CN1315857C - Preparation of Chinese medicine clinopodium polycephalum saponin - Google Patents
Preparation of Chinese medicine clinopodium polycephalum saponin Download PDFInfo
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Abstract
The present invention discloses a preparation method and medicinal applications of a clinopodium total saponin which is the effective part of a Chinese herbal medicine clinopodium for treating gynecological hemorrhagic diseases. The clinopodium total saponin is the effective part of the clinopodium; the clinopodium total saponin is obtained by extracting, enriching and refining technologies; the total saponin is more than or equal to 50%, and the buddleo-glucoside 4 (clinopodium saponin A) is more than or equal to 5%. The clinopodium total saponin prepared by the method can be used for analyzing and developing various medicament forms and can be used for tablets, orally disintegrating tablets, chewable tablets, capsules, soft capsules, oral medicinal liquid, syrup, dripping pills and injections.
Description
Technical field
The invention belongs to a kind of preparation technology and its medicinal application of effective ingredient in Chinese, the preparation technology of a kind of specifically effective ingredient in Chinese of treatment hemorrhage, especially gynecology hemorrhagic disease---Herba Clinopodii total saponins and its medicinal application.
Background technology
In daily life with hemorrhagic diseases is very common clinically, gynecological and hemorrhage especially, as: the various gynecological and hemorrhage that dysfunctional uterine hemorrhage, menorrhagia, uterine bleeding, family planning advice etc. cause account for gynaecology's outpatient service, inpatient's 1/3.Gynecological and hemorrhage is relevant with multiple factors such as hormone in vivo and endocrine functions, list can only take stopgap measures with the pharmaceutical chemicals hemostasis, and effect is unsatisfactory, and the chemicals kind that is used for the treatment of hemorrhagic diseases is limited, and some side effects are also arranged simultaneously at hematostatic, as the antifibrinolysis agent is a kind of competitive antagonism plasminogen activating factors, and high density also suppresses plasmin activity.Studies show that now traditional Chinese medicine has advantageous advantage aspect hemostasis, the traditional Chinese medical science is adjusted the sexual gland cycle from integral body, often can receive good haemostatic effect.But the gynecologic hemostatics of being supplied in the market such as Herba Clinopodii Tabellae exist: 1. water extract-alcohol precipitation or alcohol extracting-water precipitating crude preparation by using; 2. quality instability, curative effect does not have guarantee; 3. dose is big; 4. quality control index is indeterminate, problems such as poor controllability.
" Herba Clinopodii " is Da Bie Mountain area, Anhui Province comrade Liu Xitang of Huoshan County four generations hemostasis handed down from one's ancestors secret recipe, 1970, in mass movement of herbal control disease, dedicates this side to government.Included in " in one one of the Chinese pharmacopoeia from 1985, now record in " in one one of the Chinese pharmacopoeia version in 2000, above-mentioned various gynecological and hemorrhage diseases there is definite curative effect, on this basis, prepare its efficient part total saponins, make it with quality controllable system, stable curative effect, the advantage that dose is little are served the patient with modern Chinese herbal medicine.
Relevant document ancient books
The Herba Clinopodii name of an article is not seen the book on Chinese herbal medicine appendix, resource exploration its former plant as a result is Labiatae Clinopodium Polycephalum Herba Clinopodii (Herba Clinopodii Polycephali) Χ λ ι ν ο π ο δ ι υ μ π ο λ ψ χ ε π η α λ υ μ (ζ α ν ι ο τ) Χ. Ψ. and Ω υ ε τ Η σ υ α ν ε ξ Η σ υ α ν or Manyhead Clinopodium Herb Χ λ ι ν ο π ο δ ι υ μ χ η ι ν ε ν σ ε (Β ε ν τ η) Ο Κ υ ν τ ζ e, medicinal its dry aerial parts, the Manyhead Clinopodium Herb beginning is stated from Ming Dynasty's herbal for Relief of Famines (1406) cloud: " height of seedling two chis are surplus; square-stem; four ribs; the look pale green is little white; ... open light red flower, its leaf bitter "; Clinopodium Polycephalum Herba Clinopodii (Herba Clinopodii Polycephali) has another name called Herb of Peruvian Gruondcherry, and head sees Qing Dynasty's " An Illustrated Book on Plants " (1848) volume 25, the fragrant grass class, and name is said Twoanther Mosla; " Chinese medicine voluminous dictionary " records Manyhead Clinopodium Herb, cloud: nature and flavor suffering, hardship, cold, function wind and heat dispersing, detoxifcation end dysentery, hemostasis.Anhui Province is Herba Clinopodii medicinal material main producing region, for acting on developing Chinese medicine Chinese medicine, brings into play the spirit of regional Chinese medicine advantage, just the Herba Clinopodii medicinal material and the mechanism of action thereof has been carried out series of studies from the seventies in 20th century.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of Herba Clinopodii total saponins of treatment hemorrhage, especially gynecology hemorrhagic disease, its total saponins 〉=50%, saponin A 〉=5%.Herba Clinopodii total saponins can be used for making various formulations, comprising: tablet, orally disintegrating tablet, chewable tablet, capsule, oral liquid, syrup, dripping pill, injection.
Technical scheme of the present invention is as follows:
The preparation method of Herba Clinopodii total saponins: with over-ground part clean, segment, through water extract-alcohol precipitation, filter after the processing of spissated extraction workshop section → upper prop liquid with the enrichment workshop section → silica gel adsorption of resin absorption again with the refining workshop section of magnesium oxide adsorbing or propyl carbinol solvent extraction.
