CN109806293A - Purposes of the motherwort total alkaloid in the drug that preparation has angiogenesispromoting effect - Google Patents
Purposes of the motherwort total alkaloid in the drug that preparation has angiogenesispromoting effect Download PDFInfo
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- CN109806293A CN109806293A CN201711158288.5A CN201711158288A CN109806293A CN 109806293 A CN109806293 A CN 109806293A CN 201711158288 A CN201711158288 A CN 201711158288A CN 109806293 A CN109806293 A CN 109806293A
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Abstract
The present invention relates to the purposes of motherwort total alkaloid.The invention discloses purposes of the motherwort total alkaloid in the drug that preparation has angiogenesispromoting effect.Specifically, the invention discloses motherwort total alkaloids has the purposes in angiogenesispromoting effect or the drug for repairing injury of blood vessel in preparation.The object of the present invention is to provide a kind of using motherwort total alkaloid as the drug of the Angiogensis of active constituent, has good therapeutic effect to ischemic disease and postpartum haemorrhage.The present invention also provides the preparation method of motherwort total alkaloid, application prospect is good.
Description
Technical field
The present invention relates to the purposes of motherwort total alkaloid.
Background technique
The various ischemic diseases such as postpartum haemorrhage, coronary heart disease, cerebral infarction seriously endanger human health, are by drug therapy
The main method treated at present promotes ischemic tissue to form new capillary on the basis of original capilary by drug, and with
Original rete vasculosum intersects, and improves blood supply.Therefore, the drug for finding Angiogensis becomes treats grinding for ischemic disease now
Study carefully hot spot.
Traditional Chinese medicine ingredients are extremely complex, and useful effect ingredient is not understood also mostly, and resulting in Chinese medicine for many years can not beat
Enter international market.Motherwort, which is used for medicinal purpose, has long history, is Labiatae mother wort plant Leonurus
The fresh or dry aerial parts of japonicus Houtt., original name motherwort, first recorded in, the female Chinese mugwort of alias benefit, eel grass, female grass etc.,
Its acrid flavour, slight bitter, cold nature enter pericardium, Liver Channel, have the function of that the stasis of blood, menstruation regulating Li Shui are adjusted in promoting blood circulation.As people recognize motherwort
The intensification of knowledge and the progress of modern science and technology, more and more pharmacological activity are found, and especially motherwort total alkaloid exists
On gynecological disease using more and more, and the research about motherwort total alkaloid Angiogensis has not been reported.
Summary of the invention
To solve the above-mentioned problems, the present invention provides the new applications of motherwort total alkaloid Angiogensis.
Firstly, there is angiogenesispromoting effect in preparation the present invention provides motherwort total alkaloid or repair blood vessel damage
Purposes in the drug of wound.
Wherein, the drug is the drug for treating ischemic disease.
Wherein, the drug is the drug for treating ischemic angiocardiopathy and cerebrovascular disease.
Wherein, the drug is for treating coronary heart diseases and angina pectoris, artery sclerosis, cerebral thrombosis, cerebral ischemia or treatment
The drug of postpartum haemorrhage.
Wherein, the drug be by motherwort total alkaloid be active constituent, in addition pharmaceutically acceptable auxiliary material or
The preparation that the complementary ingredient of person is prepared.
Wherein, the preparation includes but is not limited to injection, powder-injection, tablet, capsule, soft capsule, pill, dripping pill
Agent, granule, oral solution, syrup, powder, paste, finish, suppository, plastics, gelling agent.
The present invention also provides a kind of methods for preparing motherwort total alkaloid, include the following steps:
A, motherwort medicinal material is weighed, is extracted with aqueous hydrochloric acid solution, is filtered；
B, by cation exchange resin on Leonurus extract, eluent is collected in elution, adjusts pH to neutrality, filtrate concentration
After dry, obtain drying solid；
C, ethyl alcohol is added to extract alkaloid drying solid.
The concentration of aqueous hydrochloric acid solution is 0.5% in step a；The number of the extraction is 2 times, the 1st salt measured with 10 times
Aqueous acid extracts, and the 2nd time the aqueous hydrochloric acid solution measured with 8 times extracts；The temperature of the extraction is 80 DEG C.
In step b, the cation exchange resin is 732 type strongly acidic cation-exchanges, the method for the elution
It is: first to be washed to weakly acidic pH, then with the elution of Nacl solution, is eluted to until alkaloid reaction is negative, collects eluent；It is excellent
Selection of land, the concentration of the Nacl solution are 3mol/L；
And/or in step c, the method that the ethyl alcohol extracts is: taking drying solid, adds 6 times of amount dehydrated alcohol ultrasonic extractions
3 times, ultrasonic power 360W, every time 20 minutes.
