(ZL 200810069671.8): soaking Coptidis rhizoma decoction pieces 100g in dilute sulphuric acid (1%) for 24 hr, and extracting for 3 times to obtain extract No. 1 (0.2g Coptidis rhizoma tablet/mL). 500mL of the extract 1 is pre-concentrated by 5 times (1g of coptis tablet/mL), and then activated carbon with the concentration of 0.5 percent is added into the extract to be stirred and decolored; precipitating the decolorized solution with 20% sodium chloride (and 0.5% zinc chloride) for 24 hr; to obtain total alkaloids (calculated by berberine, coptisine, palmatine, epiberberine and jateorhizine) 18.11g, with a content of 50% and a yield of 94.2%.
Patent technology 2(ZL 201310357973.6): 500mL of the extract No. 1 (0.2g of Coptis tablet/mL), neutralized with lime until the pH of the solution is 5.0, and filtered; the neutralized filtrate was concentrated 5 times under reduced pressure (1g of coptidis rhizoma tablet/mL); adjusting the pH value of the concentrated solution to 2 by hydrochloric acid; then, 20% of sodium chloride is added for precipitation for 24 hours to obtain the coptis total alkaloid. Mother liquor and washing liquor after total alkaloid precipitation are combined to obtain 150mL of solution, and after adsorption by using 100mL of macroporous resin, the resin is washed by using 5 times of water; then eluting with 60% ethanol, and recovering ethanol to obtain Coptidis rhizoma total alkaloids. Mixing the two total alkaloids (calculated by berberine, coptisine, palmatine, epiberberine and jateorhizine) to obtain high purity rhizoma Coptidis total alkaloids 13.71g with content of 65% and yield of 92.8%.
The technology of the invention is as follows: weighing Cornus officinalis Linn, percolating with 0.1% sulfuric acid solution until the color of percolate is light (HPLC analysis extracts total alkaloids in raw materials above 95%), measuring two parts of percolate each 500ml, respectively obtaining Cornus officinalis Linn extract (total alkaloids) according to the method of embodiment 3 and embodiment 4, analyzing the obtained total alkaloids of Coptidis rhizoma to obtain total alkaloids 13.75g in embodiment 3 with content of 69% and yield of 98.2%; 13.12g of total alkaloid in example 4, the content is 72 percent, and the yield is 98.4 percent.
TABLE 1 comparison of Total alkaloid extraction
As can be seen from the table, the conventional salting-out method has simple and safe process, but the yield is low and the purity of the product is also low.
Compared with the traditional extraction method, the yield of the patent technology 1(ZL200810069671.8) is obviously improved, but the content of the product is not improved and is only about 50%.
Compared with the traditional extraction method, the yield of patent technology 2(ZL201310357973.6) is greatly improved, and the purity of the product is also obviously improved, however, the patent technology 2 needs macroporous resin and ethanol, the process steps are complex, the production cost is greatly improved, especially the use of ethanol has obvious potential safety hazard, and the investment in production is greatly increased.
Compared with the traditional extraction method and the existing patent technology, the extraction process of the golden thread extract is simple, the product yield is high, the total alkaloid yield exceeds 98%, the product purity is high, the actual requirements of preparation production are completely met, the raw materials used in the process are all easily available, the production process is high in safety, and the risk of harming body health and operation is avoided.
Experimental example 1: in vitro Helicobacter Pylori (HP) killing effect
Control drugs:
control drug 1: omeprazole.
Control drug 2: clarithromycin.
Control drug 3: and (3) amoxicillin.
Control drug 4: and (4) metronidazole.
Control drug 5: levofloxacin.
Control drug 6: furazolidone.
Control drug 7: a tetracycline.
Control drug 8 (xianglian pill): 80g of golden thread and 20g of costus root. Pulverizing, and making into pill with Coptidis rhizoma total alkaloid content of 10.0% (berberine 5.6%, coptisine 1.6%, palmatine 1.5%, epiberberine 0.9%, and jateorhizine 0.4%).
Control drug 9 (concentrated xianglian pill): 80g of golden thread and 20g of costus root. Making into pill according to the preparation process of "Chinese pharmacopoeia" 2015 edition, wherein the content of Coptidis rhizoma total alkaloids is 25.0% (berberine 14.0%, coptisine 4.0%, palmatine 3.7%, epiberberine 2.3%, jateorhizine 1.0%).
