CN110251504A - The preparation method and new medical use of Saliggenon D - Google Patents
The preparation method and new medical use of Saliggenon D Download PDFInfo
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- CN110251504A CN110251504A CN201910617148.2A CN201910617148A CN110251504A CN 110251504 A CN110251504 A CN 110251504A CN 201910617148 A CN201910617148 A CN 201910617148A CN 110251504 A CN110251504 A CN 110251504A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract
The present invention discloses a kind of preparation method and new medical use that Saliggenon D is extracted from the root bark of white mulberry, ramulus mori, mulberry leaf, new application, which is specifically Saliggenon D single component, has the application for inhibiting xanthine oxidase, can prepare antigout, the application in inhibiting hyperuricemia drug.The compounds of this invention is significant in efficacy, easy to use, cost is relatively low, and without obvious toxic-side effects, has important clinical value.New direction is provided to improve the big phenomenon of current goat drug side-effect.
Description
Technical field
The present invention relates to preparation method and new medical use that Saliggenon D is extracted from the root bark of white mulberry, ramulus mori, mulberry leaf, tools
Saying for body is that Saliggenon D single component has the application for inhibiting xanthine oxidase, can prepare antigout, inhibiting hyperuricemia
Application in drug is also related to the pharmaceutical preparation of the drug, and the invention belongs to pharmaceutical technology fields.
Background technique
Gout is a kind of common disease that purine metabolic disturbance causes uric acid to be formed, and it is big stupid to be classified as 21 century 20 by the United Nations
One of disease.Newest epidemiological study shows that China's gout disease incidence rises year by year, and has surpassed the world average level, tradition
Anti-gout drugs-uricosureic agent (such as probenecid, Benzbromarone) often with the pairs such as fash, fever, kidney damage
Effect.Xanthine oxidase inhibitor can reduce stress reaction caused by free radical or the injury to tissue, can also reduce
The formation of uric acid in human body.Research finds have good antigout to act on by the inhibitor of action target spot of xanthine oxidase,
It is to treat the important drugs of gout and can be reduced some fatal gout complication.
Xanthine oxidase inhibitor is as anti-gout drugs, the allopurinol mainly listed the sixties in last century, though
It so uses till today always but it has many side effects, can have fever, allergic rash, abdominal pain, diarrhea, white using rear patient
Cell and decrease of platelet, or even have the side effects such as liver dysfunction (progress of xanthine oxidase inhibitor, foreign countries doctor
Learn pharmacy fascicle, 2006,33 (5), 351-353).Therefore, studying new xanthine oxidase inhibitor has highly important meaning
Justice.We have found that new xanthine oxidase inhibitor-Saliggenon D, to be extracted from the Mulberry plant root bark of white mulberry, ramulus mori, mulberry leaf
It is isolated.
There is the extract of document report ramulus mori that there is effect for reducing blood fat (analogy swallow, Southwest University, 2017, Master's thesis)；
Xiaoli Zhang research report, extract of mulberry twig have inhibit lipase active (CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2012, volume 37, the 9th
Phase, page 1323)；CN103156869A disclose a kind of sanggenon C extracted from the root bark of white mulberry, ramulus mori, mulberry leaf, Saliggenon D and
With sanggenon C, the new medical use of Saliggenon D composition as main component, specifically sanggenon C, Saliggenon D is single
Ingredient and sanggenon C, Saliggenon D and morusin, mulberry skin glucoside, oxidized resveratrol, resveratrol, 1-Deoxynojirimycin composition
Composition is preparing the application in alpha-glucosidase inhibitor medicament；Wang Caiping is studies have shown that extract of mulberry twig has adjusting
Organic anion transport improves the effect of hyperuricemia, and this extract is a kind of crude extract, the chemistry of not clear runic object
Ingredient is a kind of mixture of complexity.
