CN103436364B - A kind of preparation method of Herba Ajugae volatile oil and application thereof - Google Patents
A kind of preparation method of Herba Ajugae volatile oil and application thereof Download PDFInfo
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- CN103436364B CN103436364B CN201310377188.7A CN201310377188A CN103436364B CN 103436364 B CN103436364 B CN 103436364B CN 201310377188 A CN201310377188 A CN 201310377188A CN 103436364 B CN103436364 B CN 103436364B
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Landscapes
- Medicines Containing Plant Substances (AREA)
Abstract
The present invention relates to a kind of preparation method and application thereof of Herba Ajugae volatile oil, compared with existing antiviral synthetic drug, its toxicity is low, safe and reliable, drug action is strong, and dracocephalum heterophyllum abundant raw material, inexpensive, extraction process is simple, and preparation cost is low, can make various formulations.
Description
Technical field
The invention belongs to Chinese medicine neighborhood, relate to a kind of preventing respiratory viruses medicine, be specifically related to Herba Ajugae volatile oil in systemPurposes in standby preventing respiratory viruses medicine.
Background technology
Tibetan medical dracocephalum heterophyllum benth is labiate dracocephalum heterophyllum (DracocephalumheterophyllumBenth)Dry aerial parts, belong to herbaceos perennial, have another name called heterophyllum, heterophyllous dragonhead herb, Ji Ziqing and protect (Tibetan medicine name), XinjiangDimension language claims Ma Erzanjuxi, Zu Paer. Dracocephalum heterophyllum aerial part has effect of purging the liver of pathogenic fire heat clearly, is that Uygurs, Tibetan are for controllingTreat traditional medication of cough illness and stomach trouble. Being mainly used in treating jaundice fever, liver heat, febrile disease headache, mist, oral cavity burstsThe various disease conditions such as ulcer, bronchitis, hypertension. That Tibetan medicine ministry standard is included kind. Dracocephalum heterophyllum is distributed in Shanxi, Inner MongolGu, Ningxia, Gansu, Northwest Sichuan, western part, Qinghai, Tibet and Xinjiang; Be born in many stones of upland meadow and half-desert drylyDistrict, is distributed in to the east of Qinghai And Gansu between height above sea level 1100-2800 rice, to the west of can reach 5000m, Xinjiang is at 2200-3100 riceBetween, aboundresources.
Dracocephalum heterophyllum herb contains the compositions such as volatile oil, flavones, polysaccharide, note class, lignanoid, is worth developing and utilizing.Wang Limei, by dracocephalum heterophyllum ground herb having been carried out to the chemical constitution study of system, is divided into from obtaining 21 compounds, andCarried out Study on Its Antioxidant Activity in Vitro to separating the compound obtaining, result shows, flavone compound and Phenylpropanoid Glycosides classCompound all has stronger antioxidation activity [Shandong University's Master's thesis 2011]. The application HPLC such as Luo Zhimin measure the different places of productionThe content of oleanolic acid and Usu methyl esters in dracocephalum heterophyllum, sets up and provides with reference to [" analyzing for the quality standard of dracocephalum heterophyllum medicinal materialLaboratory ", 2009,28 (zl) 8-10]. Yujiang County willows etc. adopt AAS, measure in dracocephalum heterophyllum taking rutin as standard itemsGeneral flavone content, determine the research of dracocephalum heterophyllum total flavone extracting process. Qin Bo etc. adopt capillary gas chromatography-mass spectrum connectionUsage is studied dracocephalum heterophyllum volatile chemical component, isolates more than 184 peak through capillary chromatography, has confirmed altogether itIn 154 kinds of compositions, the content of institute's authenticating compound account for full oil 83.52%[" research and development of natural products " 2000 12(1) the 4-11 phase]. Ren Aimei etc. analyze dracocephalum heterophyllum chemical composition and bacteriostatic activity research, from methanolic extractSeparation obtains 9 compounds, and wherein compound 4 has weak inhibitory action [" Chinese herbal medicine " 2011,42 to staphylococcus aureus(4)38-41]
Viral disease has caused serious harm to the mankind's life and health at present, develops new from natural drugAntiviral drugs become focus. Commonly use clinically polytype antiviral Western medicine except virus is had inhibitory action, orAll have CDCC many or less, long-term prescription also easily produces drug resistance, and Strain also can morph becomes new resistanceBacterial strain, this makes the clinical practice of existing antiviral Western medicine and the research and development of new antiviral Western medicine face huge challenge. And at meIn the long-term clinical practice of state's traditional Chinese medical science, Tibetan medicine, application Chinese traditional herbs and Tibetan medicine treatment viral disease have obtained remarkable effect,But lack relevant effectively chemical analysis and pharmacotoxicological effect, the research of antiviral activity and mechanism. Use modern pharmacologyTheory is removed research tradition ethnic drug, and screening separates active compound, specifies its pharmacodynamic action and mechanism, is current antiviral agentFocus and the difficult point of thing research.