Control drug 10 (xianglian capsule (tablet)): 80g of golden thread and 20g of costus root. According to the preparation process of 'Chinese pharmacopoeia' 2015 edition, rhizoma coptidis capsules (tablets) are prepared, wherein the content of rhizoma coptidis total alkaloids is 33.3% (berberine 18.7%, coptisine 5.3%, palmatine 5.0%, epiberberine 3.0%, jateorhizine 1.3%).
Control drug 11 (super concentrated xianglian capsule (tablet)): 80g of golden thread and 20g of costus root. The coptidis rhizoma total alkaloids content is 60.0% (berberine 30.0%, coptisine 12.0%, palmatine 9.0%, epiberberine 8.0%, jateorhizine 2.0%) to prepare the xianglian capsule (tablet) according to the process of the embodiment 1 of the invention.
Control drug 12 (triple therapy): omeprazole 20mg, clarithromycin 500mg and amoxicillin capsule 1000 mg.
Control drug 13: xianglian pill + triple therapy (omeprazole 20mg, clarithromycin 500mg, amoxicillin capsule 1000 mg). According to Shaanxi Chinese medicine, 2015,36 (3): 296. the process.
Control drug 14: cenjian tablet and triple combination therapy (omeprazole 20mg, clarithromycin 500mg, amoxicillin capsule 1000 mg). According to "modern biomedical evolution", 2009, 9 (3): 505.
synergistic drug:
1, synergistic medicine: control drug 10+ control drug 12.
And 2, synergistic medicine: control 11 (example 1) + control 12.
And (3) synergistic medicine: control drug 10+ control drug 1.
Synergistic agent 4: control drug 10+ control drug 2.
And (5) synergistic medicine: control drug 10+ control drug 3.
And (3) synergistic medicine 6: control drug 10+ control drug 4.
And (3) synergistic medicine 7: control drug 10+ control drug 5.
And (3) synergistic medicine 8: control drug 10+ control drug 6.
Synergistic agent 9: control drug 10+ control drug 7.
The synergistic medicine 10: control drug 10+ control drug 1+ control drug 2.
The synergistic medicament 11: control drug 10+ control drug 1+ control drug 3
The synergistic agent 12: control drug 10+ control drug 1+ control drug 4
Synergistic drug 13: control drug 10+ control drug 1+ control drug 5
The synergistic agent 14: control drug 10+ control drug 1+ control drug 6
The synergistic medicine 15: control drug 10+ control drug 1+ control drug 7
The synergistic agent 16: control drug 11+ control drug 1+ control drug 2.
Synergistic agent 17: control drug 11+ control drug 1+ control drug 3
The synergistic agent 18: control drug 11+ control drug 1+ control drug 4
Synergistic agent 19: control drug 11+ control drug 1+ control drug 5
The synergistic medicine 20: control drug 11+ control drug 1+ control drug 6
The synergistic medicament 21: control drug 11+ control drug 1+ control drug 7
The experimental method comprises the following steps: the antibacterial experiment of Hp is carried out according to the research guiding principle of natural medicine (traditional Chinese medicine) new medicine; the concentration of the drug is expressed in weight percent concentration (mg/L); a double check antibiotic, expressed in total concentration; the experimental strain is NCTC 11637; MIC (minimum inhibitory concentration) of related drugs was determined according to the sesquidilution method (Chinese journal of basic medicine, 2017,23(03): 405-.
TABLE 2 MBC of drug pairs Hp (NCTC 11637)
As can be seen from Table 2, referring to the control drugs 8, 9, 10 and 11, with the continuous concentration of the product of Coptis chinensis Franch, the concentration of the total alkaloids from Coptis chinensis Franch is increased, the anti-Hp activity is increased continuously, the ratio of the increase of the anti-Hp activity to the increase of the total alkaloids from Coptis chinensis Franch is basically the same, and the anti-Hp activity tends to increase with the increase of the drug purity; overall, the anti-Hp activity of the products of Coptis (control drugs 8-11) was slightly weaker than that of the antibiotics (control drugs 1-7).
After the xianglian product (in the experimental example, xianglian capsule or super-concentrated xianglian capsule) is respectively compounded with clarithromycin, amoxicillin, metronidazole, levofloxacin, furazolidone and the like, all the product has synergistic effects (synergistic medicaments 4, 5, 6, 7 and 8); after the xianglian product (xianglian capsule or super concentrated xianglian capsule in this experimental example) is compounded with omeprazole and tetracycline, there is no synergistic effect (synergistic drugs 3 and 9).
