CN113244315A - Preparation method and application of anti-Hp coptis Chinese medicine preparation - Google Patents
Preparation method and application of anti-Hp coptis Chinese medicine preparation Download PDFInfo
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- CN113244315A CN113244315A CN202010089605.8A CN202010089605A CN113244315A CN 113244315 A CN113244315 A CN 113244315A CN 202010089605 A CN202010089605 A CN 202010089605A CN 113244315 A CN113244315 A CN 113244315A
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- fructus evodiae
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
- A61K36/718—Coptis (goldthread)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/75—Rutaceae (Rue family)
- A61K36/754—Evodia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K2236/50—Methods involving additional extraction steps
- A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
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Abstract
The invention provides an anti-Hp coptis traditional Chinese medicine preparation aiming at the characteristics of poor taste and safety, strong drug resistance of a triple therapy and the like of the existing Zuojin pill, and the anti-Hp coptis traditional Chinese medicine preparation comprises 60-95 parts by weight of a coptis extract obtained from coptis and 5-40 parts by weight of an evodia rutaecarpa extract obtained from evodia rutaecarpa, wherein the coptis extract is one of a coptis extract I, a coptis extract II and a coptis extract III. The invention also provides a preparation method and application of the anti-Hp coptis chinensis traditional Chinese medicine preparation. The anti-Hp Chinese medicinal preparation of the invention effectively eliminates the side effect of the product and improves the safety of the medicament.
Description
Technical Field
The invention is applied to the technical field of traditional Chinese medicine preparations, and particularly relates to a preparation method and application of an anti-Hp coptis traditional Chinese medicine preparation.
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). In the prior art, famous classics taking coptis as a main raw material include xianglian pills and zuojin pills, and the preparation process is rough, large in volume and poor in taste; the effective component content of the Zuojin pill and the Xianglian pill is low, the dissolution speed of the effective component is slow, the dosage is small, the effect of killing Hp is weak, and the curative effect of removing Hp is poor; if the dosage of the coptis is increased, the content of impurities is increased, and the safety problem is caused.
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; the traditional Chinese medicine and the effective components thereof have the elimination effect on the drug resistance of bacteria (Wangjie, etc. the screening of the traditional Chinese medicine which can reverse the drug resistance of bacteria [ J ], China pharmaceutical journal, 2014, 49 (21): 1892-1896.). In the prior art, anti-helicobacter pylori is mainly treated by triple therapy, but with the use of antibiotics, drug resistance to the antibiotics is generated, and the eradication rate of Hp is lower and lower.
Disclosure of Invention
The invention provides a preparation method and application of an anti-Hp coptis Chinese medicinal preparation aiming at the problems in the prior art.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
an anti-Hp coptis Chinese medicine preparation comprises 60-95 parts by weight of a coptis extract obtained from coptis chinensis and 5-40 parts by weight of an evodia rutaecarpa extract obtained from evodia rutaecarpa, wherein the coptis extract is one of a coptis extract I, a coptis extract II and a coptis extract III.
Further, the anti-Hp Chinese medicinal preparation of coptis comprises 70-90 parts by weight of coptis chinensis extract and 10-30 parts by weight of evodia rutaecarpa extract. Further preferably, the anti-Hp Chinese medicinal preparation of coptis comprises 85 parts by weight of coptis chinensis extract obtained from coptis chinensis and 15 parts by weight of evodia rutaecarpa extract. The Chinese medicinal preparation has excellent anti-helicobacter pylori effect and high biological safety.
A preparation method of the anti-Hp coptis Chinese medicine preparation comprises the following steps: weighing the coptis chinensis and the fructus evodiae according to a proportion to prepare a coptis chinensis extract and a fructus evodiae extract respectively, mixing uniformly and preparing into pills, tablets or capsules; the coptis extract is one of a coptis extract I, a coptis extract II and a coptis extract III.
Further, a preparation method of the anti-Hp Chinese goldthread preparation comprises the following steps: weighing Coptidis rhizoma and fructus evodiae at a certain proportion to obtain Coptidis rhizoma extract and fructus evodiae extract, mixing, adding appropriate amount of starch, and making into capsule; the coptis extract is one of a coptis extract I, a coptis extract II and a coptis extract III.
Further, the extraction method of the coptis chinensis extract I comprises the following steps: weighing Coptidis rhizoma, slicing, extracting with 40-70% ethanol under reflux for three times, mixing extractive solutions, filtering, recovering ethanol, and concentrating to obtain Coptidis rhizoma extract I.
Further, the extraction method of the coptis chinensis extract II comprises the following steps: weighing Coptidis rhizoma, slicing, soaking in 0.1-2% sulfuric acid water solution for 1-48 hr, and percolating to extract; neutralizing the extractive solution with lime to pH 1-9, filtering, and concentrating the filtrate under reduced pressure to dry to obtain Coptidis rhizoma extract II.
