CN104382973B - Asarum total volatile oil extract and extracting method and the purposes in treatment chronic cough medicine is prepared - Google Patents
Asarum total volatile oil extract and extracting method and the purposes in treatment chronic cough medicine is prepared Download PDFInfo
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Abstract
Asarum total volatile oil extract and extracting method and the purposes in treatment chronic cough medicine is prepared.The invention belongs to natural medicine field, discloses a kind of asarum total volatile oil extract and its extracting method and purposes.This method is that asarum coarse powder is placed in into supercritical CO2In the extraction kettle of extraction equipment, sealing；Heating, when extraction kettle temperature reaches 45~70 DEG C, open extraction kettle valve, air bleeding valve emptying air is opened when pressure is equal with sump pressure in extraction kettle, system is pressurizeed, when extraction kettle pressure, which reaches 30~40Mpa, separating still I and separating still II, reaches 5~10Mpa, when separation temperature reaches 30~50 DEG C, CO is controlled2Flow is 35~60L/h, starts the cycle over extraction；After extracting 60~240min, the asarum total volatile oil extract of extraction is received from separating still discharging opening.Inventor proves that asarum total volatile oil extract has obvious therapeutic action for various chronic cough by substantial amounts of pharmacodynamics test, can be used for preparing the medicine for treating corresponding disease.
Description
Technical field
The invention belongs to natural medicine technical field, more specifically, be related to a kind of asarum total volatile oil extract and its
Extracting method and the purposes in treatment chronic cough medicine is prepared.
Background technology
Cough is the common and multiple disease of respiratory system, is the common complication of division of respiratory disease outpatient service.Cough be paging system in itself by
To a kind of defensive reflex activity caused by stimulation, the external stimulant and the secretion of itself of air flue is removed in help, is one
The beneficial action of kind, also sees healthy population sometimes.Generally, for slightly cough-relieving need not be applied without frequently coughing
Medicine can natural remission, long term frequent or excessively fierce cough are then a kind of pathologic reactions, can not only increase patient
Pain, influence to rest and sleep, increase physical demands, can also promote advancing of disease when serious, produce other complication.
According to the difference of the course of disease, cough can be divided into acute, subacute and chronic cough.Acute cough<3 weeks, subacute cough
Cough 3-8 weeks, chronic cough >=8 week.Clinically generally 8 weeks, chest will be more than for unique symptom or cardinal symptom, time with cough
X-ray checks that Non Apparent Abnormality person is referred to as unknown cause chronic cough, abbreviation chronic cough.Common disease factor is eosinophilic's branch
Tracheitis (EB), epithelium healing cough syndrome (UACS, original claim postnasal drip symptom (PNDS)), gastroesophageal reflux induced cough
(GERC), cough variant asthma (CVA) etc., the clear and definite Chronic Cough Patients of these causes of disease largely can be controlled effectively
Treat.But some patient cause of disease after check comprehensively still fails clearly, is previously referred to as chronic idiopathic cough
(chronic idiopathic cough) or unknown cause chronic cough (unexplained chronic cough).Closely
There is the concept that experts and scholars propose the high insensitivity syndrome (Cough Hypersensitivity Syndrome, CHS) of cough over year
To describe such Chronic Cough Patients, chronic stimulation dry cough, one or more thorn are mainly shown as on this kind of patient clinical
Swashing thing such as cold air, dust, cigarette, oil smoke etc. can induce, Cough reflex sensitivity increase be such patient common pathologic, physiologic it is special
Sign.This some patients is clinically real pertinacious chronic cough patient, that is, " chronic cough ", " stupid cough " described in the traditional Chinese medical science at present
Category.In special outpatient clinic, the ratio of chronic cough is up to 10%-38%, and the survey of European and American countries shows chronic cough
Incidence of coughing also is up to 9%-33%, a scene for 1087 university student's coughs of Guangzhou Inst. of Respiratory Diseases 2006 year
Investigation display, the total incidence of colony cough are 10.9%, and the wherein total incidence of chronic cough is 3.3%, can speculate community
The cough incidence of crowd will be higher.In addition, the research for different regions shows that intractable cough or idiopathic cough account for slowly
Property cough because 12-46%.The average course of disease of this kind of patient is longer, and some is even up to many decades.
Medicament categories clinically for antibechic are various, but many Chronic Cough Patients are not with can after these drug therapies
Obtain effective alleviate.Major drugmaker researches and develops corresponding medicine for chronic cough different onset mechanism both at home and abroad at present
Thing, such as selective antagonist BCTC and JNJ17203212 for cough acceptor TRPV1 and the selectivity for TRPA1
Antagonist HC-030031 and AP-18 etc. is shown inside significantly, outer antitussive activity, but these antagonists are in clinical research
During find all to exist hyperthermia and smell lose it is quick wait side effect, limit its clinical practice.In addition, U.S.'s Pfizer pharmacy
Company and French Sanofi drugmakers develop respectively non-peptides NK1 receptor antagonists CP96345, the CP99994 of specificity and
SR140333 etc., the problems such as being also due to its internal unstability or side effect, the medicine succeeded in developing there is no to be used to face so far
Bed, there is presently no well for the medicine of chronic cough treatment.
In terms of antitussive activity screening experiment model, the overwhelming majority is to draw cough model evaluation medicine using mouse ammoniacal liquor to stop
Cough activity, mouse cough feature unobvious, and number numeration of coughing has certain subjective factor, in addition, these mouse models
It itself can not reflect the pathological and physiological condition of Chronic Cough Patients, therefore screen the cough suppressing medicine obtained to Chronic Cough Patients
Then without good specific aim.This seminar (Guangzhou Inst. of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, cough class
Topic group) using the high quick guinea pig model of the chronic cough voluntarily established, it is a kind of air flue nonspecific inflammation pathologic chronic cough
Model, based on neutrophil infiltration, show as Cough reflex sensitivity and increase, have with chronic refractory cough patients clinically
Many common pathophysiological features, strong instrument is provided for the research of chronic cough particularly pertinacious chronic cough.