The preparation method of Chinese medicine Herba Clinopodii total saponins is characterized in that may further comprise the steps:
(1) extracts workshop section
Water puts off the blood flow herbal medicine and obtains extracting solution, carries out extracting solution and concentrates; Carry out alcohol precipitation and handle, reclaim the concentrated solution that ethanol obtains extracting solution;
(2) enrichment workshop section
3. the processing of upper prop liquid
Concentrated solution is dissolved in water, obtains filtrate A and filter residue; Filter residue adds the water heating for dissolving and transfers pH value of solution is 9～10, filters to obtain liquor B, and filtrate A and liquor B are merged, and obtains upper prop liquid;
4. resin absorption
The filtrate that the last step obtains is heated to about 45 ℃, crosses D-101 (AB-8 type) or the D-201 type macroporous adsorptive resins handled well; The impurity that adsorbs on water or 10～15% the Diluted Alcohol wash-out resin column; Again with the effective ingredient of adsorbing on 60～95% ethanol-eluting resin columns, do not contain the total saponins composition to elutriant;
(3) refining workshop section
4. silica gel adsorption
Reclaim the ethanol in the elutriant, obtain concentrated solution, evenly be adsorbed in concentrated solution on the silica gel, oven dry, with the impurity component on acetone or alkaline acetone and the sherwood oil mixed solvent eluting silica gel, use the effective ingredient in the multiple extraction silica gel of ethanol again, obtain ethanol extract and concentrate;
5. magnesium oxide adsorbing or propyl carbinol solvent extraction
Magnesium oxide adsorbing: in the alcohol extracting concentrated solution, remove into magnesium oxide adsorbing impurity, filtration obtains the alcohol extracting concentrated solution, evenly be adsorbed in concentrated solution on the magnesium oxide, oven dry, use the effective ingredient in the multiple extraction magnesium oxide of dehydrated alcohol again, extracting solution reclaims ethanol to doing, and vacuum-drying promptly gets Herba Clinopodii total saponins;
The propyl carbinol solvent extraction: the alcohol extracting concentrated solution that the silica gel adsorption step is obtained is concentrated into relative density 1.20～1.25 (60 ℃ of heat are surveyed), add water saturated propyl carbinol dissolving, wash to the alkali lye layer extremely faint yellow with the propyl carbinol saturated aqueous solution that contains 0.01～0.1mol/LNaOH, again with propyl carbinol saturation water washing 1～3 time, discard water layer, the propyl carbinol reclaim under reduced pressure is extremely done; Dry thing adds an amount of dehydrated alcohol or methyl alcohol heating for dissolving, and reclaim under reduced pressure is to doing, and repetitive operation 1～3 time promptly gets Herba Clinopodii total saponins.
Described preparation method is characterized in that:
(1) extracts workshop section
Get the Herba Clinopodii medicinal material, clean, add 10～13 times of amount neutral waters (pH value 6.5～7.5), soaked overnight is extracted, and filters; The dregs of a decoction add 8～12 times of amount neutral waters again and extract, and filter; Merging filtrate, being evaporated to relative density is the concentrated solution of 1.10～1.15 (60 ℃ of heat are surveyed), is chilled to room temperature, adds ethanol to containing alcohol amount 50%～85%, stirs evenly, and leaves standstill 24～48 hours, filters filtrate recycling ethanol; Precipitation is divided 2 washings with 50%～85% ethanol (by the medicinal material amount 1/2～1/3 that feeds intake), filters, and washings and filtrate merge, and reclaims ethanol, and is concentrated into relative density 1.15～1.20 (60 ℃ of heat are surveyed);
(2) enrichment workshop section
1. the processing of upper prop liquid
Soup after the alcohol precipitation that will " extract workshop section " obtains concentrates, by crude drug weight: the ratio adding neutral water of volume of water (down with) than 3～0.5: 1 is heated to 40 ℃～50 ℃, stirring makes dissolving, left standstill 3～6 hours, and filtered, get filtrate A, it is 9～10 alkaline water liquid that precipitation adds the pH value by 1/5～1/10 of the medicinal material that feeds intake, stirring makes dissolving, filters, and gets liquor B, liquor B and filtrate A merge, and the pH value of mensuration should be closely neutral;
2. resin absorption
Filtrate after the above-mentioned merging is heated to 45 ℃, is added on the D-101 or D-201 type macroporous adsorptive resins that has handled well; Treat soup adsorb fully do after; It is closely colourless that water or Diluted Alcohol 10～15% are eluted to elutriant, discards elutriant, is washed till elutriant with 60～95% ethanol again and do not contain the total saponins composition;
(3) refining workshop section
1. silica gel adsorption
Step 1: the alcohol eluen of above-mentioned resin absorption is merged, reclaim ethanol, be concentrated into relative density 1.05～1.10 (60 ℃ of heat are surveyed), 1～2% 40～100 order silica gel that add the medicinal material amount that is equivalent to feed intake, continue to be concentrated into relative density 1.10～1.15 (60 ℃ of heat are surveyed), the silica gel that adds the medicinal material amount 5～10% that feeds intake again, after the ethanol stirring, oven dry is taken out, grind well, add 6～8 times of amount acetone, alkalescence acetone (1: 1.5～2) or sherwood oil: acetone or (2～7: 1.5～2), transfer pH9～10, room temperature (being no more than 25 ℃) dipping 10～14 times with the ethanol that contains 0.1mol/L sodium hydroxide, each dipping 6～8 hours leaches steeping fluid; Take out silica gel, dry, add 70%～95% extraction using alcohol 6～10 times, each 1～1.5 hour, united extraction liquid reclaimed ethanol, and is concentrated into 3～5% of the medicinal material amount that is equivalent to;
Step 2: with the concentrated solution after the silica gel adsorption, add 2～5% the silica gel be equivalent to the medicinal material amount, stir evenly, in 60～70 ℃ of dryings 2～3 hours, again in 100～105 ℃ of dryings 1～2 hour with an amount of ethanol; Adding 8～12 times is 95% ethanol or dehydrated alcohol extraction 5～8 times, each 1 hour, filter, and filtrate recycling ethanol is to being equivalent to 3～5% of medicinal material amount;
2. magnesium oxide adsorbing or propyl carbinol solvent extraction
Magnesium oxide adsorbing:
Step 1: the alcohol extract with silica gel adsorption after refining, evenly be sprinkled into 1～2% the magnesium oxide that is equivalent to the medicinal material amount (150 ℃ activation 3 hours), stir evenly, left standstill 30～60 minutes, repeats 3～4 times, filter, usefulness dehydrated alcohol wash-out magnesium oxide merges with supernatant liquor; Reclaim ethanol to being equivalent to 1～3% of medicinal material amount;
Step 2: with the alcohol extract behind the magnesium oxide adsorbing, record paste containing amount after, press the medicinal extract amount: magnesium oxide weight ratio 1: 5～30, mixing evenly was adsorbed in sample on the magnesium oxide, in 60～80 ℃ of dryings 1～2 hour, in 100～105 ℃ of dryings 1～2 hour, take out again, extract 6～10 times for 6～8 times with dehydrated alcohol, each 1～1.5 hour, filter united extraction liquid, be evaporated to and do or spraying drying, porphyrize is pulverized, sieve, packing promptly gets Herba Clinopodii total saponins;
The propyl carbinol solvent extraction:
With the alcohol extracting concentrated solution after the silica gel adsorption, be concentrated into relative density 1.20～1.25 (60 ℃ of heat are surveyed), the water saturated propyl carbinol dissolving that adds the 2～5g/ml that is equivalent to the medicinal material amount, heating stirs evenly, and moves in the extractor, extremely faint yellow with 0.01～0.1mol/lNaOH solution washing that propyl carbinol is saturated to the alkali lye layer, with propyl carbinol saturated aqueous solution washing 1～3 time, discard water layer again, the propyl carbinol reclaim under reduced pressure is extremely done; Dry thing adds an amount of dehydrated alcohol or methyl alcohol heating for dissolving, and reclaim under reduced pressure is to doing, and repetitive operation 1～3 time promptly gets Herba Clinopodii total saponins.
