CN100534465C - A Chinese medicinal composition, preparation method and quality control method - Google Patents
A Chinese medicinal composition, preparation method and quality control method Download PDFInfo
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- CN100534465C CN100534465C CNB2006100790388A CN200610079038A CN100534465C CN 100534465 C CN100534465 C CN 100534465C CN B2006100790388 A CNB2006100790388 A CN B2006100790388A CN 200610079038 A CN200610079038 A CN 200610079038A CN 100534465 C CN100534465 C CN 100534465C
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Abstract
The invention discloses a Chinese medicinal composition, its preparing process and quality control method, wherein the composition is prepared from sweet wormwood, honeysuckle flower and cape jasmine through the steps of distillating, boiling, ethanol extracting, making dried powder and injection.
Description
Patent application of the present invention is for dividing an application, and the original bill application number is 200410000134.X, and the applying date is on January 6th, 2004, and denomination of invention is Chinese medicine composition and preparation method thereof and the method for quality control with refrigeration function.
Technical field
The present invention relates to a kind of Chinese medicine composition, particularly have the Chinese medicine composition of refrigeration function, relate to the preparation method and the method for quality control of said composition simultaneously.
Background technology
External wind heat syndrome is that function weakens outside human body is defended, and can not regulate in the strain, and pathogenic factor is from mouth and nose, fur invasion, and the evil lung of violating is defended, and defends table and gets along well and cause a disease.Be common in diseases such as upper respiratory tract infection, influenza, acute bronchitis, pneumonia, cardinal symptom has hyperpyrexia, micro evil wind, nasal obstruction, watery nasal discharge, a general pain, cough, thirsty, laryngopharynx swelling and pain, tongue tip side of red, floating and rapid pulse etc.According to statistics, because heating causes death, the whole world has at least more than 2,000,000 every year, and especially the hyperpyrexia that causes of upper respiratory tract infection and influenza is having a strong impact on the healthy of people, and the expense that is used for the treatment of every year is up to tens yuan; Therefore, controlling affection due to external wind and heat effectively, is the arduous and urgent task of medical worker.
The reason that causes hyperpyrexia has many, as viral infection, bacterial infection, mycoplasma infection, parasitic infection etc., and the hyperpyrexia that causes of virus or bacterial infection commonly wherein.Heating was a kind of defense reaction of body originally.It can accelerate metabolic processes, and antiviral growth and breeding impels leukocytosis, strengthens the function (cytophagous activity, antibody generation and liver detoxification ability etc.) of reticuloendothelial system, helps the recovery of disease.Pattern of fever all has important value to diagnosis, judgement therapeutic effect and the prognosis of disease.Heating also can make physical demands on the other hand, causes headache, insomnia even convulsions.Excessive heat (more than 41 ℃) or lasting heating also can cause permanent brain damage and cause death dying.Therefore, it is necessary heating more than the moderate suitably being used antipyretic.
Doctor trained in Western medicine mainly is to use antipyretic analgesic (as non-steroidal drugs such as carbasalate calcium, aspirin lysine, ibuprofen, acetaminophen, naproxens) and antiviral antibacterials (if any acyclovir, Buddha's warrior attendant gastral cavity amine, virazole, penicillin etc. to the treatment of heating.) though it brings down a fever soon, toxic and side effects is big, mainly shows as nauseatingly, and gastrointestinal reaction such as vomiting, diarrhoea, stomachache and to hematoblastic influence, is had a liking for symptoms such as saliva, insomnia, erythra at also accidental dizziness.And the traditional Chinese medical science has good effect, characteristics that toxic and side effects is little on this disease of treatment, and therefore, developing the antibiotic analgesic new Chinese medicine of new highly efficient anti-virus has wide prospect.
Summary of the invention
One object of the present invention is to disclose a kind of new Chinese medicine composition with refrigeration function; Another object of the present invention is a kind of new method with refrigeration function Chinese medicine composition of open preparation; The object of the invention also is to disclose a kind of method of quality control of new Chinese medicine composition.
The crude drug of pharmaceutical composition of the present invention is formed and proportioning following (by weight):
Herba Artemisiae Annuae 1000-1400 weight portion Flos Lonicerae 600-900 weight portion Fructus Gardeniae 500-700 weight portion
The crude drug optimum ratio of the invention described above pharmaceutical composition is:
Herba Artemisiae Annuae 1250 weight portion Flos Lonicerae 750 weight portion Fructus Gardeniaes, 600 weight portions or
Herba Artemisiae Annuae 1100 weight portion Flos Loniceraes 800 weight portion Fructus Gardeniaes 700 weight portions.
This pharmaceutical composition also can add excipient and make tablet, oral liquid, capsule, granule, ejection preparation.