Meanwhile we introduce the noninvasive pulmonary function detection system of U.S. BUXCO animals, the cough number of animal is detected by instrument, cough is dived
The indexs such as volt phase, can exclude artificial subjective factor, active ingredients result more science, reliable.
Traditional Chinese medicine and pharmacy is the thousands of crystallizations come abundant practical experience of preventing and curing diseases of the Chinese nation, and the traditional Chinese medical science can distinguish that doctor trained in Western medicine fails to understand it
Disease, Chinese medicine can control that Western medicine is refractory and incurable disease, treatment of the traditional Chinese medicine to cough have long history and rich experience,
It can be complemented one another with western medicine and medical practitioners.Therefore, the safety for the treatment of intractable chronic cough is found from Chinese medicine using prior art
Effective new drug, while great market demand is met, create preferable Social benefit and economic benefit.
Chinese medicine asarum, first recorded in《Sheng Nong's herbal classic》, it is classified as top grade.2010 editions《Chinese Pharmacopoeia》Provide that asarum source is horse
Dou Ling sections plant Herba Asari Asarum Heterotropoides Fr.Schmidt var.mandshuricum (Maxim.)
Kitag., Seoul asarum Asarum sieboldii Miq.var.seoulense Nakai or asarum sieboldii Asarum
Sieboldii Miq. dry root and rhizome.It is warm-natured, acrid flavour, the thoughts of returning home, lung, kidney channel.With relieving exterior syndrome and dispelling cold, wind-expelling pain-stopping, lead to
The effect of key, Wenfei of drink, for phlegm and retained fluid cough and asthma, anemofrigid cold, headache, toothache, nasal obstruction runny nose, allergic rhinitis, nasosinusitis, arthralgia pain due to rheumatism
Treatment.Main pharmacodynamics composition is that (Zhang Huizong pharmacodynamics effect methods screen the experimental study of Chinese medicine asarum active ingredients to volatile oil
Practical tcm internal medicine magazine, 2009,23 (8):29-30；Open the analgesia of man of virtue and ability's Herba Asaris Seoul asarum asarum sieboldii Different plant parts
Effect study China traditional Chinese medicine academic periodical, 2009,27 (5):1096-1099；The town of tri- kinds of Asarum volatile oil of Cheng Mengchun
Pain antiinflammation research China traditional Chinese medicine magazine, 2006,21 (5):307-308), and think that methyl eugenol is its cough-relieving
Effective component (Zhou Huiqiu methyl eugenol pharmacological research traditional Chinese medicine journal .2000, (2):79-80).
For the extracting method of Herba Asari volatile oil, conventional has steam distillation (Steam distillation) and rope
Family name's extraction method (Soxhlet extractor method), is volatile ingredient extracting method generally acknowledged at present.Occur now
The new extracting method of volatile ingredient, such as supercritical fluid extraction (Supercritical fluid extraction), micro-
Ripple auxiliary extraction method (Microwave assisted extraction), Headspace solid phase microextractiom (Headspace solid
Phase microextraction), headspace liquid-phase microextraction method (Headspace liquid phase
Microextraction), air-flow headspace liquid-phase microextraction method (Gas flow headspace liquid phase
Microextraction) and gas flow purging micro-syringe extraction (Gas purgemicrosyringe extraction) etc.,
These methods improve the extraction efficiency of volatile ingredient.The extraction side of steam distillation and soxhlet extraction right and wrong usually
Method, but the shortcomings of time-consuming, expense solvent, extraction volatile ingredient loss is big, heating composition is unstable be present in both approaches.Other
Part Methods are newer, but technical equipment is immature, cost is high etc. be present, there is presently no effectively being promoted, are not suitable for
Industrialized production.Supercritical CO2Extraction is to use nontoxic, nonflammable explosive, inexpensive CO2As extractant, there is extraction
Equipment is simple, extraction time is short, operation temperature is low, chemical composition is not easy to be destroyed, recovery rate is high, it is impure less, it is solvent-free residual
The advantages that staying, it is extracting process ideal at present.
The content of the invention
For above the deficiencies in the prior art, primary and foremost purpose of the invention is to provide a kind of asarum total volatile oil extract
Extracting method.
It is yet another object of the invention to provide the asarum total volatile oil extract that the above method extracts to obtain.The present invention passes through
Optimize supercritical CO2Extraction conditions obtains Herba Asari volatile oil, and HPLC analysis results show that ingredient is waved with what is reported at present
Hair oil composition is significantly different, in addition to the existing cough-relieving composition (methyl eugenol) with considerable amount of conventional volatile oil, also has
There are the involatile constituents such as asarinin.
Another object of the present invention is to provide above-mentioned asarum total volatile oil extract in treatment chronic cough medicine is prepared
Purposes.The pharmacodynamic results of the present invention show that asarum routine volatile oil is preferable for acute cough's animal model cough suppressing effect, but
For chronic cough animal model, Herba Asari volatile oil cough suppressing effect prepared by the inventive method is significantly better than conventional method preparation
Volatile oil.
The present invention is by optimizing supercritical CO2The Herba Asari volatile oil that extraction conditions obtains and traditional steam distillation and
The supercritical CO of existing report2The Herba Asari volatile oil chemical composition that extraction is obtained is significantly different, and has for chronic cough
There is more preferable antitussive activity, there is presently no the document report of correlation.