Described preparation method is characterized in that:
(1) extracts workshop section
Get and meet that " the Herba Clinopodii medicinal material of a current edition regulation of Chinese pharmacopoeia cleans, and removes weeds, root, cuts into every section of 2～3cm, drop into multi-function extractor, add 12 times of amount neutral waters, soaked overnight, extracted 1 hour, and filtered (crossing 150～300 mesh sieves), centrifugal; The dregs of a decoction add 8～12 times of amount neutral waters again and extract 3～4 times, each 1 hour, filter, merge, the same method operation is squeezed into concentration tank with extracting solution, concentrating under reduced pressure, to relative density be 1.10～1.15 concentrated solution of (60 ℃ of heat are surveyed), be chilled to room temperature, add ethanol to containing alcohol amount 50%～85%, stir evenly, left standstill 24～48 hours, and filtered filtrate recycling ethanol; Precipitation is divided 2 washings with 50%～85% ethanol (by medicinal material amount l/2～1/3 that feeds intake), filters, and washings and filtrate merge, and reclaims ethanol, and is concentrated into relative density 1.15～1.20 (60 ℃ of heat are surveyed);
(2) enrichment workshop section
1. the processing of upper prop liquid
Soup after the alcohol precipitation that general " extraction workshop section " obtains concentrates, in crude drug: water is than 3～0.5: 1 ratio adds neutral water, be heated to 40 ℃～50 ℃, stirring makes dissolving, left standstill 3～6 hours, filter, get filtrate A, filtrate A squeezes into the header tank basin, precipitation is by 1/5～1/10 (or elder generation's neutral water of the medicinal material amount 1/5～1/10 that feeds intake of the medicinal material that feeds intake, heating for dissolving adds 0.1mol/lNaOH again and regulates the pH value), the pH value is 9～10 alkaline water liquid (allocating with 0.1mol/lNaOH), stirs to make dissolving, filter, get liquor B, liquor B and filtrate A merge, and the pH value of mensuration should be closely neutral;
2. resin absorption
Above-mentioned filtrate is heated to about 45 ℃, is added on the D-101 or D-201 type macroporous adsorptive resins that has handled well and (measures maximum adsorption capacity during upper prop.Reference data: D-101 type soup: resin was than about 1: 2～3ml; D-201 type soup: resin than about 1: 4～6ml); Treat that soup adsorbs fully and do back (flow velocity is got effluent liquid 200ml according to post footpath size adjustment, is concentrated into driedly, and residue should be negative through the vitriol oil-aceticanhydride reaction detection); It is closely colourless that water or Diluted Alcohol 10～15% are eluted to elutriant, discards elutriant, is washed till elutriant with 60～95% ethanol again and do not contain total saponins composition (get elutriant 200ml, reclaim and be concentrated into dried, residue is through the vitriol oil-vinegar fourth reaction detection should be negative);
(3) refining workshop section
1. silica gel adsorption
Step 1: the alcohol eluen of above-mentioned resin absorption is merged, reclaim ethanol, be concentrated into relative density 1.05～1.10 (60 ℃ of heat are surveyed), add silica gel (40～100 order) (be equivalent to feed intake medicinal material amount 1～2%), continue to be concentrated into relative density 1.10～1.15 (60 ℃ of heat are surveyed), add silica gel (the medicinal material amount that feeds intake 5～10%) again, after the adequate amount of ethanol stirring, in 60～70 ℃ of dryings 3～6 hours, again in 100～105 ℃ of dryings 2～3 hours, take out, grind well, add 6～8 times of amount acetone, alkalescence acetone or sherwood oil: acetone (1: 1.5～2 or 2～7: 1.5～2), transfer pH9～10 mixed solvents with the 0.1mol/L alkaline ethanol, room temperature (being no more than 25 ℃) dipping 10～14 times flooded 6～8 hours at every turn, leached steeping fluid; Take out silica gel, dry, add 70%～95% extraction using alcohol 6～10 times, each 1～1.5 hour, united extraction liquid reclaimed ethanol, and concentrated an amount of (be equivalent to medicinal material amount 3～5%);
Step 2: with the concentrated solution after the step 1 silica gel adsorption, add silica gel (be equivalent to medicinal material amount 2～5%), stir evenly, in 60～70 ℃ of dryings 2～3 hours, again in 100～105 ℃ of dryings 1～2 hour with an amount of ethanol; Adding 8～12 times is 95% ethanol or dehydrated alcohol extraction 5～8 times, each 1 hour, filter, and filtrate recycling ethanol is to an amount of (be equivalent to medicinal material amount 3～5%);
6. magnesium oxide adsorbing or propyl carbinol solvent extraction
Magnesium oxide adsorbing:
Step 1: the alcohol extract with silica gel adsorption after refining evenly is sprinkled into an amount of magnesium oxide (150 ℃ activation 3 hours) and (is equivalent to 1～2% of medicinal material amount, g/g), stir evenly, leave standstill operation 30～60 minutes, repeat 3～4 times, filter,, merge with supernatant liquor with dehydrated alcohol wash-out magnesium oxide; Reclaim ethanol to an amount of (be equivalent to medicinal material amount 1～3%);
