CN110269854B - New medical application of sanggenon C - Google Patents
New medical application of sanggenon C Download PDFInfo
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- CN110269854B CN110269854B CN201910649661.XA CN201910649661A CN110269854B CN 110269854 B CN110269854 B CN 110269854B CN 201910649661 A CN201910649661 A CN 201910649661A CN 110269854 B CN110269854 B CN 110269854B
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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
- 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)
- A61K36/60—Moraceae (Mulberry family), e.g. breadfruit or fig
- A61K36/605—Morus (mulberry)
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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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Abstract
The invention discloses a new medical application of sanggenon C extracted from cortex mori, ramulus mori and folium mori, in particular to an application of a single component of the sanggenon C in inhibiting xanthine oxidase, and an application in preparing anti-gout and anti-hyperuricemia medicines. The compound has the advantages of obvious curative effect, convenient use, lower cost, no obvious toxic or side effect and important clinical value. Provides a new direction for improving the phenomenon of large side effect of the existing gout medicine.
Description
Technical Field
The invention relates to a new medical application of sanggenon C extracted from cortex mori radicis, ramulus mori and folium mori, in particular to an application of a sanggenon C single component in inhibiting xanthine oxidase, which can be applied to the preparation of anti-gout and anti-hyperuricemia medicines, and also relates to a medicinal preparation of the medicines, belonging to the technical field of medicines.
Background
Gout is a common disease caused by purine metabolic disorder to form uric acid, and is listed as one of the 21 st century 20 persistent ailments by the united nations. Recent epidemiological studies show that the incidence rate of gout in China is increased year by year and is higher than the average level in the world, and the traditional anti-gout drugs, namely uric acid excretion promoting drugs (such as probenecid, benzbromarone and the like) are often accompanied by side effects of rash, fever, kidney damage and the like. Xanthine oxidase inhibitors can reduce stress reactions or damage to tissues caused by free radicals, and also reduce the formation of uric acid in the human body. Researches find that the inhibitor taking xanthine oxidase as an action target has good anti-gout effect, is an important medicament for treating gout and can reduce some fatal gout complications.
The xanthine oxidase inhibitor is used as an anti-gout drug, mainly allopurinol which is marketed in the last 60 th century, has a lot of side effects although being used up to now, and patients can have side effects such as fever, allergic rash, abdominal pain, diarrhea, leukopenia and thrombocytopenia and even liver function injury after the xanthine oxidase inhibitor is applied (research progress of the xanthine oxidase inhibitor, foreign medical and pharmaceutical handbook, 2006, 33 (5), 351-353). Therefore, the research on the novel xanthine oxidase inhibitor is of great significance. We have found that a novel xanthine oxidase inhibitor, sanggenon C, is extracted and separated from cortex Mori, ramulus Mori and folium Mori of Morus.
Extracts of mulberry twig have been reported in literature to have hypolipidemic effects (swiftlet, university of southwest, 2017, master thesis); the zhanxiaoli study reported that mulberry twig extract has lipase activity inhibition (chinese journal of chinese traditional medicine, 2012, volume 37, stage 9, page 1323); CN103156869A discloses a new medical use of sanggenon C and sanggenon D extracted from cortex Mori, ramulus Mori and folium Mori and a composition containing sanggenon C and sanggenon D as main components, specifically the use of the single components of sanggenon C and sanggenon D and the composition containing sanggenon C, sanggenon D, mulberrin, oxyresveratrol, resveratrol and deoxynojirimycin in preparing alpha-glucosidase inhibitor medicine; the Wangcolong research shows that the mulberry twig extract has the function of regulating organic ion transport and improving hyperuricemia, is a crude extract, does not have the chemical components of the crude extract and is a complex mixture.
The invention discovers for the first time that sanggenon C extracted from Morus plants has the activity of inhibiting xanthine oxidase. Before the invention is completed, reports about the application of the sanggenon C as a xanthine oxidase inhibitor in the aspects of preventing and treating gout are not found, and the invention has wide application prospect.
Disclosure of Invention
The invention aims to discover that sanggenon C extracted from cortex mori, ramulus mori and folium mori has the activity of inhibiting xanthine oxidase for the first time, has new application in preparing anti-gout and anti-hyperuricemia medicines, and has obvious innovation and technical progress.
Another object and feature of the present invention is: the sanggenon C has the effect of inhibiting xanthine oxidase and has more obvious pharmacological activity with the mulberry twig extract reported in the past literature, and the extract reported in the past is a crude extract, so the specific active ingredients are not clear; the invention has definite components and obvious technical progress and innovation.
However, in the prior art, only the sanggenon C has been reported to have the effect of resisting myocardial cell injury and the effect of inhibiting alpha-glucosidase, but the effect of inhibiting xanthine oxidase has not been reported.