The object of the invention is achieved through the following technical solutions：
A kind of extracting method of asarum total volatile oil extract, according to following operating procedure：By the root and/or rhizome of asarum
Clean, dry, crush, obtain asarum coarse powder；Asarum coarse powder is placed in supercritical CO2In the extraction kettle of extraction equipment, sealing；To extraction
Take kettle, separating still to be respectively heated, when extraction kettle temperature reaches 45~70 DEG C, extraction kettle valve is opened, when in extraction kettle
Air bleeding valve emptying air is opened when pressure is equal with sump pressure, system is pressurizeed by high-pressure pump, when extraction kettle pressure
Reach 30~40Mpa, separating still I and the pressure of separating still II and reach 5~10Mpa, when separation temperature reaches 30~50 DEG C, control
CO2Flow is 35~60L/h, starts the cycle over extraction；After extracting 60~240min, the asarum of extraction is received from separating still discharging opening
Total volatile oil extract.
The extraction kettle temperature is set in 50 DEG C；The extraction kettle pressure reaches 35Mpa；The separating still I and separating still
II pressure reaches 5Mpa, and temperature reaches 40 DEG C；The CO2Flow is controlled in 40L/h；The time of the extraction is 180min.
The asarum is Herba Asari, Seoul asarum or asarum sieboldii, more preferably Herba Asari.
A kind of asarum total volatile oil extract obtained by said extracted method, first in the asarum total volatile oil extract
Base eugenol (methyleugenol) absolute content is 30.9wt%, and the absolute content of asarinin (asarinin) is
10.5wt%, the absolute content of sesamin (sesamin) is 7.8wt%.
Purposes of the above-mentioned asarum total volatile oil extract in treatment chronic cough medicine is prepared, the asarum always volatilize
Oil extract is independent or preparation treatment chronic cough medicine is combined with other drugs.
Various formulations are made with available pharmaceutical carrier in the asarum total volatile oil extract.
The formulation is granule, tablet, capsule, soft capsule, pill, pill, effervescent tablet, ointment, syrup
Agent, injection, oral liquid, mixture, tincture, sustained release agent, controlled release agent or targeting preparation.
Pharmaceutically acceptable carrier is such as：Filler, adhesive, lubricant, disintegrant or wetting agent.Filler includes breast
Sugar, sucrose, cornstarch, sorbierite；Adhesive includes syrup, Arabic gum, gelatin, sorbierite, hydroxypropyl methyl cellulose
Or polyvinylpyrrolidone；Lubricant includes magnesium stearate；Disintegrant includes starch, polyvinylpyrrolidone, Crospovidone, micro-
Crystalline cellulose；Wetting agent such as lauryl sodium sulfate.
Described methyl eugenol (methyleugenol), i.e. structural formula are C11H14O2, chemical formula 4-allyl-1,2-
Dimethoxybenzene compound.
Described asarinin (asarinin), i.e. structural formula are C20H18O6, chemical formula 5,5'- [(1R, 3aR, 4S,
6aR)-tetrahydro-1H, 3H-furo [3,4-c] furan-1,4-diyl] bis-1,3-Benzod ioxole chemical combination
Thing.
Described sesamin (sesamin), i.e. structural formula are C20H18O6, chemical formula 5,5'- [(1S, 3aR, 4S,
6aR)-tetrahydro-1H, 3H-furo [3,4-c] furan-1,4-diyl] bis-1,3-Benzodi oxole chemical combination
Thing.
The present invention can use gas chromatography or gas chromatography-mass spectrometry or high performance liquid chromatography, respectively or same
When determine asarum total volatile oil in methyl eugenol, asarinin, the content of sesamin.
The GC conditions are DB-5MS quartz capillary columns (30m × 0.25mm × 0.25 μm, i.d.)；Split ratio
100:1, sample size：1μL；Carrier gas：High-purity helium；Flow velocity：1mL·min-1；The solvent delay time：3min, temperature programming：Column temperature
70 DEG C (6min), with 10 DEG C of min-1100 DEG C (35min) are risen to, then with 10 DEG C of min-1Speed rise to 230 DEG C
(20min), 250 DEG C of injector temperature.
The Mass Spectrometry Conditions are EI electron sources, carrier gas He；Electron energy 70eV, 230 DEG C of ion source temperature, transmission line temperature
250 DEG C, 2.0 editions spectrum storehouses of scanning range 40~450m/z, NIST.
The liquid phase chromatogram condition is Agilent Zorbax SB-C18 chromatographic columns (4.6mm × 250mm, 5 μm)；Flowing
Phase A phases are water, and B phases are acetonitrile, gradient elution, and elution program is：0~30min, 45%~60%B, 30~40min, 60%~
100%B；Run time：40min, equilibration time：10min；Volume flow：1.0mL·min-1；Detection wavelength：285nm；Post
Temperature：30℃；Sample size：10μL.
The effective dose that the present invention has the asarum total volatile oil extract of antitussive activity is counted according to the body weight 60kg of people
Calculate, be 0.6~2.3g/ man days.
The present invention principle be：
Pharmacological evaluation proves that asarum total volatile oil extract prepared by the present invention has the work of good treatment chronic cough
Property, available for preventing or treat various pertinacious chronic cough, the high quick syndrome of such as cough.