Present invention firstly discovers that the Saliggenon D extracted from Mulberry plant has the activity for inhibiting xanthine oxidase.This
Invention is found no before completing closes what Saliggenon D was applied as xanthine oxidase inhibitor, in terms of preventing and treating gout
Report, the present invention are with a wide range of applications.
Summary of the invention
The purpose of the present invention is have found that the Saliggenon D extracted from the root bark of white mulberry, ramulus mori, mulberry leaf has for the first time to inhibit yellow fast
The activity of purine oxidizing ferment, have prepare antigout, the new application in inhibiting hyperuricemia drug, have it is apparent innovative and
Technological progress.
Another object of the present invention and feature are: Saliggenon D, which has, inhibits xanthine oxidase effect and previous literature report
Road extract of mulberry twig has more obvious pharmacological activity, and previously reported extract is crude extract, so specific activity
Ingredient is unclear；The present invention is definite ingredients, has apparent technical progress and innovation.
It is another object of the invention to provide a kind of Saliggenon D preparation methods: the root bark of white mulberry or ramulus mori or mulberry leaf are ground into slightly
Powder, with 6~10 times amount 30-40% ethanol solution refluxing extraction 2-3 times, extracting solution directly passes through macroporous resin column, first uses 30-
40% column volume of ethanol elution 1~3 discards eluent, then elutes 2~5 column volumes with 50~80% ethanol solutions, collects
Ethanol eluate recycles ethyl alcohol, and concentrate acid adding tune pH is 1~4, places precipitating；Sediment is returned with 5~10 times of amount organic solvents
Stream, is filtered while hot, and silicagel column is added, and aqueous acetone solution gradient elution collects effective component, and recycling acetone places crystallization；Thick knot
Brilliant object filters out, and with methanol-water (70-30) for mobile phase, by C18 column, collects, active principle, merges, obtain Saliggenon D.
This preparation method uses extracting solution directly to carry out macroreticular resin separation without concentration for the first time, removes impurity, solves
Extract liquid causes effective component to be precipitated by concentration, serious situation is lost after macroreticular resin, improves effective component
Yield, have apparent technical progress and innovation.
And in the prior art, Saliggenon D, which only reports, has the function of inhibiting alpha-glucosidase and inhibition lipase
Effect, but to inhibit xanthine oxidase effect have not been reported.
The purity of Saliggenon D of the present invention is 95%-98%, such as can be 95%, 96%, 97%, 98% etc..This
Invent provide Saliggenon D in above-mentioned purity range, can safely and effectively be applied.Generally, Saliggenon D purity
It can achieve normal pharmacological effect 90% or more.
Preferably, the dosage form of the drug include suspension, granule, capsule, powder, tablet, emulsion, solution,
Any one in pill, injection, suppository, enema, aerosol, patch or drops.
Preferably, the drug further includes pharmacologically acceptable auxiliary material.
Preferably, the auxiliary material includes carrier, diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, cream
Agent, cosolvent, solubilizer, osmotic pressure regulator, surfactant, coating material, pH adjusting agent, antioxidant, bacteriostatic agent or
In buffer any one or at least two combination.
In the present invention, the dosage form of the drug includes suspension, granule, capsule, powder, tablet, emulsion, solution
Any one in agent, pill, injection, suppository, enema, aerosol, patch or drops.
In the present invention, the administration mode of drug can choose various ways.Such as can be oral administration, per rectum,
Non-digestive tract or local administration etc..
Pharmacodynamics test of the invention proves, Saliggenon D is with having stronger inhibition xanthine oxidase than extract of mulberry twig
Changing enzyme effect, (when concentration is 0.5mg/ml, Saliggenon D inhibiting rate is 78.69%, and extract of mulberry twig inhibiting rate is
10.18%), this result is also another apparent technological progress, novelty and outstanding contributions of the invention.