Influenza virus, is called for short influenza virus, and first, second, the third three types, cause humans and animals influenza. Flu-A diseasePoison is repeatedly the popular the most frequent important pathogen body with causing influenza Global prevalence. In the last few years, H1N1, H7N9 influenza virusPopular wreaking havoc, cause serious harm, cause social fear. Influenza virus is spherical in shape or thread, spherical diameter 80-20nm,New separated strain is thread more than spherical, is to have coating, and strand divides the RNA virus of fragment. The surface texture of influenza virus coating furcellaFor hemagglutinin (HA) and neuraminidase (NA). Hemagglutinin (HA) column, is tripolymer, and it covers with identical spacing substantiallyViral all surfaces. It is viral protective antigens. Neuraminidase (NA) is the tetramer of four subunit's compositions, noBe evenly distributed in virus surface, polymerization in groups, discharges relevant with virus. The eruption and prevalence of influenza is mainly drifted about by viral antigen(antigenicdrift) and antigen conversion (antigenicshift) cause, antigenic drift (antigenicdrift) because ofThe point mutation of HA or NA causes, and variation amplitude is little, belongs to quantitative change, causes local medium and small popular. Antigen conversion (antigenicShift) because the significantly variation of HA or NA causes, belong to qualitative change, cause the appearance of new subtype, cause global outbreak of epidemic.In the last few years, the Influenza A H1N1 of eruption and prevalence, and up-to-date H7N9 influenza is all by the novel Flu-A disease after variationThe caused Acute respiratory infectious disease of poison.
Respiratory Syncytial Virus(RSV) (RSV) is the pathogen of the modal respiratory tract infection of infant in a world wide.At present, to the control of RSV still without effectively vaccine and medicine. RSV is tunicary sub-thread minus-stranded rna virus, and coating furcella is GAlbumen, rsv infection infant causes capillary bronchitis and bronchiole pneumonia, infects adult and causes the infection of the upper respiratory tract, by hand, dirtDye article and respiratory infectious, easily popular in the winter time, be the important pathogen body of hospital-acquired infection. RSV is at airway epithelial cellInternal breeding, necrosis of bronchus thing and mucus, fibrin are sticked together, and easily cause airway obstruction, can concurrent serious ramusculeTracheitis and pneumonia, premunition power is not strong, can not prevent from infecting again, does not have so far effective prevention vaccine.
In the long-term clinical practice of Tibetan medicine and pharmacology, apply traditional Tibetan medicine treatment viral disease and obtained remarkable effect, hideDoctor recognizes the Susceptible population of influenza between twenty and fifty, is one of hot communicate illness being caused by the heresy of red bar. Dracocephalum heterophyllum is heat-clearingRemoving toxic substances class medicine, is used for treating lymphnoditis, cough with lung heat, seasonal febrile diseases epidemic disease in traditional Tibetan medicine. Therefore, from traditional Tibetan medicine, developBetter preventing respiratory viruses medicine has important using value and market prospects.
The invention provides a kind of Herba Ajugae volatile oil can apply in preparation antiviral drugs, with existing antiviralSynthetic drug is compared, and its toxicity is low, safe and reliable, and drug action is strong, and dracocephalum heterophyllum abundant raw material, inexpensive, extraction process letterSingle, preparation cost is low, can make various formulations.