Results of pharmacodynamic test shows, for guinea pig acute cough model, citric acid excites asarum prepared by the rear present invention
The basic, normal, high dosage group of total volatile oil extract can extend the cough latent period of animal compared with blank control group, reduce cavy
Cough number；(the supercritical CO under steam distillation or other conditions is prepared with conventional2Extraction) Herba Asari volatile oil compared to anxious
Property antitussive activity is relatively weak；And increase for chronic cough sensitiveness and with the guinea pig model (smoke from cigarette of airway inflammation
Exposure 14 days), the basic, normal, high dosage group of asarum total volatile oil that citric acid excites the rear present invention to prepare can be bright compared with model group
The aobvious cough latent period for extending animal, the cough number of cavy is reduced, while the inflammatory cell that can be reduced in cavy BALF is total
The ratio of number and neutrophil leucocyte, suppress airway inflammation, reach or the effect close to codeine；Always waved with the asarum routinely prepared
Hair oil is compared, wherein middle and high dosage group antibechic rate is respectively provided with significant difference, shows that asarum prepared by preparation technology of the present invention is total
The high quick guinea pig model of cough under extractive of volatile oil exposes to long-term smoke from cigarette has more preferable antitussive activity.
The beneficial effects of the invention are as follows：
(1) the invention provides a kind of medicine for treating chronic cough, the selection field of cough suppressing medicine has been expanded, has also been this
The development of technical field is made that contribution.
(2) the asarum total volatile oil extract and existing document report process conditions that prepared by the present invention are significantly different, wave
The constituent of hair oil also has larger difference, and asarum total volatile oil extract prepared by the present invention is except with considerable amount of routine
The existing cough-relieving composition (methyl eugenol etc.) of volatile oil outside, also with involatile constituents such as asarinins.
(3) in chronic cough application aspect, compared with volatile oil prepared by asarum conventional method, the asarum of the invention prepared
Total volatile oil extract has more preferable antitussive activity.
(4) method for preparing extractive provided by the invention has that rate of extraction is fast, pollution-free, technique is simple, avoids aoxidizing
The advantages that with pyrolysis, superior product quality, no solvent residue, different boiling, different volatile oil can particularly be extracted simultaneously
Take out, active ingredient is more complete.
(5) present invention prepare asarum total volatile oil extract quality control can by gas chromatography, gas-chromatography-
MS and high performance liquid chromatography carry out qualitative and quantitative analysis, and this method is simple and easy controllable.
Brief description of the drawings
Fig. 1 be asarum difference volatile oil HPLC chromatogram, wherein A：Asarum routine volatile oil (obtained by steam distillation)；
B：(present invention prepares gained to asarum total volatile oil；1：Methyl eugenol (methyleugenol) reference substance；2：Sesamin
(sesamin) reference substance；3：Asarinin (asarinin) reference substance；4、5：Ultraviolet spectra speculates homologue each other).
Fig. 2 be asarum total volatile oil to guinea pig cough's number caused by citric acid influence (, n=8), wherein A：It is empty
White group；B：Solvent group (5%Tween-80)；C：Codeine phosphate 30mg/kg groups；D、E、F：Asarum total volatile oil 50,100,
200mg/kg groups；G：Asarum routine volatile oil 200mg/kg groups；Compared with blank group：*p<0.05,**p<0.01,***p<0.001；
Compared with solvent group：▲p<0.05,▲▲▲p<0.001。
Fig. 3 be asarum total volatile oil cigarette is exposed the high quick guinea pig cough's number of cough influence (N=8), wherein
A：Blank group；B：Model group；C：Solvent group (5%Tween-80)；D：Codeine phosphate 30mg/kg groups；E、F、G：Asarum is always waved
Hair oil 50,100,200mg/kg groups；H：Asarum routine volatile oil 200mg/kg groups；Compared with model group：**p<0.01,***p<
0.001；Compared with solvent group：▲▲▲p<0.001；Compared with asarum routine volatile oil group：##p<0.01,###p<0.001。
Fig. 4 is that asarum total volatile oil exposes cough Gao Min guinea pig lung tissues pathology representative graph, wherein A to cigarette：Blank group；
B：Model group；C：Solvent group (5%Tween-80)；D：Codeine phosphate 30mg/kg groups；E、F、G：Asarum total volatile oil 50,
100th, 200mg/kg groups；H：Asarum routine volatile oil 200mg/kg groups.
Fig. 5 is that asarum total volatile oil exposes the high quick guinea pig trachea histopathology representative graph of cough, wherein A to cigarette：Blank
Group；B：Model group；C：Solvent group (5%Tween-80)；D：Codeine phosphate 30mg/kg groups；E、F、G：Asarum total volatile oil 50,
100th, 200mg/kg groups；H：Asarum routine volatile oil 200mg/kg groups.
Embodiment
The present invention is described in further detail with specific embodiment below in conjunction with the accompanying drawings, but not as the limit to the present invention
It is fixed.
Embodiment 1
The preparation and analysis of asarum total volatile oil extract
The preparation of 1.1 asarum total volatile oil extracts
Using supercritical CO2Extraction equipment extracts asarum total volatile oil extract, the root of asarum and/or rhizome are cleaned,
Dry, pulverizer crushing, obtain asarum coarse powder, asarum coarse powder is added in the charging bottle of extraction kettle, be reloaded into extraction kettle, seal；
Heating, when extraction kettle temperature reaches 50 DEG C, extraction kettle valve is opened, is opened when pressure is equal with sump pressure in extraction kettle
Air bleeding valve emptying air, pressurizes to system, reaches 5Mpa when extraction kettle pressure reaches 35Mpa, separating still I and separating still II
When, when separation temperature reaches 40 DEG C, control CO2Flow is 40L/h, starts the cycle over extraction；After extracting 180min, go out from separating still
Material mouth receives the asarum total volatile oil extract of extraction, and yield is 2.5% (mL/g).