The present invention also provides a kind of pharmaceutical compositions, and it is activity that it, which is by the motherwort total alkaloid of preceding method preparation,
Ingredient, in addition the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.
Zebra fish is widely used in the evaluating drug effect of the different extracted parts of Chinese medicine.Effective ingredient in Chinese new drug is recent
One of the hot spot of domestic traditional Chinese medicine enterprise research and development, this is mainly due to active components to embody the effective component of Chinese medicine, meets Western medicine
Research idea.Drug is screened using zebra fish just becomes a hot spot, because zebra fish has and mankind's height similarity
Volume genome has a large amount of consistent activity of height of the systems such as angiocarpy similar with animal is stepped into, hematopoiesis, nerve and metabolism
Metabolite, and show the physiologic character quite similar with the mankind.Some known drugs also occur on zebra fish
Similar therapeutic effect.The present invention is it is experimentally confirmed that motherwort total alkaloid of the present invention can effectively facilitate blood applied to zebra fish
Pipe generates, and angiogenesis and motherwort total alkaloid are in dose dependent.
The beneficial effects of the present invention are: the present invention provides a kind of using motherwort total alkaloid as the rush blood of active constituent
The drug that pipe generates, has good therapeutic effect to ischemic disease and postpartum haemorrhage.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
Fig. 1 is influence of the various concentration motherwort total alkaloid between vascular index zebrafish embryo body segment；
Fig. 2 is various concentration motherwort total alkaloid between the fluorescent microscopic imaging of the influence of angiogenesis zebra fish body segment
Figure.
Specific embodiment
The preparation of 1 motherwort total alkaloid of embodiment
The pretreatment of resin: 732 type strongly acidic cation-exchanges are washed till deionization with deionized water soaked overnight
Water is closely colourless；5 times of amount 5%HCl aqueous solution soaking 1h or so are first added, stir at any time, be washed with deionized water to outflow water it is close in
Property；5 times of amount 5%NaOH solution are added afterwards and impregnate 1h, stirs, is washed with deionized water to outflow water weakly acidic pH at any time；It is eventually adding 5
Amount 5%HCl aqueous solution soaking 2h or so again, makes cation exchange resin be converted to H-type, and be washed with deionized water to weakly acidic pH.
Motherwort medicinal material 5kg is weighed, is extracted 2 times using 80 DEG C of aqueous hydrochloric acid solution of 0.5%, solvent usage is 10,8 respectively
Times, extraction time is respectively 1.5h, filtering, and the cation pre-processed on filtered motherwort extracting solution (pH1~2) is exchanged
Resin is first washed till weakly acidic pH with deionized water, discards water lotion.Again with the elution of 3mol/L NaCl solution, it is eluted to 6BV/h
Until alkaloid reaction is negative, eluent is collected, adds saturation sodium hydroxide solution to adjust pH to neutrality, is done after filtrate concentration
It is dry.Drying solid is taken to add 6 times of amount dehydrated alcohols ultrasonic extraction 3 times, ultrasonic power 360W, every time 20 minutes, extracting solution decompression
Concentration is to get motherwort medicinal material total alkali extract (96.9g).
Beneficial effects of the present invention are illustrated by following tests example:
1 motherwort total alkaloid of test example promotes the experiment of zebra fish angiogenesis
(1) experimental material
1. drug and preparation
For reagent object, motherwort picks up from Xichang City, Sichuan Province Mianning County, by Chinese traditional medicine identification teaching and research room, Chengdu University of Traditional Chinese Medicine
Professor Ren Limin is accredited as the dry tuber of motherwort L.japonicus.The method that the total alkaloid of motherwort takes embodiment 1
Preparation.
Motherwort total alkaloid is configured to the stock solution of 50mg/mL, -10 DEG C of preservations with DMSO.Sutent
(Sunitinib, Beijing lark prestige Science and Technology Ltd., lot number: LE70P63).
2. zebra fish
Pathogen-free domestic zebra fish [the transgenosis Tg (flk1:EGFP) of blood vessel green fluorescence label] is big by Chengdu traditional Chinese medicine
Learn pharmaceutical college zebra fish experiment porch culture breeding.