Compounding a xianglian product (in the experimental example, xianglian capsules or super-concentrated xianglian capsules) with omeprazole, and then simultaneously adding clarithromycin, amoxicillin, metronidazole, levofloxacin, furazolidone and the like, so that the synergistic effect is very obvious (synergistic medicaments 10, 11, 12, 13, 14, 16, 17, 18, 19 and 20); after the xianglian product (xianglian capsule or super concentrated xianglian capsule in this experimental example) is compounded with omeprazole, tetracycline is added, so that a certain synergistic effect is achieved, but the effect is not obvious (synergistic drugs 15 and 21).
The coptidis rhizoma product (in the experimental example, coptidis rhizoma capsule or super-concentrated coptidis rhizoma capsule) is compounded with the triple materials (cooperative medicines 1 and 2), and the cooperative effect of the coptidis rhizoma product is superior to that of the control medicines 13 and 14 compared with the case that the coptidis rhizoma product (coptidis rhizoma pill or coptidis rhizoma tablet) is compounded with the triple therapy (control medicines 13 and 14), so that the concentration of the total alkaloids of the coptidis rhizoma is improved, the cooperative effect of the coptidis rhizoma product and the triple therapy is improved, and the activity of resisting Hp is improved. The synergistic effect of the xianglian product (xianglian capsule or super concentrated xianglian capsule) and the triple ingredient (synergistic drugs 1 and 2) is the same as that of the xianglian product added with omeprazole and clarithromycin (synergistic drugs 10 and 16), the xianglian product added with omeprazole and amoxicillin (synergistic drugs 11 and 17), the xianglian product added with omeprazole and metronidazole (synergistic drugs 12 and 18), the xianglian product added with omeprazole and levofloxacin (synergistic drugs 13 and 19) and the xianglian product added with omeprazole and furazolidone (synergistic drugs 14 and 20), and the synergistic effect cannot be further increased.
Therefore, the product of the xianglian has a certain killing effect on Hp when being combined with a single antibiotic, and the product of the xianglian and a bigeminy antibiotic (omeprazole, clarithromycin, amoxicillin, metronidazole, levofloxacin or furazolidone) have a good killing effect on Hp, have the same killing effect as the combined effect of the product of the xianglian and the triple antibiotic, and have good synergistic effect. However, the use of the product of incense in combination with a "dual antibiotic" greatly reduces the amount of antibiotic used compared to the use of the product of incense in combination with a "triple therapy" antibiotic.
Experimental example 2: animal experiment for preventing and treating fatty liver and hepatic fibrosis
Control drug 15 (berberine): weighing 1kg of berberine monomer, adding starch, and making into capsule with berberine content of 56%.
Control drug 16 (total alkaloids of coptis): weighing Coptidis rhizoma total alkaloids, adding starch, and making into capsule, wherein the Coptidis rhizoma total alkaloids are controlled to be 56% (berberine 33.0%, palmatine 8.8%, berberine 9.4%, and epiberberine 4.7%).
Control drug 17: pulverizing radix aucklandiae, and directly administering to stomach.
Control drug 18 (orlistat): the purchased products on the market are used according to the instruction. The mouse dose was 45 mg/kg.
Control drug 8 (xianglian pill): 80g of golden thread and 20g of costus root. Pulverizing, and making into pill with Coptidis rhizoma total alkaloid content of 10.0% (berberine 5.6%, coptisine 1.6%, palmatine 1.5%, epiberberine 0.9%, and jateorhizine 0.4%).
Control drug 9 (concentrated xianglian pill): 80g of golden thread and 20g of costus root. Making into pill according to the preparation process of "Chinese pharmacopoeia" 2015 edition, wherein the content of Coptidis rhizoma total alkaloids is 25.0% (berberine 14.0%, coptisine 4.0%, palmatine 3.7%, epiberberine 2.3%, jateorhizine 1.0%).
Control drug 10 (xianglian capsule (tablet)): 80g of golden thread and 20g of costus root. According to the preparation process of 'Chinese pharmacopoeia' 2015 edition, rhizoma coptidis capsules (tablets) are prepared, wherein the content of rhizoma coptidis total alkaloids is 33.3% (berberine 18.7%, coptisine 5.3%, palmatine 5.0%, epiberberine 3.0%, jateorhizine 1.3%).
Control drug 11 (super concentrated xianglian capsule (tablet)): 80g of golden thread and 20g of costus root. The coptidis rhizoma total alkaloids content is 60.0% (berberine 30.0%, coptisine 12.0%, palmatine 9.0%, epiberberine 8.0%, jateorhizine 2.0%) to prepare the xianglian capsule (tablet) according to the process of the embodiment 1 of the invention.