Step 2: with the alcohol extract behind the 1st magnesium oxide adsorbing, after recording paste containing amount, press medicinal extract: magnesium oxide 1: 5～30 stirs evenly, in 60～80 ℃ of dryings 1～2 hour, in 100～105 ℃ of dryings 1～2 hour, take out again, extract 6～10 times for 6～8 times with dehydrated alcohol, each 1～1.5 hour, filter, (sampling detects total saponin content should be greater than 50%, and saponin A should be greater than 5% for united extraction liquid, if do not reach, repetitive operation 1～2 time), be evaporated to dried (or spraying drying), porphyrize, pulverize, sieve, packing promptly gets total saponins in the Herba Clinopodii total saponins;
The propyl carbinol solvent extraction:
With the alcohol extracting concentrated solution after the silica gel adsorption, be concentrated into relative density 1.20～1.25 (60 ℃ of heat are surveyed), add an amount of water-saturated n-butanol and (be equivalent to 2～5g/ml) of medicinal material amount, heating stirs evenly dissolving, moves in the extractor, wash to the alkali lye layer extremely faint yellow with 0.01 saturated～0.1mol/lNaOH of propyl carbinol, with propyl carbinol saturation water washing 1～3 time, discard water layer again, the propyl carbinol reclaim under reduced pressure is extremely done; Dry thing adds an amount of dehydrated alcohol or methyl alcohol heating for dissolving, and reclaim under reduced pressure is to doing, and repetitive operation 1～3 time promptly gets Herba Clinopodii total saponins.
Herba Clinopodii total saponins is used for the development of the various formulations of medicine, can be used for tablet, orally disintegrating tablet, chewable tablet, capsule, soft capsule, oral liquid, syrup, dripping pill and injection.
Pharmacodynamic study
Heavy dose of 40mg/kg of Herba Clinopodii total saponins and middle dosage 20mg/kg (quite the clinic trial amount is by 13.33 times of batheroom scales and 6.67 times) are used for mouse, can obviously shorten the mouse docking bleeding time, reduce amount of bleeding, and shortening the clotting time, heavy dose of 10mg/kg of rabbit and middle dosage 5mg/kg (quite clinic trial amount 3.34 and 1.67 times) can make the multiple calcium clotting time of blood plasma shorten; 10mg/kg also can obviously shorten prothrombin time and KPTT, but the rat euglobulin lysis time is not had obvious influence, shows that this product can promote scleroproein to form and blood coagulation by activating blood coagulation system, thus performance hemostasis drug effect.
Herba Clinopodii total saponins gives rat heavy dose of 20mg/kg (6.67 times of clinic trial amounts), can obviously promote platelet aggregation, maximum aggregation intensity is increased, and can strengthen hematoblastic adhesivity.This effect is relevant with this product performance anastalsis.
Herba Clinopodii total saponins 20mg/kg is used for mifepristone and adds Misoprostol and cause pregnant incomplete abortion rat, can obviously reduce the uterine hemorrhage amount, and prompting this product has certain curative effect to miscarriage due to the drug induced abortion.
The blood vessel test, Herba Clinopodii total saponins concentration 0.0375mg/ml, 0.075mg/ml, 0.15mg/ml all can significantly shrink myocardium vessel, especially uterine artery are imitated strong; 1mg, 2mg, 4mg can make rabbit ear perfusion flow significantly reduce, and show that this product has direct contraction to blood vessel, help the wound closure when hemorrhage, reduce amount of bleeding.
Herba Clinopodii total saponins concentration 0.075mg/ml, 0.15mg/ml can significantly improve isolated rat uterine contraction amplitude, and 10mg/kg, 5mg/kg, 2.5mg/kg can make rabbit increase in body uterine contraction amplitude, and increase uterine motility (frequency * amplitude).Because uterine contraction can be oppressed uterine vascular, is beneficial to the uterine vascular closure.This effect may be that Herba Clinopodii total saponins is to one of metrorrhagia factor evident in efficacy.
Gynecological and hemorrhage such as dysfunctional uterine hemorrhage, menorrhagia is often relevant with endocrine disturbance, Herba Clinopodii total saponins 40,20,10mg/kg can obviously increase the young mice uterus weight, the rat estradiol level there is certain rising trend, this effect may be this product uterine hemorrhage that imbalance causes to endocrine function, one of pharmacological basis of performance drug effect.
The uterine hemorrhage Chinese medical discrimination is many to be caused by heat symptom-complex, this product cooling blood for hemostasis, the many and inflammation-related of modern medicine viewpoint heat symptom-complex reported in the past that Herba Clinopodii total saponins can reduce capillary permeability, but this test p-Xylol causes mice ear, and carrageenin causes rat paw edema does not have obvious influence.
General pharmacology is learned research
Three kinds of pharmacodynamics dosage of Herba Clinopodii total saponins are to appetite, the sleep of mouse, rat, and spiritual neural system such as coordinated movement function and cardinal principle behavior do not have obvious influence; Respiratory rate and depth of respiration to cat do not have obvious influence; Cardiovascular functions such as the heart rate of dog, blood pressure, electrocardiogram(ECG also there is not obvious influence.Show that Herba Clinopodii total saponins drug effect dosage does not all have obvious influence to animal spirit neural system, respiratory system, cardiovascular systems.