The purity of sanggenon C is 95-98%, for example, 95%, 96%, 97%, 98% and the like. The sanggenon C provided by the invention can be safely and effectively applied within the purity range. Generally, the purity of sanggenon can reach normal pharmacological effect when the purity is more than 90%.
Preferably, the dosage form of the medicament comprises any one of suspension, granules, capsules, powder, tablets, emulsions, solutions, dripping pills, injections, suppositories, enemas, aerosols, patches or drops.
Preferably, the medicament further comprises pharmacologically acceptable excipients.
Preferably, the auxiliary materials comprise any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a pH regulator, an antioxidant, a bacteriostatic agent or a buffer.
In the invention, the dosage form of the medicament comprises any one of suspension, granules, capsules, powder, tablets, emulsions, solutions, dripping pills, injections, suppositories, enemas, aerosols, patches or drops.
In the present invention, the administration mode of the drug can be selected from various modes. For example, oral, rectal, parenteral or topical administration, and the like may be used.
Pharmacodynamic experiments prove that the sanggenon C has stronger xanthine oxidase inhibiting effect (the sanggenon C inhibiting rate is 80.88 percent and the mulberry twig extract inhibiting rate is 10.18 percent when the concentration is 0.5 mg/ml) than that of the mulberry twig extract, and the result is also another obvious technical progress, innovation and outstanding contribution of the invention.
To realize the invention, the sanggenon C can be prepared according to the following method:
pulverizing cortex Mori into coarse powder, adding calcium oxide 2% of the weight of the medicinal materials, adding 40-85% ethanol solution 6-10 times the weight of the medicinal materials, reflux-extracting for 2-3 times, adjusting pH of the extractive solution to 7, recovering ethanol until no ethanol smell exists, adding into macroporous resin column for adsorption, washing with water for 4 column volumes, eluting with 50-85% ethanol solution for 4 column volumes, collecting ethanol eluate, recovering ethanol, adding acid into the concentrated solution to adjust pH to 1-4, standing for precipitation; filtering out precipitate, refluxing with 5-10 times of acetone, filtering while hot, adding into silica gel column, gradient eluting with acetone water solution, collecting effective components, recovering acetone, and standing for crystallization; filtering out the crude crystal, passing through C18 normal pressure column with methanol-water (70-30) as mobile phase, collecting the effective components, and mixing to obtain sanggenon C.
The invention discloses that the sanggenon C has the effect of inhibiting xanthine oxidase for the first time, so that the sanggenon C is used alone or in combination with other active components or auxiliary materials to prepare a medicament, and the medicament is used for preventing and treating gout and hyperuricemia and belongs to the protection scope of the invention. The composition of the invention has the functions of preventing and treating gout and hyperuricemia when being prepared into any dosage form.
The application of sanggenon C provided by the invention has the following advantages: 1. the raw materials are cheap and easy to obtain: cheap cortex mori radicis, mulberry twigs and mulberry leaves are used as raw materials and are obtained by extraction, the process is simple and feasible, and the content of sanggenon C in the cortex mori radicis is high; 2. the inhibition activity is strong; 3. the safety is high: the cortex mori radicis, the mulberry twig and the mulberry leaf are approved products which can be used as health-care food, have good safety and avoid the side effect of the prepared medicine for treating gout.
Sanggenon C has the effect of inhibiting xanthine oxidase and is confirmed by the following pharmacodynamic experiments.
1. Principle of experiment
Xanthine oxidase catalyzes xanthine to form uric acid. If the compound has an inhibitory effect on xanthine oxidase, the amount of xanthine catalyzed by xanthine oxidase decreases, uric acid produced accordingly decreases, and absorbance accordingly decreases.
2. Experimental materials
The sanggenon C and the mulberry twig extracts used in the pharmacodynamic test are both prepared by self, and allopurinol, xanthine and xanthine oxidase are purchased from sigma company. KH (Perkin Elmer) 2 PO 4 、K 2 HPO 4 NaOH and dimethyl sulfoxide (DMSO) are analytical pure and distilled water.
3. In vitro activity test method
1) Preparing a buffer solution: precisely weighing 0.9560g KH 2 PO 4 ，5.3020g K 2 HPO 4 Adding distilled water for dissolving, and diluting to 500mL to obtain (PBS).
2) Preparation of a substrate: 3.65mg of xanthine is precisely weighed, a small amount of 0.5M NaOH solution is added for dissolving, and PBS is used for fixing the volume to 50mL to obtain 0.48mM substrate solution which needs to be prepared for use.
3) Preparing an enzyme solution: taking 100 μ L xanthine oxidase with liquid transfer gun, adding PBS, and diluting to 25mL to obtain 0.04 U.mL -1 The xanthine oxidase solution is prepared in situ.
4) Preparation of a test sample: an appropriate amount of sample was precisely weighed, and the sample was dissolved in a small amount of DMSO (content: less than 5%), and then diluted with PBS buffer so that the concentration of sanggenon C extract at the time of reaction was as shown in Table 1.