3. reagent
Reagent uses dimethyl sulfoxide (DMSO, U.S.'s Sigma Aldrich) using preceding
It is dissolved as mother liquor；It is fixed with fixer (4% methylcellulose is dissolved in culture solution) when zebra fish is taken pictures；Soviet Union Buddhist nun replaces
Buddhist nun (sunitinib, Beijing lark prestige Science and Technology Ltd., lot number: LE70P63).
4. laboratory apparatus
Zebra fish breeding and cultivating system (Beijing Ai Sheng scientific & technical corporation)；
Axio Observer A1 fluorescence is inverted micro imaging system (German Zeiss company)；
M165-FC body formula fluorescence microimaging systems (German Leica company)；
Constant incubator (the permanent Science and Technology Ltd. in Shanghai one)；
AL104 electronic balance (Mettler Toled company, Switzerland)；；
Water-bath, low temperature refrigerator etc..
(2) experimental method:
1. zebra fish raising and breeding condition
Zebra fish raising is in closed circulating system, and cultivation and breeding are referring to zebrafish book standard, zebra fish
Illumination in room/dark is than being 14h/10h, 26 DEG C of room temperature, 28 DEG C of water temperature, pH 7.2-7.5, conductivity 500-550 μ s/cm,
Its every water quality indicator closes requirement.Before breeding, male and female are moved into oviposition box with 1:1 quantity, and male and female are separated with partition, it is secondary
Early morning day, which removes 30min after partition milter chases raun, can collect embryo.Embryo is cleaned up with culture solution and moves into sterile training
After supporting ware, it is placed in 28.5 DEG C of constant incubators.
2. drug-treated
Normotrophic 10hpf embryonic period, embryonic phase zebra fish (flk1-EGFP) is selected to be put into 24 orifice plates at random, 10 pieces of every hole,
Every group 50 pieces.Respectively according to blank control group, model group (containing 1.5 μ g/mLsunitinib in medical fluid), administration group (in medical fluid
It is respectively the Total alkaloids of 100,50,25,12.5,6.25 μ g/mL containing 1.5 μ g/mL sunitinib and concentration), by phase
Acute drug is answered to be dissolved in embryo medium, every hole is separately added into 1500 each working solutions of μ L, to spot in 28.5 DEG C of insulating boxs
After horse fish embryonic development to 48hpf, in the growing state of body formula fluorescence microscopy microscopic observation zebra fish body intersegmental blood vessel (ISVs),
And photo is shot using imaging system.
3. the calculating of vascular index (ISV index) between zebra fish body segment
Count vascular index (ISV index) between zebra fish body segment, including intact vessel number × 1 plus imperfect blood vessel number ×
0.5 (being calculated the intersegmental blood vessel after yolk bag).
3. experimental result and evaluation:
The result shows that as shown in Figures 1 and 2, compared with model group, each administration concentration has angiogenesis, and is administered
Concentration is bigger, and zebra fish intersegmental blood vessel index is bigger, is in dose dependent.When administration concentration is 100 μ g/mL, zebrafish embryo body
Intersegmental blood vessel index is close to blank control group, and zebra fish angiogenesis effect is best at this time, and when 12.5 μ g/mL has blood vessel raw
At, but decreased effectiveness.The Total alkaloids of 12.5-100 μ g/mL can remarkably promote angiogenesis (P < between zebra fish body segment
0.01)。
The results show, motherwort total alkaloid of the present invention can effectively repair injury of blood vessel, promote angiogenesis, can
To be prepared into angiogenesis promoting medicine, potential applicability in clinical practice is excellent.
Claims (10)
1. motherwort total alkaloid has the purposes in angiogenesispromoting effect or the drug for repairing injury of blood vessel in preparation.
2. purposes according to claim 1, it is characterised in that: the drug is the medicine for treating ischemic disease
Object.
3. purposes according to claim 2, it is characterised in that: the drug is for treating ischemic angiocardiopathy and cerebrovascular disease
The drug of disease.
4. purposes according to claim 3, it is characterised in that: the drug is for treating coronary heart diseases and angina pectoris, moving
Arteries and veins hardening, cerebral thrombosis, cerebral ischemia or the drug for treating postpartum haemorrhage.
5. purposes according to any one of claims 1-4, it is characterised in that: the drug is by motherwort total biology
Alkali is active constituent, in addition the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.
6. purposes according to claim 5, it is characterised in that: the preparation include but is not limited to injection, powder-injection,
Tablet, capsule, soft capsule, pill, pill, granule, oral solution, syrup, powder, paste, finish, suppository, plastics,
Gelling agent.