Toxicologic study
Acute toxinology experiment
Herba Clinopodii total saponins is given mouse gavaging, can not survey LD
50, maximum tolerated dose is 4.0g/kg, quite clinic trial amount (pressing batheroom scale) is 1333.3 times.Herba Clinopodii general glycoside intraperitoneal administration, mouse LD50 are 1.32g/kg, the 95% credible 1.17～1.48g/kg. that is limited to
Long-term toxicological test
(1) the long-term toxicological test of rat: Herba Clinopodii total saponins 42,84,168mg/kg dosage gavaged for 4 weeks for rat continuously, each dosage is tied up rat clotting time shortening (consistent with drug action), dosage big or middle can raise TP, ALB, heavy dose of TC of reduction, remove in addition, rat generally in order, every index detects equal Non Apparent Abnormality, and TP, ALB, TC all recover normal after two weeks of drug withdrawal.Nontoxic reacting weight is 42mg/kg, is equivalent to 14 times of clinical adult amounts on probation by the kg body weight ratio.
(2) the long-term toxicological test of dog: Herba Clinopodii total saponins 30,120mg/kg dosage, give 4 weeks of dog continuous medicine-filling, also the clotting time can be shortened (consistent) with drug action, hematological indices, blood biochemical are learned index, organ coefficient, general situation, postmortem and the equal Non Apparent Abnormality of pathologic finding, but heavy dose of dog has the reaction of feeling sick, may be for saponin stimulate due to the stomach mucous membrane, low dose of no any abnormal response, the nauseating loss for reaction of heavy dose of group dog after the drug withdrawal.Low dose of (30mg/kg) is the nontoxic reacting weight of Herba Clinopodii general glycoside dog long term toxication, by the kg body weight ratio, and 10 times of quite clinical adult amounts on probation.
Clinical study
" function of a Chinese pharmacopoeia described Herba Clinopodii preparation in 2000 is " cooling blood for hemostasis with curing mainly.Be used for dysfunctional uterine hemorrhage, menorrhagia, postpartum hemorrhage, hysteromyoma hemorrhage, hematuria is had blood in stool, and spits blood spitting of blood, nosebleed epistaxis, simple purpura, primary thrombocytopenic purpura etc.”
Treat various hemorrhages: use Clinopodium Polycephalum Herba Clinopodii (Herba Clinopodii Polycephali) pulvis, pill, capsule, tablet and injection and treat hemorrhage 277 examples of each section, produce effects (hemostasis) fully 239 examples as a result, effective (amount of bleeding obviously reduces) 23 examples, invalid 15 examples, efficient is 94.6%, wherein with Obstetric and Gynecologic Department, surgery and urology department hemostatic healing efficacy the best, to the satisfactory efficacy of internal medicine and department of eye.Case 142 examples for oral administration are observed, and have 70.4% patient to stop blooding in 2d, and 90.8% stops blooding in 5d; External curing 73 example is observed, and has 43.8% to stop blooding in 5min, and 67.1% stops blooding at 10min.
The treatment dysfunctional uterine bleeding: reports such as Li Suhong, Wen Lanying, use the comparison that Herba Clinopodii Tabellae and contrast medicine Carbazochromi Salicylas are treated 69 routine DUB, Herba Clinopodii is treated 49 examples, and Carbazochromi Salicylas is treated 20 examples, and produce effects is an oligohemia 1/3rds in 7 days after the medication.The result is: the Herba Clinopodii obvious effective rate is 79.59%, and Carbazochromi Salicylas is 20%, statistical information x
2Check, both compare p＜0.01, and there were significant differences;
Treatment menorrhagia, medicine outflow in postpartum blood: red bayberry, the Yuan Fang report, the observation of curative effect of Herba Clinopodii oral liquid and Tabellae Clinopodii treatment traditional Chinese medical science uterine bleeding card, total effective rate is respectively 86.67% and 96.67%; Also have the etiological treatment effect, as menorrhagia and metropathia hemorrhagica example, menstrual cycle, amount and look all recover normal substantially after treating; Not only haemostatic effect is satisfied after ectopic pregnancy patient's medication, and can absorb by promoting blood, makes that an awful ache in the belly and enclosed mass disappears, thereby underwent operative can not obtain recovery from illness.
Treat the hemorrhage application of other sections: clinical study finds that heredity telangiectasis, anaphylactoid purpura, simple purpura, thrombopathy and hemophilia etc. are all had curative effect preferably, also have report to cooperate penicillin to be used for the treatment of diphtheria, improve the diphtheria curative ratio.
Embodiment
Described preparation method:
Approach one
(1) extracts workshop section
Get and meet " the Herba Clinopodii medicinal material of a current edition regulation of Chinese pharmacopoeia, clean, remove weeds, root, cut into every section of 2～3cm, 100kg (total saponin content 0.31%) is dropped into multi-function extractor, add 12 times of amount neutral waters (pH value 6.5～7.5), soaked 24 hours, extracted 1 hour, and filtered (crossing 200 mesh sieves), centrifugal; The dregs of a decoction add 12 times of amount neutral waters again and extract 3 times, each 1 hour, filter, merge, the same method operation is squeezed into concentration tank with extracting solution, and being evaporated to relative density is the concentrated solution of 1.10～1.15 (60 ℃ of heat are surveyed), be chilled to room temperature, add ethanol to containing alcohol amount 50%～60%, stir evenly, left standstill 24～48 hours, filter filtrate recycling ethanol; Precipitation is divided 2 washings with 60% ethanol (by the medicinal material amount 1/2 that feeds intake), filters, and washings and filtrate merge, and reclaims ethanol, and is concentrated into relative density 1.15～1.20 (60 ℃ of heat are surveyed).