The weight-reducing experimental method is carried out according to the research guiding principle of natural medicines (traditional Chinese medicines) and new medicines: c57 mice were divided into 11 groups, and the blank group (10) was given normal diet, and the high fat group (100) was given high fat diet; detecting the body weight after 20 weeks, wherein the body weight is over 40g, and the molding is successful; c57 mice successfully modeled in the high fat group were divided into 10 groups (10 mice each); continuously feeding high-fat feed to each high-fat group; the dose of berberine group (control drug 15) is 100mg/kg, the doses of total alkaloids (berberine, palmatine, berberine and epiberberine) of other drug groups are 100mg/kg, and the dose of radix aucklandiae group (control drug 17) is 1329 mg/kg; the Olympic group (control 18) dose was 45 mg/kg; the high-fat group which is successfully molded continues to be fed with high-fat feed, but no medicine is used as a model group, and normal group (blank group) and the model group are respectively fed with physiological saline with the same volume; the feeding is continuously carried out for 16 weeks. Then detecting the body weight; taking a liver to detect the fat content; liver slice detection detects liver fibrosis and cirrhosis. The specific results are shown in Table 3.
TABLE 3 comparison of effects on weight loss and prevention of hepatic fibrosis
Note: compared with the normal group, # P <0.05, # P < 0.01; p <0.05, P < 0.01; compared to the orlistat group: Δ P < 0.05.
As can be seen from Table 3, the indexes of body weight, liver fat content, degree of hepatic fibrosis, liver cirrhosis, etc. in the model group are significantly increased as compared with the normal group, indicating success of modeling (# P < 0.05). Compared to the model group, each group had an effect except that costus root (control drug 17) had no effect. The comparison of the medicines shows that the berberine (contrast medicine 15) has the effects of losing weight, preventing fatty liver and preventing hepatic fibrosis and liver cirrhosis (P is less than 0.05), but all the effects are weaker than the coptis total alkaloid (contrast medicine 16); compared with orlistat (contrast medicament 18), berberine has slightly poor weight reducing effect and fatty liver preventing effect, but has better effect in preventing liver cirrhosis and hepatic fibrosis; the effects of the total alkaloids in losing weight, preventing fatty liver, preventing hepatic fibrosis and preventing liver cirrhosis are all better than orlistat. Compared with orlistat (control drug 18), the xianglian pill (control drug 8) has little difference between the weight-reducing effect and the fatty liver preventing effect, but the effect of preventing hepatic fibrosis and hepatic cirrhosis is obviously better than that of orlistat; the concentrated xianglian pill (contrast medicament 9) and xianglian capsule (tablet) (contrast medicament 10) have better effects of losing weight, preventing fatty liver, preventing hepatic fibrosis and preventing liver cirrhosis than orlistat (contrast medicament 18) and reach a significant or extremely significant level. Although the costustoot has no effects of losing weight and the like, after the costustoot (the contrast medicament 17) and the coptis total alkaloids (the contrast medicament 16) are compounded (the contrast medicaments 8-11), the weight loss, the fatty liver prevention, the hepatic fibrosis prevention, the hepatic cirrhosis prevention and the like of the compound are obviously improved compared with the single coptis total alkaloids, which shows that the compound formed by the coptis and the costustoot has the synergistic effect of losing weight, preventing the fatty liver, the hepatic fibrosis and the hepatic cirrhosis. In conclusion, the effect of the hyperconcentration xianglian capsule (tablet) (the contrast medicament 11) in the aspects of losing weight, preventing fatty liver, preventing hepatic fibrosis and preventing liver cirrhosis is optimal, and particularly, the effect in the aspects of preventing hepatic fibrosis and preventing liver cirrhosis is obviously better than that of other groups.
Referring to the attached figure 1, the blank group, the model group and the xianglian capsule (tablet) (contrast drug 10) are respectively sliced, and the fatty liver, the hepatic fibrosis and the liver cirrhosis forms are observed by adopting an HE staining method and a Masson staining method. It can be seen that the blank group had no fatty liver (vacuoles), the model group had severe fatty liver (vacuoles were very much), and the control drug 10 group was significantly reduced; the blank group has almost no hepatic fibrosis, the hepatic tissue structure is complete and clear, the model group has fibrosis and severe fibrosis (liver cirrhosis), the control drug 10 group has obvious improvement on the aspects of hepatic fibrosis and liver cirrhosis compared with the model group, has a small amount of fibrosis, and has obvious effects of preventing hepatic fibrosis and liver cirrhosis.