This preparation of drug combination method: above three flavors, Flos Lonicerae, Herba Artemisiae Annuae add 13-18 times of water gaging and soaked 2-4 hour, and heating decocts distillation 1-3 time, and each 1-3 hour, collect volatile oil simultaneously, standby.Merge decoction liquor, being evaporated to relative density is 1.03-1.08, and high speed centrifugation is got supernatant, the classification ultrafiltration, and it is 1.08-1.15 that ultrafiltrate is evaporated to 40-60 ℃ of relative density, vacuum drying gets Flos Lonicerae, Herba Artemisiae Annuae dried cream powder.Fructus Gardeniae is ground into coarse powder, doubly measures the 60-85% alcohol heating reflux 1-3 time with 5-7, each 1-2 hour, merge medicinal liquid, filter, filtrate recycling ethanol also is concentrated into 1-2: 1-2, transfer pH4.0 with hydrochloric acid, 100 ℃ were heated 0.5-1.5 hour, cold preservation 10-14 hour, filter, it is 1.10-1.12 that filtrate is concentrated into 45-55 ℃ of relative density, vacuum drying gets the Fructus Gardeniae dried cream powder.Get Herba Artemisiae Annuae, Flos Lonicerae volatile oil through adjuvant behind the routine parcel, with above-mentioned dried cream powder mixing.At last directly or add pharmaceutically acceptable excipient and make clinical acceptable forms, as tablet, oral liquid, capsule, granule, ejection preparation through conventional operation.It is as solvent, disintegrating agent, correctives, antiseptic, coloring agent etc. that medicine of the present invention can add conventional drug excipient.
The preparation method of ejection preparation of the present invention: get Herba Artemisiae Annuae, Flos Lonicerae volatile oil, after adding 5-7 weight portion poloxamer 108 grinding mixings, add in 900 parts by volume (weight portion/parts by volume the is g/ml herein) water for injection, stirring makes clear and bright, add Flos Lonicerae in the above-mentioned technology, Herba Artemisiae Annuae dried cream powder again, the Fructus Gardeniae dried cream powder stirs and makes dissolving, and transferring pH value with sodium hydroxide solution is 7.5-8.0, adds injection water to 1000 parts by volume.Use G
4Sintered filter funnel filters, embedding, and 100 ℃ of flowing steam sterilizations promptly get injection, every 10ml; Can also make lyophilized injectable powder by freeze-drying in embedding, sterilization back; Or in water for injection, add Flos Lonicerae, Herba Artemisiae Annuae dried cream powder, during the Fructus Gardeniae dried cream powder, add the 0.2-5 caffolding agent doubly of total dried cream powder again, as glucose or mannitol or sodium chloride etc., dissolving, the accent pH value is 7.5-8.0, filters, sterilizes, packing, injectable powder is made in lyophilization.Or, make other injection types such as suspension type injection, infusion solution etc. by common process.
Pharmaceutical composition of the present invention can also adopt following method preparation:
Herba Artemisiae Annuae 1000-1400 weight portion Flos Lonicerae 600-900 weight portion Fructus Gardeniae 500-700 weight portion
The preparation of Flos Lonicerae, Herba Artemisiae Annuae dried cream powder: Flos Lonicerae extracting in water 1-3 time (80-100 ℃), each 1-2 hour, amount of water was 9-16 times, extracting solution is put in addition; After Herba Artemisiae Annuae adds 3-6 times of water gaging and runs through, extracted volatile oil in vapor distillation 5-8 hour, volatile oil is put in addition, extract Flos Lonicerae and Herba Artemisiae Annuae extracting solution, filter, being evaporated to relative density is 1.10 (60 ℃), adds ethanol and makes and contain the alcohol amount and be 70-80%, left standstill 20-36 hour, filter, it is 1.20 (60 ℃) that filtrate decompression is concentrated into relative density, and transferring pH value with hydrochloric acid is about 1.8-2.3, with equivalent ethyl acetate extraction 9-12 time, get extract, be evaporated to no ethyl acetate flavor, inclining concentrated solution, vacuum drying gets Flos Lonicerae, Herba Artemisiae Annuae dried cream powder;
The preparation of Fructus Gardeniae dried cream powder: Fructus Gardeniae is ground into coarse powder, doubly measures the 70-90% alcohol heating reflux 1-3 time with 5-8, each 1-2 hour, merge medicinal liquid, filter, filtrate recycling ethanol also is concentrated into 1: 1, transferring Ph with hydrochloric acid is 2.5-3.5, and 100 ℃ were heated 1-2 hour, added the hard paraffin of 1% medical material amount, stir evenly, cold preservation 10-14 hour, filter, the n-butanol extraction of filtrate usefulness equivalent 5-7 time, concentrating under reduced pressure is to no n-butyl alcohol flavor, and vacuum drying gets the Fructus Gardeniae dried cream powder.
Above-mentioned Flos Lonicerae, Herba Artemisiae Annuae dried cream powder, two kinds of intermediate of Fructus Gardeniae dried cream powder, can be directly or add pharmaceutically acceptable excipient or clinical acceptable forms is made in solubilizing agent through conventional operation, as capsule, tablet, oral liquid, granule, injection etc.