(2) enrichment workshop section
1. the processing of upper prop liquid
Soup after the alcohol precipitation that general " extraction workshop section " obtains concentrates, in crude drug: the ratio of water than 2: 1 adds neutral water, is heated to 40 ℃～50 ℃, stirs and makes dissolving, left standstill 3～6 hours, filter, filtrate is squeezed into the header tank basin, and precipitation adds the 10L neutral water, the heated and stirred dissolving, add 0.1mol/lNaOH again and regulate the pH value, measure the pH value, transfer to 6.8 to the basic dissolving of precipitation.
2. resin absorption
Above-mentioned filtrate is heated to about 45 ℃, is added on the D-101 that has handled well, soup: the resin ratio is 1: 2ml; Treat that soup adsorbs fully and do back (flow velocity is got effluent liquid 200ml according to post footpath size adjustment, is concentrated into driedly, and residue should be negative through the vitriol oil-aceticanhydride reaction detection); Closely colourless with 10% ethanol elution to elutriant, discard elutriant, be washed till elutriant with 70% ethanol again and do not contain total saponins composition (get elutriant 200ml, reclaim and be concentrated into dried, residue is through the vitriol oil-vinegar fourth reaction detection should be negative).
(3) refining workshop section
1. silica gel adsorption
Step 1: the alcohol eluen of above-mentioned resin absorption is merged, reclaim ethanol, be concentrated into relative density 1.05～1.10 (60 ℃ of heat are surveyed), add silica gel (40～60 order) 1kg and stir evenly.Continue to be concentrated into relative density 1.10～1.15 (60 ℃ of heat are surveyed), add silica gel 9kg again, after stirring with adequate amount of ethanol, in 70 ℃ of dryings 3 hours, again in 105 ℃ of dryings 2 hours, take out, grind well, add 6 times of alkaline sherwood oils of amount: acetone is 1: 1.5, mixed solvent is transferred pH9～10 with the 0.1mol/L alkaline ethanol, room temperature (being no more than 25 ℃) dipping 12 times (back twice not adjust pH) flooded 6 hours at every turn, leached steeping fluid; Take out silica gel, dry, add 85% extraction using alcohol 6 times, each 1 hour, united extraction liquid reclaimed ethanol, and concentrated solution gets 4L.
Step 2: the 2nd time the concentrated solution after the 1st absorption is added silica gel 3kg, stir evenly, in 70 ℃ of dryings 2 hours, again in 105 ℃ of dryings 2 hours with an amount of ethanol; Adding 8 times is 95% extraction using alcohol 6 times, each 1 hour, filter, and filtrate recycling ethanol is to concentrated solution 4L.
2. magnesium oxide adsorbing
Step 1: the alcohol extract with silica gel adsorption after refining, evenly be sprinkled into magnesium oxide 1kg, stir evenly, leave standstill operation 30 minutes, repeats 4 times, filter, usefulness dehydrated alcohol wash-out magnesium oxide merges with supernatant liquor; Reclaim ethanol to 1.5L.
Step 2: with the alcohol extract behind the 1st magnesium oxide adsorbing, record paste containing amount after, press medicinal extract: magnesium oxide 1: 20, stir evenly, in 80 ℃ of dryings 1 hour, again in 105 ℃ of dryings 1 hour, take out, extract each 1 hour 8 times for 6 times with dehydrated alcohol, filter united extraction liquid (sampling detects total saponin content should be greater than 50%, saponin A should greater than 5%), be evaporated to dried (or spraying drying), porphyrize is pulverized, sieve, packing, promptly.Total saponins is 52.7% among the Herba Clinopodii total saponins 367g of gained, and buddleo-glucoside IV (Herba Clinopodii saponin A) is 8.1%.
Approach two
From the silica gel adsorption of " extraction " workshop section to " making with extra care " workshop section all with approach one.
With the alcohol extracting concentrated solution after the silica gel adsorption, be concentrated into relative density 1.20～1.25 (60 ℃ of heat are surveyed), add an amount of water-saturated n-butanol 3L, heating, stir evenly dissolving, with 0.01 saturated～0.1mol/lNaOH of propyl carbinol wash to the alkali lye layer to faint yellow, again with propyl carbinol saturation water washing 1～3. time, discard water layer, the propyl carbinol reclaim under reduced pressure is extremely done; Dry thing adds an amount of ethanol or methyl alcohol heating for dissolving, and reclaim under reduced pressure promptly gets Herba Clinopodii total saponins 264g to doing, and its total saponins is 61.2%, and buddleo-glucoside IV (Herba Clinopodii saponin A) is 12.5%.
Approach three
Magnesium oxide adsorbing step 1 from " extraction " workshop section to " making with extra care " workshop section is all with approach one.
With the supernatant liquor after the absorption, reclaim ethanol to being concentrated into relative density 1.20～1.25 (60 ℃ of heat are surveyed), remainder promptly gets Herba Clinopodii total saponins 239g with approach two operations, and its total saponins is 63.5%, and buddleo-glucoside IV (Herba Clinopodii saponin A) is 15.3%.
Described medicinal application:
Herba Clinopodii total saponins process above-mentioned its total saponins of the preparation method who provides 〉=50%, buddleo-glucoside IV (Herba Clinopodii saponin A) 〉=5%, Herba Clinopodii total saponins is faint yellow or yellow powder; Gas is little, bitter, puckery, and water-soluble, methyl alcohol or dilute methanol, ethanol or Diluted Alcohol are slightly soluble in acetone, are insoluble to low polar solvents such as chloroform; Moisture content (weight loss on drying) but 5.0%, organic solvent is residual up to specification.Its total saponins 〉=50%, buddleo-glucoside IV (Herba Clinopodii saponin A) 〉=5%; The Herba Clinopodii total saponins that this law obtains can be used for the development of the various formulations of medicine, can be used for tablet, orally disintegrating tablet, chewable tablet, capsule, soft capsule, oral liquid, syrup, dripping pill and injection.