Further, the extraction method of the coptis chinensis extract III comprises the following steps: weighing Coptidis rhizoma extract I or Coptidis rhizoma extract II, and preparing into 0.05-0.2g/mL solution with distilled water; filtering, adding 0.1-20% (W/V) sodium chloride, standing for 1-24 hr, and filtering to obtain precipitate 1; extracting the filtrate mother liquor with butanol at a ratio of 1:1 for 2-4 times, and recovering butanol to obtain extract 2; and mixing the precipitate 1 and the extract 2, and drying to obtain a coptis chinensis extract III.
Further, the extraction method of the fructus evodiae extract comprises the following steps: weighing 30-100% of fructus evodiae, reflux-extracting with 5-10 times of 40-70% ethanol for 3 times, and recovering ethanol to obtain fructus evodiae extract; pulverizing other 0-40% of fructus evodiae, and sieving with No. 5 sieve to obtain fructus evodiae fine powder; and uniformly mixing the obtained fructus evodiae fine powder and the obtained fructus evodiae extract, and drying to obtain the fructus evodiae extract.
An application of the anti-Hp Chinese medicinal preparation of coptis in the aspect of anti-Hp medicines in combination with antibiotics.
Further, the antibiotic comprises one of clarithromycin, amoxicillin, metronidazole, levofloxacin, furazolidone, omeprazole and tetracycline.
Furthermore, the Chinese medicinal preparation of coptis inhibits the drug resistance of helicobacter pylori to antibiotics.
Furthermore, coptisine in the coptis extract inhibits the drug resistance of helicobacter pylori to antibiotics.
Compared with the prior art, the invention has the beneficial effects that:
(1) the anti-Hp Chinese medicinal preparation of coptis is improved on the basis of famous Jingfang Zuojin pills, and comprises a coptis extract and an evodia rutaecarpa extract, wherein the extraction rate of coptisine in coptis by the extraction method reaches over 95 percent, and the anti-helicobacter pylori effect is good; meanwhile, the combination of the medicinal composition and the fructus evodiae effectively eliminates the side effect of the product and improves the safety of the medicament; the traditional Chinese medicine composition is used in combination with a clinical standard therapy (triple therapy) for treating Hp, so that the curative effect can be further improved, and the drug resistance of antibiotics and the toxic and side effects of the triple therapy can be reduced or even eliminated;
(2) the coptis chinensis traditional Chinese medicine preparation disclosed by the invention is high in alkaloid content, so that the prepared traditional Chinese medicine preparation is small in size and convenient to process into capsules, tablets (coatings), pills (coatings) and the like, the taste of the preparation can be effectively improved, and the clinical compliance is remarkably improved;
(3) the coptis chinensis alkaloid in the coptis chinensis extract is higher than that in the prior art, the coptis chinensis alkaloid content in the coptis chinensis extract III is highest, the coptis chinensis alkaloid content in the coptis chinensis extract II is related to the pH value, and the coptis chinensis alkaloid content in the coptis chinensis extract II is increased when the pH value is less than 2.
(4) The Chinese medicinal preparation of coptis root of the invention not only has the effect of resisting helicobacter pylori, but also has the effect of curing stomach and intestinal diseases, and has better prevention effect on digestive tract tumors (especially gastric cancer);
(5) the coptis chinensis traditional Chinese medicine preparation is combined with antibiotics, so that the antibacterial activity of the antibiotics can be obviously improved, and the effect of inhibiting the durability of the antibiotics is achieved;
(6) the coptis chinensis traditional Chinese medicine preparation disclosed by the invention is low in polysaccharide content, is a low-sugar Hp-resistant coptis chinensis traditional Chinese medicine preparation, is suitable for various crowds, and is wide in application range.
Drawings
FIG. 1 is an HPLC chromatogram of a Coptidis rhizoma extract I in the preparation method and application of an anti-Hp Coptidis rhizoma Chinese medicinal preparation of the present invention.
FIG. 2 is an HPLC chromatogram of a Coptidis rhizoma extract II in the preparation method and application of an anti-Hp Coptidis rhizoma Chinese medicinal preparation of the present invention.
FIG. 3 is an HPLC chromatogram of Coptidis rhizoma extract III in the preparation method and application of an anti-Hp Coptidis rhizoma Chinese medicinal preparation of the present invention.
In the HPLC charts of the attached drawings 1, 2 and 3, from right to left: berberine, palmatine, coptisine and epiberberine.
Detailed Description
The technical solution of the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments. 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:
preparing a coptis chinensis extract I:
weighing 95Kg of coptis chinensis tablets, performing reflux extraction on the coptis chinensis tablets for 3 times by using 5 times of 40% ethanol, combining extracting solutions, filtering and recovering a solvent, and concentrating the extract into thick paste to obtain a coptis chinensis extract I weighing 30 Kg; HPLC content analysis is carried out on the coptis extract I, and 17.5 percent of berberine, 5.1 percent of palmatine, 5.6 percent of coptisine and 2.5 percent of epiberberine are obtained; the HPLC chromatogram is shown in figure 1.