The analysis of 1.2 asarum total volatile oils
1.2.1 liquid phase chromatogram condition
The high performance liquid chromatographs of Agilent 1260, Zorbax SB-C18 chromatographic columns (4.6mm × 250mm, 5 μm)；Flowing
Phase A phases are water, and B phases are acetonitrile, gradient elution, and elution program is：0~30min, 45%~60%B, 30~40min, 60%~
100%B；Run time：40min, equilibration time：10min；Volume flow：1.0mL·min-1；Detection wavelength：285nm；Post
Temperature：30℃；Sample size：10μL.
1.2.2 analysis result
Analysis result from chromatogram as shown in figure 1, be not difficult to find out, with volatile oil (the steam distillation preparation routinely prepared
Gained, SD volatile oil, Fig. 1 A) compare, this seminar is by optimizing SFE-CO2Extraction conditions obtained by asarum always volatilize
Oily (Fig. 1 B), not only contains all volatile ingredients of SD volatile oil, further comprises part involatile constituent (chromatographic peak 2
For sesamin, the asarinin of chromatographic peak 3, chromatographic peak 4 and 5 speculates homologue each other by ultraviolet spectra).Current most of texts
Offer and think SD methods and SFE-CO2Volatile oil obtained by method finds that contained volatile ingredient is more similar through analysis, and does not have also so far
There is the report containing involatile constituents such as asarinins in the asarum total volatile oil for see preparation, show prepared by the present invention
Asarum total volatile oil is significantly different with the volatile oil of existing literature report on composition composition.
Embodiment 2
Acute antitussive effect of the asarum total volatile oil extract to guinea pig cough caused by citric acid
2.1 experiment material
Experimental animal：Regular grade Hartley cavys, male and female half and half, body weight 250-350g, by Guangdong Province medical experiment animal
Center provides, animal quality certification number：SCXK (Guangdong) 2008-0002.
Reagent and instrument：Monohydrate potassium (Guangzhou Chemical Reagent Factory, lot number：20121001-2), the used time is configured to
0.8M normal saline solution；The noninvasive Buxco pulmonary function detections system of animal (Buxco companies of the U.S.)；Aeroneb Pro are atomized
Device (Aerogen (Ireland) Co., Ltd)；Gastric perfusion needle (Guangdong Medical Lab Animal Center).
2.2 experimental method
Evaluating drug effect is carried out using citric acid induction guinea pig acute cough model.Take 112 Hartley cavys, by its by
One, which is placed in the noninvasive L bodies of Buxco pulmonary function detections system 6 of animal, retouches in instrument, drift meter air velocity 2.5L/min, uses
Aeroneb Pro atomizers are passed through the 0.8M of atomization citric acid ultra-pure water solution aerosol 1min, and the particle of atomization is averagely straight
2.5 μm of footpath, 5min to be observed, monitor the cough number in 6min, the sound of cough is recorded by the microphone of indoor placement and amplification,
Sound wave is analyzed through Biosystem XA softwares, then through computer software processing voice data record cough number, while by passing through
The observer for crossing training supplements observation.Cavy of the cough number more than 10 times is selected to be tested for qualified animal.
Take and screen 56 qualified Hartley cavys, male and female half and half, be randomly divided into 7 groups, blank group gives 1mL/100g's
Physiological saline, solvent group give isometric coordinative solvent (the Tween-80 aqueous solution of concentration of volume percent 5%), positive drug
Group gives isometric 30mg/kg codeine phosphates, and administration group gives isometric asarum total volatile oil extract (embodiment 1
Sample 50mg/kg, 100mg/kg,
200mg/kg), asarum routine volatile oil (200mg/kg, steam distillation prepare gained), 1 time a day, continuously gives
Medicine 3 days.2h carries out citric acid atomization provocative test (atomization bar in the noninvasive Buxco pulmonary function detections system of animal after last dose
Part is the same), atomization excites 1min, and induction cavy produces acute cough, observes 5min, calculates cough number (N) in 6min, cough
Cough incubation period, and with formula " antibechic rate=(NBlank control-NAdministration group)/NBlank control× 100% " calculates the antibechic rate of each administration group.
Data are usedRepresent, each group parameter is carried out using the statistical softwares of IBM SPSS Statistics 19.0 single
Analysis of variance.Between group compare, p<0.05 is to have significant difference.
2.3 experimental result
(1) influence of the asarum total volatile oil extract to acute cough's guinea pig model cough number
Cough number and cough inhibiting rate of each group animal after citric acid atomization excites in 6min are shown in Table 1 and Fig. 2.By
Table 1 and Fig. 2 understand that compared with blank group, the basic, normal, high dosage group of asarum total volatile oil extract can reduce the cough of cavy
Cough number, wherein middle and high dosage has significant difference (p<0.05), antibechic rate respectively reaches 42.7% and 51.4%.Asarum
Conventional volatile oil is better than asarum total volatile oil (antibechic rate 53.8%) for the acute antitussive activity of cavy, but therebetween without aobvious
Write sex differernce.
Result above shows that asarum total volatile oil extract has good acute antitussive effect, and has dose-effect relationship.
The asarum total volatile oil of table 1 to guinea pig cough's number caused by citric acid influence (N=8)
Note：Compared with blank group：*p<0.05,**p<0.01,***p<0.001；Compared with solvent group：▲p<0.05,▲▲▲p<
0.001。
(2) asarum total volatile oil is on the preclinical influence of guinea pig cough caused by citric acid
Cough latent period of each group animal after citric acid atomization excites in 6min is shown in Table 2.As shown in Table 2, with blank
Group is compared, asarum total volatile oil extract various dose group can prolonged guinea pig cough latent period, wherein high dose group p<
0.05.Asarum total volatile oil extract high dose group extends the effect of cough latent period close to codeine phosphate.Asarum is conventional
Volatile oil can also significantly extend cough latent period (p<0.01), and effect is better than codeine phosphate.