5) Taking allopurinol as a positive control, sequentially adding 200 mu L of a sample solution to be tested, 500 mu L of a positive control solution and 2800 mu L of a blank solution, 500 mu L of an enzyme solution and 2800 mu L of PBS into a test tube, incubating for 15min at 37 ℃, adding 500 mu L of a substrate to start reaction, reading 1 time at 295nm every 30s, recording absorbance A, and counting for 5min.
4. Results of the experiment
The inhibition (%) was calculated from the change in the A values of the sample group and blank group using the following formula: inhibition (%) = (1-a sample/a blank) × 100%, inhibition results are shown in the following table.
TABLE 1 inhibition of xanthine oxidase by test substances
The result shows that the allopurinol has good dose-effect relationship on the inhibition effect of the xanthine oxidase activity by changing the concentration of the allopurinol. The sanggenon C has good dose-effect relation to the inhibition effect of the xanthine oxidase activity and strong inhibition effect at the concentration of 2.0,1.0,0.5,0.2,0.1, 0.05mg/ml. And has stronger activity than allopurinol, stronger activity than ramulus Mori extract, and IC thereof 50 About 20 times or so.
Detailed Description
The invention is illustrated in detail by the following examples, without intending to be limited thereto, the specific embodiments of which are as follows:
examples 1,Extraction and preparation of sanggenon C
Crushing 10kg of white mulberry root-bark into coarse powder, adding 2000g of calcium oxide, adding 8 times of 70% ethanol solution, performing reflux extraction for 3 times, each time for 2 hours, adjusting the pH value of an extracting solution to 7, recovering ethanol until no alcohol smell exists, adding the extracting solution into an AB-8 macroporous resin column for adsorption, washing 4 column volumes with water, eluting 4 column volumes with 70% ethanol solution, collecting ethanol eluent, recovering ethanol, adding acid into a concentrated solution to adjust the pH value to =2, and standing for precipitation; filtering out precipitate, refluxing with 8 times of acetone, filtering while hot, adding into silica gel column, gradient eluting with acetone water solution, collecting effective components, recovering acetone, and standing for crystallization; filtering out the crude crystal, passing through C18 normal pressure column with methanol-water (70-30) as mobile phase, collecting effective components, and mixing to obtain sanggenon C with content of 96.8%.
Examples 2,Preparation of ramulus Mori extract
Taking dry ramulus Mori, adding ethanol, thermally refluxing for three times, each time for 2 hr, mixing extractive solutions, filtering, recovering ethanol from filtrate under reduced pressure, concentrating into soft extract, and drying under reduced pressure to obtain ramulus Mori extract.
Claims (5)
1. The application of sanggenon C in preparing the medicine for resisting hyperuricemia is characterized in that the sanggenon C has the function of inhibiting xanthine oxidase.
2. The use according to claim 1, wherein the sanggenon C has a purity of 95% -98%.
3. The use according to claim 1 or 2, wherein the medicament is in the form of any one of suspension, granule, capsule, powder, tablet, emulsion, solution, drop pill, injection, suppository, enema, aerosol, patch or drop.
4. The use according to claim 1 or 2, wherein the medicament further comprises a pharmaceutically acceptable excipient.
5. The use according to claim 4, wherein the pharmaceutically acceptable excipient comprises any one or a combination of at least two of a filler, a binder, a wetting agent, a disintegrant, a co-solvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a pH regulator, an antioxidant, a bacteriostatic agent or a buffer.
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| CN201910649661.XA CN110269854B (en) | 2019-07-18 | 2019-07-18 | New medical application of sanggenon C |
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| CN201910649661.XA CN110269854B (en) | 2019-07-18 | 2019-07-18 | New medical application of sanggenon C |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010037201A (en) * | 2008-07-31 | 2010-02-18 | Nichinichi Seiyaku Kk | Remedy of gout |
| WO2011108059A1 (en) * | 2010-03-01 | 2011-09-09 | 株式会社サウスプロダクト | Xanthine oxidase inhibitor |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010037201A (en) * | 2008-07-31 | 2010-02-18 | Nichinichi Seiyaku Kk | Remedy of gout |
| WO2011108059A1 (en) * | 2010-03-01 | 2011-09-09 | 株式会社サウスプロダクト | Xanthine oxidase inhibitor |
Non-Patent Citations (3)
| Title |
|---|
| Sanggenon C protects against pressure overload‑induced cardiac hypertrophy via the calcineurin/NFAT2 pathway;LILI XIAO;《MOLECULAR MEDICINE REPORTS》;20171231;第16卷(第4期);第5338-5346页 * |
| 急性痛风性关节炎中西医治疗研究进展;尹磊;《河北医药》;20170331;第39卷(第5期);第751-756,759页 * |
| 桑的化学成分和生物活性研究进展;顾关云;《国外医药·植物分册》;20071231;第22卷(第1期);第12-17页 * |
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