Preparing a coptis chinensis extract II:
weighing 95Kg of coptis chinensis tablets, soaking the coptis chinensis tablets in 30 times of 0.1 percent (V/V) of sulfuric acid aqueous solution for 48 hours, and then percolating and extracting; neutralizing the extracting solution with limewater solution until the pH value of the solution is 1, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain Coptidis rhizoma extract II with weight of 25.5 Kg; HPLC content analysis is carried out on the coptis extract II, and 22.2% of berberine, 6.5% of palmatine, 7.0% of coptisine and 2.9% of epiberberine are obtained; the HPLC chromatogram is shown in figure 2.
Preparing a coptis extract III:
weighing 30Kg of coptis extract I, and preparing 0.05g/mL solution by using distilled water; filtering, adding 20% (W/V) sodium chloride, standing for 1 hr, and filtering to obtain precipitate I; extracting the filtrate mother liquor with butanol at a ratio of 1:1 for 2-4 times, and recovering butanol to obtain extract II; mixing the precipitate I and the extract II, and drying to obtain 15Kg of coptis extract III; HPLC content analysis is carried out on the coptis extract III, and the berberine comprises 36.5 percent of berberine, 10.8 percent of palmatine, 11.5 percent of coptisine and 4.9 percent of epiberberine; the HPLC chromatogram is shown in figure 3.
Preparing the evodia rutaecarpa extract:
weighing 5Kg of fructus evodiae, and crushing 1.67Kg of fructus evodiae and sieving with a No. 5 sieve to obtain fructus evodiae fine powder; extracting the other 3.33Kg of fructus evodiae with 5 times of 70% ethanol under reflux for 3 times, and recovering ethanol to obtain fructus evodiae extract; then mixing the obtained fructus evodiae fine powder and fructus evodiae extract, and drying at 60 ℃ to obtain 2.33Kg of fructus evodiae extract.
And uniformly mixing the obtained fructus evodiae extract and the coptis chinensis extract I, adding a proper amount of starch, uniformly mixing, and filling into capsules to obtain the Hp-resistant traditional Chinese medicine preparation. Through detection, the anti-Hp activity of the anti-Hp traditional Chinese medicine preparation is detected, the MIC for Hp is 200mg/L, the IC50 for JBU is 250mg/L, the activity is high, and no drug resistance exists.
Example 2:
preparing a coptis chinensis extract I:
weighing 60Kg of coptis chinensis tablets, performing reflux extraction on the coptis chinensis tablets for 3 times by using 70 percent ethanol in an amount which is 5 times that of the coptis chinensis tablets, combining extracting solutions, filtering and recovering a solvent, and concentrating the filtrate into thick paste to obtain 18Kg of coptis chinensis extract I; HPLC content analysis is carried out on the coptis extract I, and 17.8 percent of berberine, 5.3 percent of palmatine, 5.5 percent of coptisine and 2.4 percent of epiberberine are obtained.
Preparing a coptis chinensis extract II:
weighing 60Kg of coptis chinensis tablets, soaking the coptis chinensis tablets in 30 times of 2 percent (V/V) of sulfuric acid aqueous solution for 1 hour, and then percolating and extracting; neutralizing the extracting solution with limewater solution until the pH value of the solution is 2, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain Coptidis rhizoma extract II with weight of 19 Kg; HPLC content analysis is carried out on the coptis extract II, and berberine accounts for 18.2%, palmatine 5.3%, berberine 5.7% and epiberberine 2.5%.
Preparing a coptis extract III:
weighing 19Kg of coptis extract II, and preparing 0.2g/mL of coptis extract with distilled water; filtering, adding 0.1% (W/V) sodium chloride, standing for 24 hr, and filtering to obtain precipitate I; extracting the filtrate mother liquor with butanol at a ratio of 1:1 for 2-4 times, and recovering butanol to obtain extract II; mixing the precipitate I and the extract II, and drying to obtain 8Kg of coptis extract III; HPLC content analysis is carried out on the coptis extract III, and berberine accounts for 37.5 percent, palmatine 10.1 percent, coptisine 11.1 percent and epiberberine 5.0 percent; the HPLC chromatogram is shown in figure 3.
Preparing the evodia rutaecarpa extract:
weighing 40Kg of fructus evodiae, and crushing 16Kg of fructus evodiae and sieving through a No. 5 sieve to obtain fructus evodiae fine powder; taking the other 24Kg of fructus evodiae, performing reflux extraction for 3 times by using 40% ethanol in an amount which is 5 times that of the fructus evodiae, and recovering the ethanol to obtain fructus evodiae extract; then mixing the obtained fructus evodiae fine powder and fructus evodiae extract, and drying at 60 ℃ to obtain 18.66Kg of fructus evodiae extract.