The influence preclinical on guinea pig cough caused by citric acid of the asarum total volatile oil of table 2 (N=8)
Note：Compared with blank group：*p<0.05,**p<0.01；Compared with solvent group：▲p<0.05,▲▲p<0.01。
Embodiment 3
Asarum total volatile oil extract increases the antitussive effect of guinea pig model to chronic cough sensitiveness
3.1 experiment material
Experimental animal：Regular grade Hartley cavys, male and female half and half, body weight 250-350g, by Guangdong Province medical experiment animal
Center provides, animal quality certification number：SCXK (Guangdong) 2008-0002.
Reagent and instrument：Monohydrate potassium (Guangzhou Chemical Reagent Factory, lot number：20121001-2), the used time is configured to
0.8M normal saline solution；The noninvasive Buxco pulmonary function detections system of animal (Buxco companies of the U.S.)；Aeroneb Pro are atomized
Device (Aerogen (Ireland) Co., Ltd)；Cell counting count board (Zhejiang Yuhuan county Chu Men medical apparatus factory)；Gastric perfusion needle (Guangdong
Save medical experiment animal center).
3.2 experimental method
Qualified Animal screening procedure is the same as embodiment 2.Take and screen qualified animal 64, be randomly divided into 8 groups, blank group and mould
Type group gives 1mL/100g physiological saline, solvent group give isometric coordinative solvent (concentration of volume percent 5%
The Tween-80 aqueous solution), positive drug group gives isometric 30mg/kg codeine phosphates, and administration group gives isometric asarum
Total volatile oil extract (embodiment 1 sample 50mg/kg, 100mg/kg, 200mg/kg), asarum routine volatile oil (200mg/kg,
Steam distillation prepares gained), daily gastric infusion 1 time, successive administration 14 days.In addition to blank group, every group of sootiness 20min, often
Secondary 10 red rose cigarette (Guangdong China Tobacco Industry Co., Ltd, tar content 13mg, nicotine amount 1.3mg, CO contents
15mg), 2 times a day, continuous 14 days, cavy chronic cough evaluating drug effect model is established.24h after last sootiness, using citric acid
Atomization excites 1min (the noninvasive Buxco pulmonary function detections system of animal, atomization condition is with embodiment 2), and induction cavy produces cough,
5min is observed, calculates cough number (N), antibechic rate and cough latent period in 6min.Animal excites rear 24h, 3% amobarbital
Sodium is anaesthetized, heart extracting blood, the PBS row guinea pig bronchial alveolar wasses (BALF) of 6mL ice, while takes lung and tracheal tissue, and 10%
Formaldehyde is fixed.
Observation procedure and index：
(1) calculate citric acid and excite cough number in 6min, and with formula " antibechic rate=(NModel group-NAdministration group)/NModel group×
100% " calculates the antibechic rate of each administration group；
(2) cough latent period that citric acid excites each administration group in 6min is calculated；
(3) airway inflammation index：1. BALF inflammatory cells sum (TCC)：Atomization is taken to excite BALF irrigating solutions after end 24h
0.5mL, 3000r/min centrifuge 10min, precipitation plus 0.3mL erythrocyte cracked liquids, and vibration mixes, and stands 10min, 3000r/min
10min is centrifuged, precipitation is suspended with 0.5mL PBS, takes the total counting number of cell counting count board row inflammatory cell under 10 μ L light microscopes
(TCC)；2. BALF cell classifications：Fixed BALF cell smears, flowing water rinse 5min, haematoxylin dyeing 20sec, and flowing water rinses
5min, 1% hydrochloride alcohol decolouring 5sec, flowing water rinse 5min, eosin stains 5sec, and flowing water rinses 5min, neutral tree after drying
Glue mounting, cell classification is carried out under light microscope；3. lung, tracheal tissue's pathological observation：Lung, tracheal tissue HE dyeing；Lung group
Knit whether main detection bronchus, alveolar, companion's row parteriole structure are complete, and whether the arrangement of air flue cilliated epithelium is neat, bronchus,
The infiltration of inflammatory cell is whether there is around blood vessel, whether there is congestion and edema etc.；Whether tracheal tissue's main detection epithelium is complete, and tube chamber is
No regular, tube wall, which whether there is, to be thickened, and whether cilium arrangement is neat, whether there is and comes off, whether there is inflammatory cell infiltration etc..
3.3 experimental result
(1) asarum total volatile oil extract increases the influence of guinea pig model cough number to chronic cough sensitiveness
Compared with blank group, citric acid atomization excites the model group cavy after smoke from cigarette exposure 14d, the cough in 6min
Number significantly increases (p<0.01), the high quick guinea pig model modeling success of cough.Compared with model group, asarum total volatile oil extract
Basic, normal, high dosage group can be with the cough number (p of the reduction cavy of highly significant<0.001), antibechic rate respectively reaches
53.3%th, 79.1% and 83.4%.Compared with asarum routine volatile oil, asarum total volatile oil extract middle dose group has notable
Sex differernce (p<0.01), high dose group has significant differences (p<0.001), show asarum total volatile oil extract to length
The high quick guinea pig model of cough under the exposure of phase smoke from cigarette has more preferable antitussive activity (the results are shown in Table 3 and Fig. 3).