7. a kind of method for preparing motherwort total alkaloid, characterized by the following steps:
A, motherwort medicinal material is weighed, is extracted with aqueous hydrochloric acid solution, is filtered；
B, by cation exchange resin on Leonurus extract, eluent is collected in elution, is adjusted pH to neutrality, is done after filtrate concentration
It is dry, obtain drying solid；
C, ethyl alcohol is added to extract alkaloid drying solid.
8. preparation method according to claim 7, it is characterised in that: the concentration of aqueous hydrochloric acid solution is 0.5% in step a；
The number of the extraction is 2 times, and the 1st time the aqueous hydrochloric acid solution measured with 10 times extracts, and the 2nd time the aqueous hydrochloric acid solution measured with 8 times mentions
It takes；The temperature of the extraction is 80 DEG C.
9. preparation method according to claim 7, it is characterised in that: in step b, the cation exchange resin is 732
The method of type strongly acidic cation-exchange, the elution is: first to be washed to weakly acidic pH, then with the elution of Nacl solution, washing
It takes off until alkaloid reaction is negative, collects eluent；Preferably, the concentration of the Nacl solution is 3mol/L；
And/or in step c, the method that the ethyl alcohol extracts is: drying solid is taken, adds 6 times of amount dehydrated alcohols ultrasonic extraction 3 times,
Ultrasonic power is 360W, 20 minutes every time.
10. a kind of pharmaceutical composition, it is characterised in that: it is the motherwort total prepared by claim 7-9 any one method
Alkaloid is active constituent, in addition the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.
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Citations (5)
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|---|---|---|---|---|
| CN1376669A (en) * | 2002-04-19 | 2002-10-30 | 北京现代国立医药科技有限公司 | Extracting process and usage of general leonurine |
| CN1724000A (en) * | 2004-07-22 | 2006-01-25 | 孙毅 | Injection for treating cardiovascular and cerebrovascular diseases, and its prepn. method |
| CN1883549A (en) * | 2005-06-23 | 2006-12-27 | 北京凯瑞创新医药科技有限公司 | A Chinese medicinal preparation, its preparation process and quality control method |
| CN102172366A (en) * | 2008-08-13 | 2011-09-07 | 北京和润创新医药科技发展有限公司 | Method for separating total alkaloids from motherwort by using ion exchange resin |
| CN103565786A (en) * | 2012-07-20 | 2014-02-12 | 复旦大学 | Applications of leonurine in preparation of medicines used for treating atherosclerosis |
-
2017
- 2017-11-20 CN CN201711158288.5A patent/CN109806293A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1376669A (en) * | 2002-04-19 | 2002-10-30 | 北京现代国立医药科技有限公司 | Extracting process and usage of general leonurine |
| CN1724000A (en) * | 2004-07-22 | 2006-01-25 | 孙毅 | Injection for treating cardiovascular and cerebrovascular diseases, and its prepn. method |
| CN1883549A (en) * | 2005-06-23 | 2006-12-27 | 北京凯瑞创新医药科技有限公司 | A Chinese medicinal preparation, its preparation process and quality control method |
| CN102172366A (en) * | 2008-08-13 | 2011-09-07 | 北京和润创新医药科技发展有限公司 | Method for separating total alkaloids from motherwort by using ion exchange resin |
| CN103565786A (en) * | 2012-07-20 | 2014-02-12 | 复旦大学 | Applications of leonurine in preparation of medicines used for treating atherosclerosis |
Non-Patent Citations (4)
| Title |
|---|
| XIAN HU等: "Protective Effects of Herba Leonuri in Ischemic Models", 《NATURAL PRODUCTS》 * |
| 井晓莉等: "益母草联合卡孕栓预防产后出血的效果观察", 《中国性科学》 * |
| 彭湘君等: "益母草中生物碱的提取、分离、鉴定实验", 《实验室研究与探索》 * |
| 朱红玲等: "益母草碱对心肌缺血的保护作用及机制研究进展", 《中医药导报》 * |
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Effective date of registration: 20190917 Address after: No. 133, No. two, three ring road, Tianpeng Town, Pengzhou City, Pengzhou, Sichuan Applicant after: CHENGDU FIRST PHARMACEUTICAL Co.,Ltd. Address before: 610000 No. 1166, Willow Road, Wenjiang District, Sichuan, Chengdu Applicant before: Chengdu University of Traditional Chinese Medicine |
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Application publication date: 20190528 |