Summary of the invention
The preparation method who the invention provides a kind of Herba Ajugae volatile oil, the method comprises the following steps:
The first step, takes 200g dracocephalum heterophyllum herb, and chopping is long into about 1cm, adds 2000ml round-bottomed flask, adopts 95 DEG CWater vapour, distillation 1.5h, collects distillate.
Second step, divides and extracts distillate three times with 150ml absolute ether, merges organic 120ml of making an appointment.
The 3rd step, gets 7g anhydrous Na2SO4Dry organic phase adds in the organic phase of gained in step 2. ;
The 4th step, water-bath evaporating solvent ether at 38 DEG C, reclaims distillate ether, and collects yellow oily in flaskThing, obtains Herba Ajugae volatile oil 0.1804g; ;
The 5th step ,-20 DEG C of preservations, uses ultraviolet irradiation 30min sterilizing by the prepared Herba Ajugae volatile oil of the 4th step,Both.
A preparation method for Herba Ajugae volatile oil, prepared Herba Ajugae volatile oil can be used for preparing preventing respiratoryVirus drugs.
Beneficial effect:
Herba Ajugae volatile oil provided by the present invention can suppress viruses adsorption, and prevention virus infection, suppresses virusThe too many levels such as gene duplication, direct inactivation of viruses are brought into play obvious antivirus action, so Herba Ajugae volatile oil and extractCan in preparation antiviral drugs, apply. Herba Ajugae volatile oil provided by the invention and extract can be antiviral in preparationMedicine is to be prepared into pharmaceutical composition with single or compound mode. Especially exhale in preparation treatment with single or compound modeIn the pharmaceutical composition of suction road virus infections, apply. Due to soft capsule, hard shell capsules, dripping pill, tablet, dispersing tablet, granule, injectionThe preparation of the pharmaceutical dosage forms such as liquid, oral liquid, suppository is that researcher in this field is to understand, can realize easily different leafBlue or green blue volatile oil and extract combine with respective carrier and are prepared into various pharmaceutical dosage forms; Soft capsule or hard shell capsules or dripping pill,Or tablet or dispersing tablet or granule or parenteral solution or oral liquid or suppository.
The invention has the advantages that:
1, dracocephalum heterophyllum is pure Tibetan medicine, and toxicity is low, safe.
2, Herba Ajugae volatile oil and extract can suppress viruses adsorption, and prevention virus infection, suppresses viral geneCopy, directly the too many levels such as inactivation of viruses is brought into play obvious preventing respiratory viruses effect, Herba Ajugae volatile oil and extract canTo apply preparing in preventing respiratory viruses medicine. There is obvious resisiting influenza virus, the effect of anti-adenovirus.
3, can treat breathing problem, have good prospect in medicine.
4, abundant raw material, inexpensive, extraction process is simple, preparation cost is low, can be prepared into easily various formulations.
Detailed description of the invention
Below in conjunction with specific embodiment, further set forth the present invention.
The preparation of embodiment mono-Herba Ajugae volatile oil and extract
(1) preparation of Herba Ajugae volatile oil
Get appropriate dracocephalum heterophyllum herb (being broken into about 1cm long) and add 2000ml round-bottomed flask, water flowing steam, water steamedHeat up in a steamer 1.5h, collect distillate; Repeatedly extract on a small quantity distillate with absolute ether, collect organic phase; Add anhydrous Na2SO4Dry organicPhase; By organic phase air-distillation in the situation that zeolite exists, reclaim distillate ether, collect yellow oil in flask,To Herba Ajugae volatile oil; By volatile oil-20 DEG C of preservations, with front ultraviolet irradiation 30min sterilizing.
(2) preparation of dracocephalum heterophyllum fractionated extracts
Dracocephalum heterophyllum is soaked in alcohol 7 days, often stir and leach active ingredient during this time. Separate out supernatant, with rotationEvaporimeter refluxed evaporator recovered alcohol, obtains total medicinal extract. Total medicinal extract is dissolved with 500ml distilled water, with petroleum ether extraction, by stoneOil ether phase refluxed evaporator, collecting remaining liq is ligroin extraction; Residue water is extracted with ethyl acetate, by ethyl acetatePhase refluxed evaporator, collecting remaining liq is ethyl acetate extract; To remain water extracting n-butyl alcohol, by the n-butanol steaming that refluxes mutuallySend out, collecting remaining liq is n-butanol extract; Remaining aqueous-phase reflux evaporation, collects remaining liq and is water. Collect fourPlant extract room temperature standing and drying, 4 DEG C of preservations, with ultraviolet irradiation 30min sterilizing.