Result above shows that asarum total volatile oil extract, which increases cavy to chronic cough sensitiveness, has preferably treatment
Effect, and have dose-effect relationship, wherein asarum total volatile oil extract has approached under 100mg/kg (middle dose group) dosage conditions
Therapeutic effect under codeine phosphate 30mg/kg dosage, and then can better than phosphoric acid under 200mg/kg (high dose group) dosage conditions
Treat because of the therapeutic effect under 30mg/kg dosage.
The asarum total volatile oil of table 3 cigarette is exposed the high quick guinea pig cough's number of cough influence (N=8)
Note：Compared with model group：**p<0.01,***p<0.001；Compared with solvent group：▲▲▲p<0.001；It is conventional with asarum
Volatile oil group is compared：##p<0.01,###p<0.001。
(2) asarum total volatile oil on smoke from cigarette exposure Cough reflex sensitivity on increasing the preclinical influence of guinea pig cough
After each group animal cigarette exposure 14d, the cough latent period after citric acid atomization excites in 6min is shown in Table 4.By
Table 4 understand, compared with model group, asarum total volatile oil extract various dose group can prolonged guinea pig cough latent period, its
In middle and high dosage group there is significant differences (p<0.001), and between each dosage group there is dose-effect relationship.It is conventional with asarum
Volatile oil is compared, and it (is respectively p that the middle and high dosage group cough latent period of asarum total volatile oil extract, which is respectively provided with significant difference,<
0.05、p<0.01)。
The preclinical influence of the asarum total volatile oil of table 4 quick guinea pig cough high on cigarette exposure cough (N=8)
Note：Compared with model group：**p<0.01,***p<0.001；Compared with solvent group：▲▲▲p<0.01；Routinely waved with asarum
Hair oil group is compared：#p<0.05,##p<0.01。
(3) asarum total volatile oil increases the shadow that TCS counts in cavy BALF to smoke from cigarette exposure Cough reflex sensitivity
Ring
Compared with blank group, what TCS had a highly significant in the model group BALF after cigarette exposure 14d increases (p<
0.001), modeling success.Compared with model group, asarum total volatile oil extract various dose group extremely can significantly reduce cavy
Inflammatory cell sum (p in BALF<0.001), and tool dose-effect relationship；Compared with asarum routine volatile oil, asarum total volatile oil carries
Taking thing high dose group TCS to count has significant difference (p<0.05)；Codeine phosphate can not reduce air flue hypersensitivity
Inflammatory cell in airway inflammation cavy BALF is total (being shown in Table 5).
The influence total to the high quick cavy inflammatory cell of cigarette exposure cough of the asarum total volatile oil of table 5 (N=8)
Note：Compared with model group：*p<0.05,***p<0.001；Compared with solvent group：▲▲p<0.01,▲▲▲p<0.001；With
Asarum routine volatile oil group is compared：#p<0.05。
(4) asarum total volatile oil increases the influence of cell classification in cavy BALF to smoke from cigarette exposure Cough reflex sensitivity
Compared with blank group, cigarette exposure 14d after model group BALF in macrophage (Mac) ratio significantly reduce and in
Property granulocyte (Neu) ratio significantly raises, and has significant differences (p<0.001), modeling success.With model group phase
Than asarum total volatile oil extract various dose group can reduce the ratio of Neu in cavy BALF, wherein low, high dose group tool
There is significant differences (p<0.01).Asarum total volatile oil can raise Mac ratio simultaneously, and wherein high dose group has very
Good significant difference (p<0.001)；Compared with asarum routine volatile oil, asarum total volatile oil extract can be reduced significantly
Neu ratio；The inflammatory cell ratio that codeine phosphate can not be reduced in air flue hypersensitivity airway inflammation cavy BALF (is shown in Table
6)。
The asarum total volatile oil of table 6 cigarette is exposed the high quick cavy cell classification of cough influence (N=8)
Note：Compared with model group：**p<0.01,***p<0.001；Compared with solvent group：▲▲p<0.01；Routinely waved with asarum
Hair oil is compared：#p<0.05。
(5) asarum total volatile oil increases the observation of Guinea pig lung, tracheal tissue's pathology to smoke from cigarette exposure Cough reflex sensitivity
Pathologic result is as shown in Figure 4 after the exposure of each group animal smoke from cigarette and pharmaceutical intervention.As seen from the figure, normally
Group (Fig. 4 A) guinea pig bronchial, alveolar, companion's row parteriole structural integrity, air flue cilliated epithelium marshalling, bronchus, blood vessel
Around the infiltration without inflammatory cell, without congestion and edema；Compared with Normal group, model group (Fig. 4 B) guinea pig lung tissue is presented
Typical pathologic inflammation changes, the lodging of bronchial mucosa cilium, exuviation, official jargon inflammatory exudate, and peribronchial is largely scorching
Disease cellular infiltration, alveolar septum is broadening, and alveolar structure is disorderly, the fracture of part alveolar septum；Solvent group (Fig. 4 C) pathologic
Change substantially same model group；Compared with model group, asarum total volatile oil group is high, in and low dose group (Fig. 4 E, F, G) Guinea pig lung
Histopathology is improved in varying degrees, wherein high, middle dose group improves very obvious, bronchus, alveolar structure are substantially complete, branch
Tracheal cilia without obvious lodging, epithelium without substantially coming off, basic no inflammation cellular infiltration around high dose group bronchus, blood vessel,
Middle dose group is only shown in a little inflammatory cell infiltration；And the improvement of low dose group pathologic is poor, it is seen that bronchial lumen inflammatory oozes
Go out, the lodging of mucous layer cilium, artery wall thickening, official jargon are narrow and small, there is more inflammatory cell infiltration around bronchus, blood vessel；Phosphoric acid
Codeine group (Fig. 4 D) pathologic also makes moderate progress compared with model group, and alveolar septum is broadening, bronchus, perivascular inflammatory
Cellular infiltration is reduced.Compared with asarum routine volatile oil group (Fig. 4 H), the middle and high dosage group inflammatory cell leaching of asarum total volatile oil
Profit improvement degree becomes apparent.