Claims (2)
1, the preparation method of Chinese medicine Herba Clinopodii total saponins is characterized in that may further comprise the steps:
(1) extracts workshop section
Get the Herba Clinopodii medicinal material, clean, add the neutral water of 10～13 times of amounts and pH value 6.5～7.5, soaked overnight is extracted, and filters; The dregs of a decoction add 8～12 times of amount neutral waters again and extract, and filter; Merging filtrate, relative density is 1.10～1.15 concentrated solution when being evaporated to 60 ℃ of heat surveys, is chilled to room temperature, adds ethanol to containing alcohol amount 50%～85%, stirs evenly, and leaves standstill 24～48 hours, filters filtrate recycling ethanol; Precipitation is the medicinal material amount 1/2～1/3 that feeds intake with 50%～85% ethanol, divides 2 washings, filters washings and filtrate merging, recovery ethanol, and relative density 1.15～1.20 when being concentrated into 60 ℃ of hot surveys;
(2) enrichment workshop section
1. the processing of upper prop liquid
Soup after the alcohol precipitation that will " extract workshop section " obtains concentrates, by crude drug weight: water volume ratio 3～0.5: 1 ratio adding neutral water is heated to 40 ℃～50 ℃, stirring makes dissolving, left standstill 3～6 hours, and filtered, get filtrate A, it is 9～10 alkaline water liquid that precipitation adds the pH value by 1/5～1/10 of the medicinal material that feeds intake, stirring makes dissolving, filters, and gets liquor B, liquor B and filtrate A merge, and the pH value of mensuration should be closely neutral;
2. resin absorption
Filtrate after the above-mentioned merging is heated to 45 ℃, is added on the D-101 or D-201 type macroporous adsorptive resins that has handled well; Treat soup adsorb fully do after; It is closely colourless that water or Diluted Alcohol 10～15% are eluted to elutriant, discards elutriant, is washed till elutriant with 60～95% ethanol again and do not contain the total saponins composition;
(3) refining workshop section
1. silica gel adsorption
Step 1: the alcohol eluen of above-mentioned resin absorption is merged, reclaim ethanol, relative density 1.05～1.10 when being concentrated into 60 ℃ of heat surveys, 1～2% 40～100 order silica gel that add the medicinal material amount that is equivalent to feed intake, relative density 1.10～1.15 when continuing to be concentrated into 60 ℃ of heat surveys, the silica gel that adds the medicinal material amount 5～10% that feeds intake again, after the ethanol stirring, oven dry is taken out, grind well, the acetone that adds 6～8 times of amounts 1: 1.5～2, alkalescence acetone or 2～7: 1.5～2 sherwood oil: acetone, transfer pH 9～10 with the ethanol that contains 0.1mol/L sodium hydroxide, be no more than 25 ℃ of dippings 10～14 times under the room temperature, each dipping 6～8 hours leaches steeping fluid; Take out silica gel, dry, add 70%～95% extraction using alcohol 6～10 times, each 1～1.5 hour, united extraction liquid reclaimed ethanol, and is concentrated into 3～5% of the medicinal material amount that is equivalent to;
Step 2: with the concentrated solution after the silica gel adsorption, add 2～5% the silica gel be equivalent to the medicinal material amount, stir evenly, in 60～70 ℃ of dryings 2～3 hours, again in 100～105 ℃ of dryings 1～2 hour with an amount of ethanol; Adding 8～12 times is 95% ethanol or dehydrated alcohol extraction 5～8 times, each 1 hour, filter, and filtrate recycling ethanol is to being equivalent to 3～5% of medicinal material amount;
2. magnesium oxide adsorbing or propyl carbinol solvent extraction
Magnesium oxide adsorbing:
Step 1: the alcohol extract with silica gel adsorption after refining, evenly be sprinkled into be equivalent to the medicinal material amount 1～2% magnesium oxide 150 ℃ of activation 3 hours, stir evenly, left standstill 30～60 minutes, repeats 3～4 times, filter, usefulness dehydrated alcohol wash-out magnesium oxide merges with supernatant liquor; Reclaim ethanol to being equivalent to 1～3% of medicinal material amount;
Step 2: with the alcohol extract behind the magnesium oxide adsorbing, record paste containing amount after, press the medicinal extract amount: magnesium oxide weight ratio 1: 5～30, mixing evenly was adsorbed in sample on the magnesium oxide, in 60～80 ℃ of dryings 1～2 hour, in 100～105 ℃ of dryings 1～2 hour, take out again, extract 6～10 times for 6～8 times with dehydrated alcohol, each 1～1.5 hour, filter united extraction liquid, be evaporated to and do or spraying drying, porphyrize is pulverized, sieve, packing promptly gets Herba Clinopodii total saponins;
The propyl carbinol solvent extraction:
With the alcohol extracting concentrated solution after the silica gel adsorption, relative density 1.20～1.25 when being concentrated into 60 ℃ of heat surveys, the water saturated propyl carbinol dissolving that adds the 2～5g/ml that is equivalent to the medicinal material amount, heating stirs evenly, and moves in the extractor, extremely faint yellow with 0.01～0.1mol/lNaOH solution washing that propyl carbinol is saturated to the alkali lye layer, with propyl carbinol saturated aqueous solution washing 1～3 time, discard water layer again, the propyl carbinol reclaim under reduced pressure is extremely done; Dry thing adds an amount of dehydrated alcohol or methyl alcohol heating for dissolving, and reclaim under reduced pressure is to doing, and repetitive operation 1～3 time promptly gets Herba Clinopodii total saponins.