Mixing the obtained fructus evodiae extract and Coptidis rhizoma extract II, and making into pill to obtain Hp-resistant Chinese medicinal preparation. Through detection, the anti-Hp activity of the anti-Hp traditional Chinese medicine preparation is detected, the MIC for Hp is 300mg/L, the IC50 for JBU is 350mg/L, the activity is high, and no drug resistance exists.
Example 3:
preparing a coptis chinensis extract I:
weighing 85Kg of coptis chinensis tablets, performing reflux extraction on the coptis chinensis tablets for 3 times by using 60 percent ethanol in an amount which is 5 times that of the coptis chinensis tablets, combining extracting solutions, filtering and recovering a solvent, and concentrating the filtrate into thick paste to obtain a coptis chinensis extract I, wherein the weight of the coptis chinensis extract I is 25.5 Kg; HPLC content analysis is carried out on the coptis extract I, and 17.6 percent of berberine, 5.5 percent of palmatine, 5.7 percent of coptisine and 2.6 percent of epiberberine are obtained.
Preparing a coptis chinensis extract II:
weighing 85Kg of coptis chinensis tablets, soaking the coptis chinensis tablets in 30 times of 1 percent (V/V) of sulfuric acid aqueous solution for 12 hours, and then percolating and extracting; neutralizing the extracting solution with limewater solution until the pH value of the solution is 4, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain Coptidis rhizoma extract II with weight of 26.5 Kg; HPLC content analysis is carried out on the coptis extract II, and berberine accounts for 18.4%, palmatine 5.4%, berberine 5.5% and epiberberine 2.6%.
Preparing a coptis extract III:
weighing 25.5Kg of coptis extract I, and preparing 0.1g/mL solution by using distilled water; filtering, adding 10% (W/V) sodium chloride, standing for 12 hr, and filtering to obtain precipitate I; extracting the filtrate mother liquor with butanol at a ratio of 1:1 for 2-4 times, and recovering butanol to obtain extract II; mixing the precipitate I and the extract II, and drying to obtain 12Kg of coptis extract III; HPLC content analysis is carried out on the coptis extract III, and the berberine comprises 36.7 percent of berberine, 10.9 percent of palmatine, 11.6 percent of coptisine and 4.7 percent of epiberberine; the HPLC chromatogram is shown in figure 3.
Preparing the evodia rutaecarpa extract:
weighing 15Kg of fructus evodiae, and crushing 5Kg of fructus evodiae and sieving through a No. 5 sieve to obtain fructus evodiae fine powder; taking the other 10Kg of fructus evodiae, performing reflux extraction for 3 times by using 60% ethanol in an amount which is 5 times that of the fructus evodiae, and recovering the ethanol to obtain fructus evodiae extract; then mixing the obtained fructus evodiae fine powder and fructus evodiae extract, and drying at 60 ℃ to obtain 6Kg of fructus evodiae extract.
Mixing the obtained fructus evodiae extract and Coptidis rhizoma extract III, adding appropriate amount of starch, mixing, and making into capsule to obtain the Hp-resistant Chinese medicinal preparation. Through detection, HPLC analysis shows that the content of berberine in the capsule is 14.0%, palmatine 4.4%, berberine 4.5% and epiberberine 2.1%; the content of total alkaloids is 25.0%. The anti-Hp Chinese medicinal preparation has the advantages of high anti-Hp activity and no drug resistance, and the detection result shows that the MIC of the anti-Hp Chinese medicinal preparation is 250mg/L for Hp and the IC50 of JBU is 300mg/L for Hp.
Example 4:
preparing a coptis chinensis extract I:
weighing 75Kg of coptis chinensis tablets, performing reflux extraction on the coptis chinensis tablets for 3 times by using 60 percent ethanol in an amount which is 5 times that of the coptis chinensis tablets, combining extracting solutions, filtering and recovering a solvent, and concentrating the filtrate into thick paste to obtain a coptis chinensis extract I weighing 22.5 Kg; HPLC content analysis is carried out on the coptis extract I, and 17.8 percent of berberine, 5.6 percent of palmatine, 5.7 percent of coptisine and 2.4 percent of epiberberine are obtained.
Preparing a coptis chinensis extract II:
weighing 75Kg of coptis chinensis tablets, soaking the coptis chinensis tablets in 30 times of 1 percent (V/V) of sulfuric acid aqueous solution for 6 hours, and then percolating and extracting; neutralizing the extracting solution with limewater solution until the pH value of the solution is 6, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain Coptidis rhizoma extract II weighing 23 Kg; HPLC content analysis is carried out on the coptis extract II, and berberine accounts for 18.4%, palmatine 5.6%, berberine 5.5% and epiberberine 2.4%.