Embodiment bis-Herba Ajugae volatile oil Gc-mss
Herba Ajugae volatile oil is gas chromatography-mass spectrometry analysis (TraceDSQGC-MS combined instrument, U.S.'s thermoelectricity for compositionCompany). GC conditions is: chromatographic column DB-5ms; Column length: 30m; Thickness of liquid film: 0.25 μ m; Internal diameter: 0.25mm; Carrier gas:He; Flow velocity: 1.0mL/min; Column temperature: 40～250 DEG C of temperature programmings (10 DEG C/min), constant temperature 20min; Sample size 1 μ L. Mass spectrum barPart: shunt mode sample introduction, split ratio 30: 1; Injector temperature: 250 DEG C; Boost line temperature: 280 DEG C; Ion source temperature: 250DEG C; Ionization mode: EI; Electron energy: 70eV; Electron multiplication tube voltage: 1256kV; Acquisition mode: scanning; Quality of scanning modelEnclose: 40～600amu.
Volatile oil is analyzed with the coupling of gas-matter the retention time (sequentially) of various compositions, title, moleculeFormula, relatively percentage composition and degree of conformity are in table 1. Herba Ajugae volatile oil yield 0.083% (W/W). From Herba Ajugae volatile oilMiddle Preliminary Identification 40 compounds. Wherein there are 19 constituent contents to be greater than 1%, account for 87.53% of volatile oil total amount. ContentHigh have cineole (22.18%), 6,6-dimethyl-bis-ring [3.1.1] hept-2-ene"-2-methyl alcohol (11.28%), a cis terpeneProduct alcohol (11.11%), 4-(1-Methylethyl)-benzaldehyde (5.79%), [1S-(1,2,5)]-4,6,6-trimethyl-bis-ring[3.1.1] heptan-3-alkene-2-alcohol (4.91%), 4-(1-Methylethyl)-2-cyclic ethylene-1-ketone (4.74%), [1S-(1,3,5)]-6,6-dimethyl-2-methylene-bis-ring [3,1,1] heptane-3-alcohol (4.13%), (1,2,5)-2,6,6-methyl-bis-ring[3,1,1] heptane-3-ketone (4.03%). Herba Ajugae volatile oil is containing terpene 69.20%, and wherein terpene alcohol accounts for 34.45%, monoterpene28.76%, sequiterpene 5.99%.
Table 1 Herba Ajugae volatile oil chemical composition
Embodiment tri-Herba Ajugae volatile oils and extract antiviral effect in vitro
(1) Herba Ajugae volatile oil and the fractionated extracts toxicity to cell
1 virus and cell line
Adenovirus (adenovirus, ADV3), influenza A type virus H1N1, MDCK (MDCK), Hep-2 (people's laryngocarcinoma)Cell provides by Center for Disease Control of Gansu Province.
2 animals
Kunming mouse, male and female half and half, body weight 18-22g, Lanzhou University's medical animal experiment center
3 medicines
The preparation Herba Ajugae volatile oil fractionated extracts taking 1%DMSO as solvent, ACV powder-injection (the general raw system in WuhanMedicine Co., Ltd) as positive control
Cultured cell, becomes 5 dose concentration (4mg/ by volatile oil and the continuous doubling dilution of extract with cell maintenance mediumMl, 2mg/ml, 1mg/ml, 0.5mg/ml, 0.25mg/ml), join respectively (cell in 96 orifice plates that cell grown up to individual layerBe respectively Hep-2 cell or influenza infection mdck cell that adenovirus infection is used), every hole 0.1ml liquid, each dosage2 holes of concentration. Set up normal cell control group simultaneously. Be placed in 37 DEG C, 5%CO2In incubator, cultivate inverted microscope lower every dayObserve and record cytopathic effect (CPE). Cytopathy deciding degree standard: (-) represents that cell is without pathology, (+) expression～There is pathology in 25% cell, (++) represents that pathology appears in 25%～50% cell, and it is sick that (+++) represents that 50%～75% cell occursBecome, (++++) represent that pathology appears in 75%～100% cell. After Continuous Observation 48h, calculate medicine according to Reed-Muench methodMedian toxic concentration (CC50). (as shown in table 2)
Medicine to cytotoxic effect main manifestations is: cell refractivity increases, and wall thickening, diminishes at cell rounding, occursGlutinous sticky, fragmentation, it is large that space between cells becomes, and part cell attachment ability declines and comes off, and medicine is along with the increase of concentration, to cellToxicity strengthens gradually. Medicine respectively to Hep-2 cell and mdck cell cytotoxicity as table 1.