2,, it is characterized in that more specifically step is according to the described preparation method of claim 1:
(1) extracts workshop section
Get and meet that " the Herba Clinopodii medicinal material of a current edition regulation of Chinese pharmacopoeia cleans, and removes weeds, root, cuts into every section of 2～3cm, drops into multi-function extractor, adds 12 times of amount neutral waters, and soaked overnight was extracted 1 hour, crossed the filtration of 150～300 mesh sieves, and is centrifugal; The dregs of a decoction add 8～12 times of amount neutral waters again and extract 3～4 times, each 1 hour, filter, merge, the same method operation is squeezed into concentration tank with extracting solution, concentrating under reduced pressure, relative density is 1.10～1.15 concentrated solution during to 60 ℃ of heat surveys, is chilled to room temperature, adds ethanol to containing alcohol amount 50%～85%, stir evenly, left standstill 24～48 hours, and filtered filtrate recycling ethanol; Precipitation is the medicinal material amount 1/2～1/3 that feeds intake with 50%～85% ethanol, divides 2 washings, filters, and washings and filtrate merge, and reclaims ethanol, and is concentrated into 60 ℃ of hot relative densities 1.15～1.20 of surveying;
(2) enrichment workshop section
1. the processing of upper prop liquid
Soup after the alcohol precipitation that will " extract workshop section " obtains concentrates, by crude drug: water is than 3～0.5: 1 ratio adding neutral water is heated to 40 ℃～50 ℃, stirring makes dissolving, leaves standstill 3～6 hours, filters, get filtrate A, filtrate A squeezes into the header tank basin, precipitation by the medicinal material that feeds intake 1/5～1/10, be 9～10 alkaline water liquid with the pH value of 0.1mol/lNaOH allotment, stirring makes dissolving, filter, get liquor B, liquor B and filtrate A merge, and the pH value of mensuration should be closely neutral;
2. resin absorption
Above-mentioned filtrate is heated to about 45 ℃, is added on the D-101 or D-201 type macroporous adsorptive resins that has handled well, measure maximum adsorption capacity during upper prop, reference data: D-101 type soup: resin was than about 1: 2～3ml; D-201 type soup: resin was than about 1: 4～6ml; Treat that soup adsorbs fully and do the back: flow velocity is got effluent liquid 200ml according to post footpath size adjustment, is concentrated into driedly, and at this moment residue should be negative through the vitriol oil-aceticanhydride reaction detection; It is closely colourless that water or Diluted Alcohol 10～15% are eluted to elutriant, discard elutriant, be washed till elutriant with 60～95% ethanol again and do not contain the total saponins composition: get elutriant 200ml, reclaim and be concentrated into dried, at this moment residue is through the vitriol oil-vinegar fourth reaction detection should be negative;
(3) refining workshop section
1. silica gel adsorption
Step 1: the alcohol eluen of above-mentioned resin absorption is merged, reclaim ethanol, relative density 1.05～1.10 when being concentrated into 60 ℃ of heat surveys, add 40～100 order silica gel, be equivalent to 1～2% of the medicinal material amount that feeds intake, relative density 1.10～1.15 when continuing to be concentrated into 60 ℃ of heat surveys, 5～10% of the medicinal material amount that feeds intake again adds silica gel, after the adequate amount of ethanol stirring, in 60～70 ℃ of dryings 3～6 hours, in 100～105 ℃ of dryings 2～3 hours, take out again, grind well, add 6～8 times of amount 1: 1.5～2 acetone, alkalescence acetone or 2～7: 1.5～2 sherwood oils: acetone, transfer pH 9～10 mixed solvents with the 0.1mol/L alkaline ethanol, be no more than 25 ℃ of dippings 10～14 times under the room temperature, each dipping 6～8 hours leaches steeping fluid; Take out silica gel, dry, add 70%～95% extraction using alcohol 6～10 times, each 1～1.5 hour, united extraction liquid reclaimed ethanol, and is concentrated in right amount, is equivalent to 3～5% of medicinal material amount;
Step 2: with the concentrated solution after the step 1 silica gel adsorption, add 2～5% silica gel be equivalent to the medicinal material amount, stir evenly, in 60～70 ℃ of dryings 2～3 hours, again in 100～105 ℃ of dryings 1～2 hour with an amount of ethanol; Adding 8～12 times is 95% ethanol or dehydrated alcohol extraction 5～8 times, each 1 hour, filter, and filtrate recycling ethanol is equivalent to 3～5% of medicinal material amount to an amount of;
2. magnesium oxide adsorbing or propyl carbinol solvent extraction
Magnesium oxide adsorbing:
Step 1: the alcohol extract with silica gel adsorption after refining, evenly be sprinkled into be equivalent to medicinal material weight 1～2% magnesium oxide 150 ℃ of activation 3 hours, stir evenly, leave standstill operation 30～60 minutes, repeat 3～4 times, filter, with dehydrated alcohol wash-out magnesium oxide, merge with supernatant liquor; Reclaim ethanol to an amount of, be equivalent to 1～3% of medicinal material amount;
Step 2: with the alcohol extract behind the 1st magnesium oxide adsorbing, record paste containing amount after, press medicinal extract: magnesium oxide 1: 5～30, stir evenly, in 60～80 ℃ of dryings 1～2 hour, in 100～105 ℃ of dryings 1～2 hour, take out again, extract 6～10 times for 6～8 times with dehydrated alcohol, each 1～1.5 hour, filter united extraction liquid, sampling detects total saponin content should be greater than 50%, saponin A should be greater than 5%, if do not reach repetitive operation 1～2 time, concentrating under reduced pressure or spraying drying are to doing, porphyrize is pulverized, and sieves, packing promptly gets total saponins in the Herba Clinopodii total saponins;
The propyl carbinol solvent extraction:
With the alcohol extracting concentrated solution after the silica gel adsorption, be concentrated into 60 ℃ of heat and survey relative density 1.20～1.25, add water-saturated n-butanol, be equivalent to 2～5g/ml of medicinal material amount, heating, stir evenly dissolving, move in the extractor, with 0.01 saturated～0.1mol/lNaOH of propyl carbinol wash to the alkali lye layer to faint yellow, wash 1～3 time with the propyl carbinol saturation water again, discard water layer, the propyl carbinol reclaim under reduced pressure is extremely done; Dry thing adds an amount of dehydrated alcohol or methyl alcohol heating for dissolving, and reclaim under reduced pressure is to doing, and repetitive operation 1～3 time promptly gets Herba Clinopodii total saponins.
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| 中国药典2000版第一部 ，586，化学工业出版社 2002 * |
| 断血流总苷对药物流产模型大鼠子宫出血量的影响 戴敏等，中药材，第25卷第5期 2002 * |
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