Preparing a coptis extract III:
weighing 23Kg of coptis extract II, and preparing 0.08g/mL solution by using distilled water; filtering, adding 5% (W/V) sodium chloride, standing for 6 hr, and filtering to obtain precipitate I; extracting the filtrate mother liquor with butanol at a ratio of 1:1 for 2-4 times, and recovering butanol to obtain extract II; mixing the precipitate I and the extract II, and drying to obtain 11Kg of coptis extract III; HPLC content analysis is carried out on the coptis extract III, and the berberine comprises 36.7 percent of berberine, 10.7 percent of palmatine, 11.6 percent of coptisine and 4.9 percent of epiberberine; the HPLC chromatogram is shown in figure 3.
Preparing the evodia rutaecarpa extract:
weighing 25Kg of fructus evodiae, extracting with 5 times of 50% ethanol under reflux for 3 times, and recovering ethanol to obtain fructus evodiae extract; then mixing the obtained fructus evodiae fine powder and fructus evodiae extract, and drying at 60 deg.C to obtain 6.0Kg of fructus evodiae extract.
Mixing the obtained fructus evodiae extract and Coptidis rhizoma extract III, and making into floating type tablet to obtain anti-Hp Chinese medicinal preparation. Through detection, the anti-Hp activity of the anti-Hp traditional Chinese medicine preparation is detected, the MIC for Hp is 250mg/L, the IC50 for JBU is 300mg/L, the activity is high, and no drug resistance exists.
Example 5:
preparing a coptis chinensis extract I:
weighing 80Kg of coptis chinensis tablets, performing reflux extraction for 3 times by using 50 percent ethanol in an amount which is 5 times that of the coptis chinensis tablets, combining extracting solutions, filtering and recovering a solvent, and concentrating the extract into thick paste to obtain 24Kg of coptis chinensis extract I; HPLC content analysis is carried out on the coptis extract I, and 17.8 percent of berberine, 5.5 percent of palmatine, 5.7 percent of coptisine and 2.3 percent of epiberberine are obtained.
Preparing a coptis chinensis extract II:
weighing 80Kg of coptis chinensis slices, soaking the coptis chinensis slices in 30 times of 0.5 percent (V/V) of sulfuric acid aqueous solution for 18 hours, and then percolating and extracting; neutralizing the extracting solution with limewater solution until the pH value of the solution is 9, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain Coptidis rhizoma extract II weighing 24.5 Kg; HPLC content analysis is carried out on the coptis extract II, and berberine accounts for 18.7%, palmatine 5.7%, berberine 5.5% and epiberberine 2.4%.
Preparing a coptis extract III:
weighing 24Kg of coptis extract I, and preparing 0.1g/mL solution by using distilled water; filtering, adding 1% (W/V) sodium chloride, standing for 12 hr, and filtering to obtain precipitate I; extracting the filtrate mother liquor with butanol at a ratio of 1:1 for 2-4 times, and recovering butanol to obtain extract II; mixing the precipitate I and the extract II, and drying to obtain 12Kg of coptis extract III; HPLC content analysis is carried out on the coptis extract III, and the berberine comprises 36.7 percent of berberine, 10.8 percent of palmatine, 11.6 percent of coptisine and 4.9 percent of epiberberine; the HPLC chromatogram is shown in figure 3.
Preparing the evodia rutaecarpa extract:
weighing 20Kg of fructus evodiae, and crushing 14Kg of fructus evodiae and sieving through a No. 5 sieve to obtain fructus evodiae fine powder; taking the other 6Kg of fructus evodiae, performing reflux extraction for 3 times by using 60% ethanol in an amount which is 5 times that of the fructus evodiae, and recovering the ethanol to obtain fructus evodiae extract; then mixing the obtained fructus evodiae fine powder and fructus evodiae extract, and drying at 60 ℃ to obtain 15.2Kg of fructus evodiae extract.
And uniformly mixing the obtained fructus evodiae extract and the coptis chinensis extract I, and preparing the mixture into tablets to obtain the Hp-resistant traditional Chinese medicine preparation. Through detection, the anti-Hp activity of the anti-Hp traditional Chinese medicine preparation is detected, the MIC for Hp is 250mg/L, the IC50 for JBU is 300mg/L, the activity is high, and no drug resistance exists.
Experimental example 1: in vitro Helicobacter Pylori (HP) killing effect
Comparative drug 1: weighing 2.2kg of berberine monomer, mixing with the fructus evodiae extract uniformly, adding starch to prepare the capsule, and analyzing the berberine alkaloid content to be 25% by HPLC.
Comparative drug 2: weighing 2.2kg of epiberberine monomer, uniformly mixing with the evodia rutaecarpa extract, adding starch to prepare the capsule, and analyzing the content of coptis alkaloid by HPLC to be 25% of epiberberine.
Comparative drug 3: weighing 2.2kg of coptisine monomer, uniformly mixing with the evodia rutaecarpa extract, adding starch to prepare the capsule, and analyzing the coptisine content to be 25% by HPLC.
Control drugs:
control drug 1: clarithromycin.
Control drug 2: and (3) amoxicillin.
Control drug 3: and (4) metronidazole.
Control drug 4: levofloxacin.