Tracheae pathological observation is as shown in Figure 5 after the exposure of each group animal smoke from cigarette and pharmaceutical intervention.As seen from the figure, normal group
(Fig. 5 A) guinea pig tracheal epithelia is complete, and cilium marshalling, tube chamber is regular, and tube wall is without thickening, basic no inflammation cellular infiltration；
Compared with Normal group, model group (Fig. 5 B) guinea pig trachea is presented typical pathologic inflammation and changed, and tracheal mucosa epithelial cilia falls
Volt, epithelial cell shedding, a large amount of inflammatory cell infiltrations of submucosa, basilar memebrane thicken in various degree；Solvent group (Fig. 5 C) tracheae
The substantially same model group of pathological change；Compared with model group, asarum total volatile oil is high, middle dose group (Fig. 5 E, F) guinea pig trachea disease
Reason improves in various degree, and tracheal epithelium structure is substantially complete, cilium arrangement primitive rule, basilar memebrane without substantially thickening, tube wall without
Obvious inflammatory cell infiltration, the visible a little mucosal epithelium of middle dose group come off；And low dose group (Fig. 5 G) tracheal tissue's pathology changes
It is kind not very obvious, it is little with model group difference.The substantially same model group of codeine phosphate group (Fig. 5 D) tracheae pathology, has no obvious
Improve.Compared with asarum routine volatile oil group (Fig. 5 H), the middle and high dosage group of asarum total volatile oil is in airway epithelia structural integrity
Property, airway walls inflammatory cell infiltration etc. histopathology improves degree and becomes apparent.
Embodiment 4
Asarum total volatile oil extract prepared by the method for Example 1 presses 1:0~5 ratio (weight ratio) adds sesame oil,
It is well mixed, it is standby as decoction.1 part of gelatin is taken, adds 0.6-1.2 parts glycerine and 0.2% methyl hydroxybenzoate-propyl p-hydroxybenzoate
(mass ratio 4:1) mixture (preservative), more than 2h is soaked with the water of 0.7-1.4 mass times, dissolves by heating, gas is removed under reduced pressure
Bubble, it is standby in 60-65 DEG C of insulation.Above-mentioned decoction is put in pellet press, it is capsule material to state glue clearly above, in 45-55 DEG C of condition
Under, it is pressed into soft capsule.
Embodiment 5
Asarum total volatile oil extract prepared by the method for Example 1 adds the beta-cyclodextrin inclusion compound of 2-9 mass times, and mixing is
It is even, crospovidone is added, is mixed, is pelletized, is dried, whole grain, adds magnesium stearate, is well mixed, tabletting, produces piece
Agent.
Above-mentioned embodiment is the preferred embodiments of the present invention, can not be limited the invention, and others are appointed
The change or other equivalent substitute modes what is made without departing from technical scheme, are included in the protection of the present invention
Within the scope of.
Claims (7)
- A kind of 1. asarum total volatile oil extract for being used to treat chronic cough, it is characterised in that the extraction side of the extract Method is according to following operating procedure：The root of asarum and/or rhizome are cleaned, dry, crushed, obtains asarum coarse powder；Asarum coarse powder is put In supercritical CO2In the extraction kettle of extraction equipment, sealing；Extraction kettle, separating still are respectively heated, when extraction kettle temperature reaches During to 45~70 DEG C, extraction kettle valve is opened, it is empty to open air bleeding valve emptying when pressure is equal with sump pressure in extraction kettle Gas, system is pressurizeed by high-pressure pump, when extraction kettle pressure reaches 30~40 Mpa, separating still I and the pressure of separating still II Reach 5 Mpa, when separation temperature reaches 40 DEG C, control CO2Flow is 35~60 L/h, starts the cycle over extraction；Extraction 60~240 After min, the asarum total volatile oil extract of extraction is received from separating still discharging opening.
- 2. extract according to claim 1, it is characterised in that：The extraction kettle temperature is set in 50 DEG C；The extraction Kettle pressure reaches 35 Mpa；The CO2Flow is controlled in 40 L/h；The time of the extraction is 180 min.
- 3. extract according to claim 1, it is characterised in that：The asarum is Herba Asari, Seoul asarum or asarum sieboldii.
- 4. extract according to claim 1, it is characterised in that：The asarum is Herba Asari.
- 5. the extract according to any one of claim 1 ~ 4 is preparing the purposes in treating chronic cough medicine, its feature It is：The asarum total volatile oil extract is independent or preparation treatment chronic cough medicine is combined with other drugs.
- 6. purposes according to claim 5, it is characterised in that：The asarum total volatile oil extract and available pharmaceutical carrier Various formulations are made.
- 7. purposes according to claim 6, it is characterised in that：The formulation is granule, tablet, capsule, pill, soft Paste, syrup, injection, mixture, tincture, sustained release agent, controlled release agent or targeting preparation.
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| JP5547453B2 (en) * | 2009-10-30 | 2014-07-16 | サントリーホールディングス株式会社 | Method for producing optically active lignan |
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| CN103610722A (en) * | 2013-12-13 | 2014-03-05 | 沈阳药科大学 | Asarum heterotropoide extract, preparation method and application of extract |
| CN103690520A (en) * | 2013-12-30 | 2014-04-02 | 沈阳药科大学 | Patch containing essential oil of single leaf asarum, as well as preparation method and medical application of patch |
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