Table 2 Herba Ajugae volatile oil and the toxic action of extraction object to Hep-2 and mdck cell
From table 2 data, dracocephalum heterophyllum water extract is minimum to the cytotoxicity of Hep-2, is 1300.16 μ g/ml, acetic acidEthyl ester and n-butanol extract are the highest to the cytotoxicity of Hep-2, are 158.47 μ g/ml. Dracocephalum heterophyllum water extract is to MDCK'sCytotoxicity is minimum, is 1104 μ g/ml, and ethyl acetate extract is the highest to the cytotoxicity of MDCK, is 37.04 μ g/ml.
(2) Herba Ajugae volatile oil and fractionated extracts antagonism adenovirus activity
Adopt cytopathy political reform to evaluate anti-adenovirus activity, Hep-2 cell is inoculated to 96 orifice plates and make cell grow up to individual layer. WithAdenovirus (ADV3) is diluted to 100TCID by maintenance medium50/ 0.1ml is for subsequent use. Establish respectively different dense Experimental agents group, positive drugThing control group ACV, normal cell control group and virus control group, all establish three multiple holes. According to viral replicative cycle,While measuring Antiviral Effect activity, take different administering modes, experiment point 4 processed group are carried out: 1. breed inhibition method: Yu DanConfluent monolayer cells adds 100TCID in hole50The virus of/0.1ml, after 37 DEG C of absorption 2h, abandons supernatant, and every hole adds 0.2ml variable concentrationsPastille maintenance medium, 37 DEG C, 5%CO2Cultivate; 2. infect blocked method: the pastille nutrient solution with variable concentrations is incubated with cell in advanceEducate 2h, abandon liquid, then with 100TCID50The virus infected cell of/0.1ml, after 37 DEG C of absorption 2h, adds 0.2ml cell maintenance medium,Put 37 DEG C, 5%CO2Incubator is cultivated; 3. mixed in equal amounts method: 100TCID50The virus of/0.1ml, 0.1ml liquid mixed in equal amounts addsCell, puts 37 DEG C, 5%CO2Incubator is cultivated; 4. directly kill method: by the liquid of variable concentrations and 100TCID50The disease of/0.1mlPoison mixed in equal amounts is even, puts 37 DEG C, 5%CO2After incubator effect 2h, then get 0.2ml by its infection cell. After absorption 2h, abandonClearly, every hole adds 0.2ml maintenance medium, 37 DEG C, 5%CO2Cultivate. Continuous three days observation of cell lesion degrees, return by ProbitMethod is calculated the half effective concentration (EC of medicine50). Medicine therapeutic index (TI) is pressed TI=CC50/EC50Calculate.
Table 3 Herba Ajugae volatile oil and the active function of extraction object to adenovirus
From table 3 data, Herba Ajugae volatile oil and four kinds of extracts all have certain anti-adenovirus activity. Different leaf green grass or young cropsThe anti-adenovirus activity of blue volatile oil is the highest, and its TI value of mixed in equal amounts method is 7.77. Ethyl acetate extract infects blocked method, anti-glandVirus activity is minimum, and its TI value is 1.86.