Control drug 5: furazolidone.
Control drug 6: omeprazole.
Control drug 7: a tetracycline.
Synergistic drug:
1, synergistic medicine: example 3+ control drug 1.
And 2, synergistic medicine: example 3+ control drug 2.
And (3) synergistic medicine: example 4+ control drug 3.
Synergistic agent 4: example 1+ control drug 4.
And (5) synergistic medicine: example 5+ control drug 5.
And (3) synergistic medicine 6: example 2+ control drug 6.
And (3) synergistic medicine 7: example 3+ control drug 7.
And (3) synergistic medicine 8: comparative drug 1+ control drug 1.
Synergistic agent 9: comparative drug 2+ control drug 2.
The synergistic medicine 10: control 3+ control 3.
The synergistic medicament 11: control drug 1+ control drug 4
The synergistic agent 12: control 2+ control 5
Synergistic drug 13: control drug 3+ control drug 6
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 experimental strain is NCTC 11637; the MBC of the drugs and the synergistic drugs in the examples was determined by the sesquidilution method (Chinese journal of basic medicine, 2017,23(03): 405-.
TABLE 1 MBC of drug pairs Hp (NCTC 11637)
As can be seen from Table 1, each example showed a good killing effect on Hp, and it can be seen that the Chinese medicinal preparation of the present invention showed a killing effect on Hp. After the combination of the examples and antibiotics (clarithromycin, amoxicillin, omeprazole, metronidazole, levofloxacin, furazolidone and tetracycline), the Hp killing capability of different antibiotics and examples is greatly improved, which shows that the traditional Chinese medicine preparation and the antibiotics have good synergistic effect. After the single coptisine (berberine, coptisine and epiberberine) is used together with the antibiotic, the activity of the antibiotic is improved to a small extent, almost no synergistic effect exists, and only the coptisine is used together with the omeprazole to have the small synergistic effect.
Experimental example 2: inhibitory Effect on urease (urease) Activity
The comparative drugs and control drugs in the examples and experimental example 1 of the present invention were tested for inhibition of urease activity, the Pharmaceutical preparations in the examples of the present invention were compared with antibiotics, and the experimental method reference examined the IC50 of the drugs (European Journal of Pharmaceutical Sciences,2017: S09280717300660); setaria edulis urease (JBU) was purchased from Solebao Biotechnology, Inc. The IC50 for the drug is shown in table 2.
TABLE 2 IC50 of drug vs JBU
Medicine | IC50(mg/L) | Medicine | IC50(mg/L) |
Example 1 | 250 | |
290 |
Example 2 | 350 | |
290 |
Example 3 | 300 | |
300 |
Example 4 | 300 | |
250 |
Example 5 | 300 | |
290 |
|
1100 | |
340 |
|
20 | |
300 |
|
550 | |
240 |
|
1200 | |
15 |
|
900 | |
200 |
|
1000 | Synergistic agents 11 | 700 |
|
1100 | Synergistic agent 12 | 14 |
|
1500 | Synergistic agents 13 | 500 |
|
2000 | ||
|
1400 |
As can be seen from Table 2, the antibiotic has little effect on the activity of urease, while the Chinese medicinal preparation of the present invention has a better inhibitory effect on the activity of urease. After the traditional Chinese medicine preparation in each embodiment of the invention is compounded with antibiotics (clarithromycin, amoxicillin, omeprazole, metronidazole, levofloxacin, furazolidone and tetracycline), the activity of inhibiting urease is almost unchanged.
Experimental example 3: effect on the helicobacter pylori (Hp) drug resistance Gene hef A
The effects of various traditional Chinese medicine preparations on helicobacter pylori (Hp) drug-resistant gene hef a of the control drugs and the control drugs in the embodiments and the experimental example 1 of the invention are tested, and the concentration of the drug on the Hp efflux pump hef a gene of each drug is detected by a PCR method (study on the action and mechanism of Liuyu, Jinghua Weikang capsules and the formula-disassembled anti-drug-resistant helicobacter pylori [ D ]. Beijing university of traditional Chinese medicine 2014). The effect of the drug on the concentration of hef A gene is shown in Table 3.
TABLE 3 Effect of drugs on the expression of the efflux Pump hef A Gene of Hp
Medicine | hef A | Medicine | hef A |
Internal |
10 | |
2 |
Example 1 | 6 | |
1 |
Example 2 | 5 | |
2 |
Example 3 | 4 | |
4 |
Example 4 | 4 | |
3 |
Example 5 | 5 | |
3 |
|
4 | |
3 |
|
4 | |
25 |
|
5 | |
18 |
|
5 | |
1 |
|
5 | Synergistic agents 11 | 22 |
|
7 | Synergistic agent 12 | 20 |
|
6 | Synergistic agents 13 | 2 |
As can be seen from Table 3, the expression of the efflux pump hef A gene of Hp was down-regulated in each example of the inventive Chinese medicinal formulation and the control drug group; in the synergistic medicine, the expression of the hef A gene can be reduced by the traditional Chinese medicine preparation and the synergistic medicine of the antibiotic, and in addition, the expression of the hef A gene can be obviously reduced by the synergistic medicine of the coptisine monomer and the antibiotic, so that after the traditional Chinese medicine preparation, the coptisine monomer and the antibiotic (clarithromycin, amoxicillin, omeprazole, metronidazole, levofloxacin, furazolidone and tetracycline) are compounded, the expression of the hep efflux pump hef A gene is further reduced, and the reduction amplitude is very obvious, which indicates that the traditional Chinese medicine preparation and the coptisine monomer can inhibit the drug resistance of the antibiotic.