Experimental example 3: safety test of drugs
The safety of the drug was tested by using various kinds of Chinese medicinal preparations as control drugs and synergistic drugs in Experimental example 1 of the present invention.
The experimental method comprises the following steps: and balancing 230 Km mice with the age of 4 weeks by a barrier isolation system for 3-5 days, wherein the sterile feed and the water are sufficient. Randomly dividing the mice into 23 groups of 10 mice each; the control drug components of the invention are respectively prepared into 20 percent solution, except for the negative control group, the control drug experiment components are respectively gavaged for 1mL, and are gavaged once in 8 hours and are continuously gavaged for three times (the total dose is 18 g/kg). Then, the mice were allowed to feed freely, the body weight was measured 3 days later, and after 15 days, the body weight change of the mice was observed and the mortality of each group was counted, and the results are shown in Table 4.
Table 4 safety evaluation test results
Note: compared to the normal group:*P<0.05。
as can be seen from table 4, the oral administration of products of zonulin or drug groups of zonulin in combination with either single antibiotic or dual antibiotic did not induce the death of mice, and had no significant effect on the body weight of mice, whereas all drug groups added with triple therapy antibiotics induced the death of mice. Therefore, the product of the xianglian is very safe to mice. As the purity of the product of Coptis chinensis Franch increases (see control drugs 8, 9, 10, 11), the body weight of the mice is closer to that of the mice in the negative control group, and it can be seen that the safety also tends to increase with the increase of the purity of the product of Coptis chinensis Franch. The single feeding of the berberine and the orlistat with high dose to the mice has great influence on the safety of the mice and even causes the death of the mice; the mice are also killed to a certain extent by singly feeding the mice with high dose of the coptis total alkaloids.
The product of the xianglian is compounded with 1 antibiotic, has no influence on the body weight and the death rate of the mice, and is safe. The product of Coptis chinensis Franch was combined with 2 antibiotics, and although the death of the mice was not induced, the weight of the mice decreased, indicating that the safety was somewhat affected, but not significantly (synergistic drugs 3-16). After the product of copperleaf meadowrue root and rhizome is compounded with three antibiotics, the weight of a mouse is obviously reduced to reach a remarkable level, and the death of the mouse is also caused, which indicates that the medicine is low in safety (13 and 14 as control medicines and 2 as synergistic medicine).
The product of the invention has better Hp resistance, and the Hp resistance effect is obviously improved compared with the product of the invention which is used independently when the product of the invention is used together with an antibiotic; when the antibiotic is combined with two antibiotics, the effect of resisting Hp is very ideal; the combined use of the three antibiotics increases the anti-Hp effect to a certain extent, and compared with the combined use of two antibiotics, the effect is not obvious, but the safety of the medicament is obviously reduced. The common use of the Chinese goldthread and coptis root product has better effects of losing weight, preventing fatty liver, preventing hepatic fibrosis and preventing liver cirrhosis, while the effects of the single Chinese goldthread and total alkaloids or costustoot on losing weight, preventing fatty liver, preventing hepatic fibrosis and preventing liver cirrhosis are not or are poor, and the safety of the combined medicine is high.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above-described embodiments. It will be understood by those skilled in the art that various changes, substitutions of equivalents, and alterations can be made without departing from the spirit and scope of the invention.
Claims (10)
1. A preparation method of a super-concentrated xianglian product is characterized by comprising the following steps:
1) preparing a golden thread extract: weighing Cornus officinalis, percolating, neutralizing until pH is 2.0-7.0, and filtering; concentrating the filtrate under reduced pressure to 0.5-2g of Cornus officinalis/mL; adding halide salt into the filtrate, precipitating, and filtering to obtain extract I; adding halide salt and high-valence halide salt into the filtered mother liquor, precipitating and filtering to obtain an extract II; mixing the extract I and the extract II to obtain a Cornus officinalis extract;
2) preparation of an elecampane extract: weighing radix aucklandiae, and extracting volatile oil under reflux; filtering the extracted water solution, repeatedly refluxing and extracting the filtered residues for 1-2 times, and combining the filtered water solutions to obtain an extract III; concentrating the extracting solution III to 1-2g of elecampane/mL under reduced pressure; adding ethanol, and filtering to obtain an alcohol solution; recovering ethanol, and oven drying to obtain radix aucklandiae extract; mixing the volatile oil and the water-extraction and alcohol-precipitation extract of costus root to obtain an extract of costus root;
3) mixing the extract of the golden thread and the extract of the costus root, adding auxiliary materials, and granulating to obtain the super-concentrated xianglian product.