(3) Herba Ajugae volatile oil and fractionated extracts are to anti-influenza virus activity
By the 100CCID of virus liquid50/ 0.1ml concentration,, adds at room temperature after pretreatment 10min with 15 μ gmL-1 pancreatinEnter to mdck cell and adsorb 2h, then use PBS washed cell individual layer 3 times for subsequent use. Within the scope of safe concentration, every kind of medicine dividesDo not choose 4 concentration gradients, be mixed with 1.2% agarose covering of the pastille of corresponding concentration, set up virus control group simultaneouslyClose normal cell control group. In medicine group to the pastille covering that adds variable concentrations in corresponding aperture, virus control group and normalIn cell control group, add the 1.2% agarose covering that does not conform to medicine. 35 DEG C, 5%CO2Cultivate. Every day, observation of cell form becameChange, after 72h, inject paraformaldehyde along bore edges, 4 DEG C are spent the night. Discard covering next day, violet staining 30min. Running water punchingAfter washing and drying, record plaque test number under each drug concentration. Calculate medicine to viral inhibiting rate by following formula: virus suppressesRate (%)=(virus group plaque number-medicine group plaque number)/virus group plaque number, then adopts the Probit Return Law to calculate medicineHalf toxic concentration (EC50)
The active function of table 4 Herba Ajugae volatile oil and extraction object resisiting influenza virus H1N1
From table 4 data, Herba Ajugae volatile oil and extract all have stronger anti-influenza A H 1 N 1 virus activity.The anti-H1N1 activity of dracocephalum heterophyllum ligroin extraction mixed in equal amounts method is the highest, and its TI value is 12.99. Ethyl acetate extract is anti-H1N1 activity is minimum, and infecting its TI value of blocked method is 1.43.
Resisiting influenza virus effect in the body of embodiment tetra-dracocephalum heterophyllum water extracts
(1) the acute toxicity LD of dracocephalum heterophyllum water extract to mouse50
According to Sun Shi synthesis, first carry out prerun experiment, calculate D0And D100. At D0And D100Dosage range in establish 5Dosage group, between group, dose ratio is 1: 0.8, random packet, every group of 10 mouse, male and female half and half. Observe after single administration in 15dAnimal dead situation, records the poisoning symptom of mouse and the death of animal and distributes, and calculates LD50. Dracocephalum heterophyllum water extract LD50For 15mg/kg.
(2) protective effect of dracocephalum heterophyllum water extract influenza virus infected death
Adopt influenza a virus infection method: except toxicity control group, all the other each experimental mice are all through etherization,The experiment virus liquid that splashes into a certain amount of LD50 of 40 μ l with sample injector intranasal, medicine is made into the suspension of a series of concentration, attacks in virusHit and start gastric infusion in latter 1 hour, Normal group and virus control group give respectively isometric(al) distilled water. Administration 12 days altogether,Every day 1 time. Observe animal morbidity and death toll, dead mouse anatomic observation mouse lung, to have or not pathology as influenza infectionCriterion. Result is calculated death prevention rate rate and extending life rate according to the observation. It is little that each dosage group all can alleviate infectionThe disease symptom of mouse. Dead protective rate is 30%～40%, and extending life rate is 61.56%～73.84%.
Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described. In addition should be understood thatAfter having read the content of the present invention's instruction, those skilled in the art can make various changes or modifications the present invention, theseThe equivalent form of value falls within the application's appended claims limited range equally.
Claims (1)
1. Herba Ajugae volatile oil, in an application of preparing aspect preventing respiratory viruses medicine, is characterized in that described different leafThe preparation method of blue or green blue volatile oil comprises the steps:
The first step, takes 200g dracocephalum heterophyllum herb, is chopped into 1cm long, adds 2000ml round-bottomed flask, adopts 95 DEG C of water to steamVapour, distillation 1.5h, collects distillate;
Second step, divides and extracts distillate three times with 150ml absolute ether, merges organic phase 120ml;
The 3rd step, gets 7g anhydrous Na2SO4Dry organic phase adds in the organic phase of gained in step 2;
The 4th step, water-bath evaporating solvent ether at 38 DEG C, reclaims distillate ether, and collects yellow oil in flask,To Herba Ajugae volatile oil 0.1804g;
The 5th step ,-20 DEG C of preservations, uses ultraviolet irradiation 30min sterilizing, both by the prepared Herba Ajugae volatile oil of the 4th step.
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