Inhibit xanthine oxidase effect due to having present invention firstly discloses Saliggenon D, by Saliggenon D list
Medicament solely or with other active constituents or auxiliary material cooperation is made, as long as the medicament is for preventing and treating gout and antihyperuricemic
Disease all belongs to the scope of protection of the present invention.Composition of the invention all has prevention and treatment when any dosage form is made
The effect of gout, hyperuricemia.
The application of Saliggenon D provided by the invention, have following advantage: 1. raw materials are cheap and easy to get: with cheap mulberry
White skin, ramulus mori, mulberry leaf are raw material, and extracted acquisition, simple process is feasible, and Saliggenon D content in the root bark of white mulberry is higher；2. suppression
System activity is strong；3. highly-safe: the root bark of white mulberry, ramulus mori, mulberry leaf are one of the articles that can be used as health food of approval, are had good
Safety, avoid the treatment gout side effects of pharmaceutical drugs of preparation.
Had by Saliggenon D and inhibit xanthine oxidase effect, is confirmed by following pharmacodynamic experiment.
1, experimental principle
Xanthine oxidase can be catalyzed xanthine, form uric acid.If compound can have inhibition to make to xanthine oxidase
With then the amount of xanthine oxidase catalysis xanthine will be reduced, and the uric acid accordingly generated will be reduced, and corresponding absorbance is just
It can reduce.
2, experimental material
Saliggenon D that this pharmacodynamics test is used, extract of mulberry twig are self-control, allopurinol, xanthine, xanthine oxidase
Change enzyme and is purchased from sigma company.KH2PO4、K2HPO4, NaOH, dimethyl sulfoxide (DMSO) be analyze pure, distilled water.
3, external activity test method
1) preparation of buffer: precision weighs 0.9560g KH2PO4, 5.3020g K2HPO4, distilled water dissolution is added, it is fixed
Hold to 500mL up to (PBS).
2) preparation of substrate: precision weighs xanthine 3.65mg, adds a small amount of 0.5M NaOH solution to dissolve, is settled to PBS
50mL needs ready-to-use up to 0.48mM substrate solution, substrate solution.
3) enzyme solution is prepared: liquid-transfering gun takes 100 μ L of xanthine oxidase, and PBS is added, is settled to 25ml up to 0.04UmL-1
Xanthine oxidase solution, enzyme solutions need it is ready-to-use.
4) preparation of test sample: precision weighs appropriate amount of sample, first with a small amount of DMSO (content be lower than 5%) sample dissolution,
Then it is diluted with PBS buffer solution, concentration is as shown in table 1 when reacting Saliggenon D, extract.
5) using Allopurinol as positive control, by test sample solution, positive control solution and each 200 μ of blank solution
L, 500 μ L of enzyme solution, 2800 PBS μ L are sequentially added in test tube, and after 37 DEG C of incubation 15min, 500 μ L of substrate starting reaction is added,
It at 295nm, is read 1 time every 30s, records absorbance A, amount to 5min.
4, experimental result
Inhibiting rate (%) can be calculated by the variation of sample sets and blank group A value with following equation: inhibiting rate (%)=
(1-A sample/A blank) × 100%, inhibiting rate result see the table below.
Inhibiting rate of 1 determinand of table to xanthine oxidase
The result shows that changing the concentration of Allopurinol, Allopurinol has the inhibiting effect of xanthine oxidase activity good
Dose-effect relationship.Saliggenon D of the present invention is in the case where concentration is 2.0,1.0,0.5,0.2,0.1,0.05mg/ml concentration, to xanthine
The inhibiting effect of oxidase active has good dose-effect relationship, and inhibiting effect is very strong.And it is more stronger than Allopurinol activity, than
Extract of mulberry twig activity is strong, IC50About 20 times or so.