2. A process for preparing a super concentrated xianglian product according to claim 1, comprising the following steps:
1) preparing a golden thread extract: weighing Cornus officinalis, percolating with 0.1% -2% sulfuric acid solution, neutralizing percolate with lime or calcium hydroxide to pH 2.0-7.0, and filtering; concentrating the filtrate under reduced pressure to 0.5-2 g/mL of Corni fructus Coptidis rhizoma, cooling, and filtering; adding 1-20% of halide salt into the filtrate, standing at 0-25 deg.C for 1-96 hr, precipitating, and filtering to obtain extract I; adding 1-20% of halide salt and 0.1-2% of high-valence halide salt into the filtered mother liquor, standing at 0-25 deg.C for 1-96 hr, precipitating, and filtering to obtain extract II; mixing the extract I and the extract II to obtain a Cornus officinalis extract;
2) preparation of an elecampane extract: weighing radix aucklandiae, extracting with 5 times of water under reflux for 1-3 hr, and collecting volatile oil; filtering the extracted water solution, repeatedly refluxing and extracting the filtered residues for 1-2 times, and combining the filtered water solutions to obtain an extract III; concentrating the extracting solution III to 1-2g of elecampane/mL under reduced pressure; adding 1-3 times of ethanol, standing for 1-24 hours, and filtering to obtain an alcohol solution; recovering ethanol, and oven drying to obtain radix aucklandiae extract; mixing the volatile oil and the water-extraction and alcohol-precipitation extract of costus root to obtain an extract of costus root;
3) mixing the extract of the golden thread and the extract of the costus root, adding auxiliary materials, and granulating to obtain the super-concentrated xianglian product.
3. Use of a product of Coptis chinensis Franch in a medicament for preventing and treating fatty liver, hepatic fibrosis, liver cirrhosis and liver cancer, the product of Coptis chinensis Franch is a Chinese medicinal composition comprising Coptidis rhizoma and radix aucklandiae as main ingredients, and the product of Coptis chinensis Franch comprises the super-concentrated product of Coptis chinensis Franch according to any one of claims 1-2.
4. The use of the xianglian product of claim 3 in the preparation of drugs for preventing and treating fatty liver, liver fibrosis, liver cirrhosis and liver cancer, characterized by: the rhizoma Coptidis product comprises at least one of rhizoma Coptidis pill, rhizoma Coptidis tablet, rhizoma Coptidis capsule, concentrated rhizoma Coptidis pill, and super-concentrated rhizoma Coptidis product.
5. Use of a Coptis chinensis Franch product in a medicament for preventing and/or treating helicobacter pylori, the Coptis chinensis Franch product is a Chinese medicinal composition containing Coptis chinensis Franch and Costus root as main ingredients, and the Coptis chinensis Franch product comprises the super-concentrated Coptis chinensis Franch product according to any one of claims 1-2.
6. Use of the product of xianglian according to claim 5 in the preparation of a medicament for the prevention and/or treatment of helicobacter pylori, characterized in that: the rhizoma Coptidis product comprises at least one of rhizoma Coptidis pill, rhizoma Coptidis tablet, rhizoma Coptidis capsule, concentrated rhizoma Coptidis pill, and super-concentrated rhizoma Coptidis product.
7. Use of a product of concatenate with one or two antibiotics in combination in a medicament for the prevention and/or treatment of helicobacter pylori.
8. Use of a product of zonulin according to claim 7 in combination with one or two antibiotics in a medicament for the prophylaxis and/or treatment of helicobacter pylori, characterized in that: the product of rhizoma Coptidis is a Chinese medicinal composition containing Coptidis rhizoma and radix aucklandiae as main ingredients.
9. Use of a capsule or a super-concentrated product of rhizoma Coptidis in combination with two antibiotics in the preparation of a medicament for the prevention and/or treatment of helicobacter pylori.
10. Use of a capsule of coptidis or a super-concentrated product of coptidis according to claim 9 in combination with two antibiotics for the prophylaxis and/or treatment of helicobacter pylori, characterized in that: the super concentrated xianglian product is the super concentrated xianglian product in claim 1 or 2.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114558060A (en) * | 2022-03-16 | 2022-05-31 | 重庆伊士腾生物科技有限公司 | Weight-losing target of xianglian product and preparation method of xianglian product |
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