When the berberine monomer or the epiberberine monomer is compounded with part of antibiotics (clarithromycin, amoxicillin, omeprazole, metronidazole, levofloxacin, furazolidone and tetracycline), the expression of the hep efflux pump hef A gene is rapidly increased, which indicates that the side effect of promoting the antibiotic resistance is achieved.
Experimental example 4: safety of medicine
The safety of the drug was tested by using various Chinese medicinal preparations for the control group and the comparative drug in each example and experimental example 1.
The experimental method comprises the following steps: 180 Km mice with the age of 4 weeks are balanced by a barrier isolation system for 3-5 days, and the sterile feed and water are sufficient. Randomly dividing the mice into 15 groups of 10 mice each; the traditional Chinese medicine preparation, the contrast medicine and the control group medicine in the embodiments 1-5 of the invention are respectively prepared into 20 percent solution, except the negative control group, each medicine experiment group is respectively gavaged with 0.6mL, and is gavaged once in 8 hours and is 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 mortality of each group was counted, and the results are shown in Table 4.
Control group:
control group 1: berberine monomer.
Control group 2: an epiberberine monomer.
Control group 3: coptisine monomer.
Control group 4: coptis chinensis.
Control group 5: the coptis extract I.
Control group 6: and (4) a coptis extract II.
Control group 7: coptidis rhizoma extract III.
Table 4 safety evaluation test results
As can be seen from Table 4, the administration of a large dose of Coptidis rhizoma directly to the mice (control group 4) had a significant effect on the body weight of the mice; with the purification of the coptis alkaloid (control groups 1-3 and 5-6), the influence on the weight of the mouse is reduced, and the safety is improved; when a single coptidis rhizoma alkaloid monomer (berberine monomer, coptidis rhizoma monomer and epiberberine monomer) is compounded with the evodia rutaecarpa extract (contrast drugs 1-3), the influence on the weight of a mouse is further reduced, which shows that the safety of the drugs is further improved. The embodiments 1 to 5 of the invention are the effects of the composition of the coptis extract and the evodia extract on the weight of a mouse, and detection results show that the embodiments of the invention have small effects on the weight of the mouse. The test result shows that the traditional Chinese medicine preparation has better influence on the body weight of the mouse than the control group medicine.
Experimental example 5: polysaccharide content and appearance of the extract
The appearance of the coptis chinensis extract I is thick extract, and the polysaccharide content of the coptis chinensis extract I is 32% by detecting the polysaccharide content of the coptis chinensis extract I by using an anthrone sulfate method (such as the royal autumn chrysanthemum, the content of zymosan is determined by an anthrone-sulfuric acid method, Chinese veterinary medicine 2007,34 (1): 39).
The appearance of the coptis chinensis extract II is thick extract, and the polysaccharide content is 36 percent by detecting the polysaccharide content by using an anthrone sulfate method.
The appearance of the coptis extract III is powdery particles, and the polysaccharide content is 18 percent by detecting the polysaccharide content by using an anthrone sulfate method.
With the combination of experimental examples 1-5, compared with the existing ZUOJIN pill and XIANGLIAN pill, the traditional Chinese medicine preparation of the invention has low polysaccharide content, is a low-sugar Hp-resistant traditional Chinese medicine preparation, and has wide application range; the content of total alkaloids as main ingredients is higher, the volume of a traditional Chinese medicine preparation with the same drug effect is smaller, the content of impurities is small, and the safety is higher (see table 4); and when the composition is used together with antibiotics, the composition has obvious synergistic effect and can inhibit the drug resistance of the antibiotics, which is not possessed by the prior Hp-resistant medicines, Zuojin pills, Xianglian pills and the like.
Particularly, the coptis chinensis extract III is easier to process into capsules or gastric floating tablets, and the safety is higher compared with a traditional Chinese medicine preparation synthesized by the coptis chinensis extract I and the coptis chinensis extract II (Table 4); the total alkaloid content is higher (examples 1-5), the polysaccharide content is low, the low-sugar traditional Chinese medicine preparation is wide in application range, and the volume of the finally obtained traditional Chinese medicine preparation is smaller.