Specific embodiment
The present invention is to be described in detail by the following examples, but be not intended that the invention is limited to this, specifically
Embodiment is as follows:
Embodiment 1,It is prepared by the extraction of Saliggenon D
Root bark of white mulberry 10kg is ground into coarse powder, with 8 times amount 40% ethanol solution refluxing extraction 3 times, 2 hours every time, filtration, mention
It takes liquid directly to pass through macroporous resin column, first with 40% ethanol elution, 1 column volume, discards eluent, then with 70% ethanol solution
4 column volumes are eluted, ethanol eluate is collected, recycle ethyl alcohol, concentrate acid adding tune pH is 2, places precipitating；Sediment is with 6 times
Acetone reflux is measured, is filtered while hot, silicagel column is added, aqueous acetone solution gradient elution collects effective component, and recycling acetone puts thick knot
Brilliant object filters out, and with methanol-water (70-30) for mobile phase, by C18 normal pressure column, collects, active principle, merges, obtain Saliggenon D.
Embodiment 2,The preparation of extract of mulberry twig
Dry ramulus mori is taken, adds alcohol heat reflux three times, 2 hours every time, combined extract, filtration, filtrate was through being recovered under reduced pressure
Ethyl alcohol is simultaneously concentrated into thick paste, is dried under reduced pressure to get extract of mulberry twig.
Claims (6)
- Inhibit xanthine oxidase effect 1. Saliggenon D has, antigout can be treated, in inhibiting hyperuricemia drug in preparation Using.
- 2. Saliggenon D described in claim 1 is the preparation method comprises the following steps: the root bark of white mulberry or ramulus mori or mulberry leaf are ground into coarse powder, with 6~10 times of amounts 30-40% ethanol solution refluxing extraction 2-3 times, extracting solution directly passes through macroporous resin column, first uses 30-40% ethanol elution 1~3 A column volume discards eluent, then elutes 2~5 column volumes with 50~80% ethanol solutions, collects ethanol eluate, recycling Ethyl alcohol, concentrate acid adding tune pH are 1~4, place precipitating；Sediment is flowed back with 5~10 times of amount organic solvents, is filtered, is added while hot Enter silicagel column, aqueous acetone solution gradient elution collects effective component, and recycling acetone places crystallization；Coarse crystallization object filters out, with first Alcohol-water (70-30) is mobile phase, by C18 column, collects, active principle, merges, obtain Saliggenon D.
- 3. according to claim 1, Saliggenon D described in 2, which is characterized in that the purity of the Saliggenon D is 95%-98%.
- 4. application according to claim 1, which is characterized in that the dosage form of the drug includes suspension, granule, capsule It is any in agent, powder, tablet, emulsion, solution, pill, injection, suppository, enema, aerosol, patch or drops It is a kind of.
- 5. application according to claim 4, which is characterized in that the drug further includes pharmaceutically acceptable medicinal tax Shape agent.
- 6. application according to claim 5, which is characterized in that the pharmaceutical excipient includes carrier, diluent, figuration Agent, filler, adhesive, wetting agent, disintegrating agent, emulsifier, cosolvent, solubilizer, osmotic pressure regulator, surfactant, In coating material, pH adjusting agent, antioxidant, bacteriostatic agent or buffer any one or at least two combination.
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| CN201910617148.2A CN110251504B (en) | 2019-07-10 | 2019-07-10 | Preparation method and novel medical application of sanggenon D |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103156869A (en) * | 2013-03-26 | 2013-06-19 | 赵全成 | Sanggenone C and sanggenone D extracted from morus plants and new medicine application of composition |
| CN105452269A (en) * | 2013-06-17 | 2016-03-30 | 尤妮金公司 | Compositions and methods for joint health |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103156869A (en) * | 2013-03-26 | 2013-06-19 | 赵全成 | Sanggenone C and sanggenone D extracted from morus plants and new medicine application of composition |
| CN105452269A (en) * | 2013-06-17 | 2016-03-30 | 尤妮金公司 | Compositions and methods for joint health |
Non-Patent Citations (1)
| Title |
|---|
| 夏道宗: "青梅有效部位防治高尿酸血症和痛风的作用及机制研究", 《中国博士学位论文全文数据库》 * |
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