Experimental example 6: coptidis rhizoma extract II with alkaloid content and appearance
The alkaloid content and appearance of Coptidis rhizoma extract II of examples 1-5 are shown in the following table. The detection method of the content of the coptis alkaloid is carried out according to the quality detection method of coptis chinensis in the 'Chinese pharmacopoeia' 2015 edition.
Coptidis rhizoma extract II | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 |
pH of |
1 | 2 | 4 | 6 | 9 |
Berberine (%) | 22.2 | 18.2 | 18.4 | 18.4 | 17.3 |
Palmatine (%) | 6.5 | 5.3 | 5.4 | 5.6 | 5.2 |
Coptisine (%) | 7 | 5.7 | 5.5 | 5.5 | 5 |
Epiberberine (%) | 2.9 | 2.5 | 2.6 | 2.4 | 2.2 |
Total Alkaloids (%) | 38.6 | 31.7 | 31.9 | 31.9 | 29.7 |
Appearance of the product | Yellow colour | Yellow colour | Light yellow | Yellow brown | Dark brown color |
As can be seen from the table, in the extraction process of the coptis chinensis extract II, the content of coptis chinensis alkaloid is related to the pH value, the color of the coptis chinensis extract II is deepened along with the increase of the pH value, the content of total alkaloids is reduced, and especially when the extracted pH value is lower than 2, the content of alkaloid in the product is obviously increased.
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. An Hp-resistant coptis chinensis traditional Chinese medicine preparation is characterized in that: the medicinal composition comprises 60-95 parts by weight of coptis chinensis extract obtained from coptis chinensis and 5-40 parts by weight of evodia rutaecarpa extract obtained from evodia rutaecarpa, wherein the coptis chinensis extract is one of a coptis chinensis extract I, a coptis chinensis extract II and a coptis chinensis extract III.
2. The method for preparing the anti-Hp Chinese goldthread preparation according to claim 1, wherein the method comprises the following steps: weighing the coptis chinensis and the fructus evodiae according to a proportion to prepare a coptis chinensis extract and a fructus evodiae extract respectively, mixing uniformly and preparing into pills, tablets or capsules; the coptis extract is one of a coptis extract I, a coptis extract II and a coptis extract III.
3. The method for preparing the anti-Hp Chinese goldthread preparation according to claim 2, wherein the method comprises the following steps: the extraction method of the coptis chinensis extract I comprises the following steps: weighing Coptidis rhizoma, slicing, extracting with 40-70% ethanol under reflux for three times, mixing extractive solutions, filtering, recovering ethanol, and concentrating to obtain Coptidis rhizoma extract I.
4. The method for preparing the anti-Hp Chinese goldthread preparation according to claim 2, wherein the method comprises the following steps: the extraction method of the coptis chinensis extract II comprises the following steps: weighing Coptidis rhizoma, slicing, soaking in 0.1-2% sulfuric acid water solution for 1-48 hr, and percolating to extract; neutralizing the extractive solution with lime to pH 1-9, filtering, and concentrating the filtrate under reduced pressure to dry to obtain Coptidis rhizoma extract II.
5. The method for preparing the anti-Hp Chinese goldthread preparation according to claim 2, wherein the method comprises the following steps: the extraction method of the coptis chinensis extract III comprises the following steps: weighing Coptidis rhizoma extract I or Coptidis rhizoma extract II, and preparing into 0.05-0.2g/mL solution with distilled water; filtering, adding 0.1-20% (W/V) sodium chloride, standing for 1-4 hr, and filtering to obtain precipitate 1; extracting the filtrate mother liquor with butanol at a ratio of 1:1 for 2-4 times, and recovering butanol to obtain extract 2; and mixing the precipitate 1 and the extract 2, and drying to obtain a coptis chinensis extract III.
6. The method for preparing the anti-Hp Chinese goldthread preparation according to claim 2, wherein the method comprises the following steps: the extraction method of the fructus evodiae extract comprises the following steps: weighing fructus evodiae, reflux-extracting 30-100% of fructus evodiae with 5-10 times of 40-70% ethanol for 3 times, and recovering ethanol to obtain fructus evodiae extract; pulverizing other 0-40% of fructus evodiae, and sieving with No. 5 sieve to obtain fructus evodiae fine powder; and uniformly mixing the obtained fructus evodiae fine powder and the obtained fructus evodiae extract, and drying to obtain the fructus evodiae extract.
7. The use of the anti-Hp Chinese goldthread preparation according to claim 1 or 2 in combination with an antibiotic for an anti-Hp medicament.
8. Use according to claim 7, characterized in that: the antibiotic comprises one of clarithromycin, amoxicillin, metronidazole, levofloxacin, furazolidone, omeprazole and tetracycline.
9. Use according to claim 7, characterized in that: the Chinese medicinal preparation of coptis inhibits the drug resistance of helicobacter pylori to antibiotics.
10. Use according to claim 7, characterized in that: the coptisine in the coptis extract inhibits the drug resistance of helicobacter pylori to antibiotics.
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