Described injection can further make with following method: get water for injection 800-1200 parts by volume and boil, drop into above-mentioned two intermediate that make, stir evenly, seethe with excitement after 3-7 minute, be cooled to room temperature, cold preservation 20-36 hour, filter, it is 2-3 that filtrate is transferred PH, adds 1% active carbon, boiled cold preservation 20-36 hour after-filtration, filtrate 8-14 minute, be heated to boiling, transferring PH in the heating process is 5.05, the 9-13 minute cool to room temperature that seethe with excitement, cold preservation 40-58 hour, filter, add 0.3-0.8 weight portion sodium sulfite, standardize solution 1000 parts by volume stir and get solution 50 parts by volume, be heated to 65 ℃ and add tween 80 3-5 parts by volume, stir evenly, add volatile oil, stir evenly, (molecular weight is 30,000 to filter ultrafiltration, 10,000), cross the microporous filter membrane of 0.22 μ m, packing, flowing steam sterilization 35-50min.
Described parts by volume/weight portion is corresponding with ml/g.
The method of quality control that this compositions is made medicament comprises discriminating and/or assay and/or inspection.
Discrimination method comprises a kind of and/or several in the following method:
A. get this compositions ejection preparation 5ml, add 1%H
2SO
4Aqueous solution adjust pH 3 adds water saturated n-butanol extraction 1-3 time, and each 10ml merges butanol solution, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Extracting honeysuckle control medicinal material 0.5g adds water 20ml backflow 0.5-1.5 hour in addition, filters, and filtrate adds n-butyl alcohol according to the preparation of need testing solution preparation method, medical material solution in contrast; Get the chlorogenic acid reference substance again, add methanol and make the solution that every 1ml contains 2mg, in contrast product solution; According to thin layer chromatography (" appendix VIB of Chinese pharmacopoeia nineteen ninety-five version) test, draw each 4 μ l of above-mentioned three kinds of solution, put respectively on same silica gel H plate, with 8-9: 0.5-1.5: 0.5 ethyl acetate-formic acid-water is developing solvent, launches, and takes out, dry, inspection is known under ultra-violet lamp; In the test sample chromatograph, respectively with Flos Lonicerae control medicinal material and the corresponding position of chlorogenic acid reference substance chromatograph on, show the speckle of same color;
B. get this compositions ejection preparation 5ml, add water saturated n-butyl alcohol collection and drive 1-3 time, each 10ml merges n-butyl alcohol liquid, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Other gets Fructus Gardeniae control medicinal material 1g, adds water 15-25ml and refluxes 1 hour, filters, and filtrate adds n-butyl alcohol according to the preparation of need testing solution preparation method, medical material solution in contrast; Get the gardenoside reference substance again, add methanol and make the solution that every 1ml contains 4mg, in contrast product solution; According to thin layer chromatography (" appendix vIB of Chinese pharmacopoeia nineteen ninety-five version) test, draw above-mentioned three kinds of solution each 51, put respectively on same high-efficient silica gel GF254 lamellae, with 6-8: 2-4: 1-3: 0.1-0.3 chloroform-acetonitrile-methanol-strong aqua ammonia is developing solvent, launch, take out, dry, inspection is known under ultra-violet lamp; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show identical color speckle; With the corresponding position of Fructus Gardeniae control medicinal material chromatograph on, show the speckle of same color;
C. get this compositions ejection preparation 5ml, add 1%H
2SO
4Aqueous solution adjust pH 3 adds water saturated n-butanol extraction 2 times, and each 10ml merges butanol solution, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Other gets Herba Artemisiae Annuae control medicinal material 2g, adds water 20ml, and supersound extraction 1h filters, and filtrate adds the preparation method preparation of n-butyl alcohol according to need testing solution, medical material solution in contrast; Test according to thin layer chromatography (appendix VIB of (Chinese Pharmacopoeia) nineteen ninety-five version), draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica gel G thin plate, with 7-9: 1-3: 1-3: 0.1-3 chloroform-acetonitrile-methanol-strong aqua ammonia is developing solvent, launch, take out, dry, inspection is known under ultra-violet lamp; In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color;
Assay comprises a kind of and/or several in the following method:
A. the Fructus Gardeniae salidroside content is measured, the photograph high performance liquid chromatography (" appendix VID of Chinese pharmacopoeia nineteen ninety-five version) measure; Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, and the 0.05mol/L sodium hydrogen phosphate is transferred pH6.0 with phosphoric acid, 80-90: 10-14 sodium hydrogen phosphate-acetonitrile is a mobile phase; Detect wavelength 237nm, theoretical tower; The plate number calculates by the gardenoside peak should be not less than 2500; The preparation of reference substance solution, precision take by weighing gardenoside reference substance 6mg, put in the 100ml measuring bottle, add the dissolving of 40-60% methanol aqueous solution and are diluted to scale, shake up, promptly; This compositions ejection preparation 1ml is measured in the preparation of need testing solution, precision, puts in the 100ml measuring bottle, adds the 40-60% methanol aqueous solution and is diluted to scale, shake up, precision is got 5ml again, puts in the 10ml measuring bottle, add the 40-60% methanol aqueous solution to scale, shake up, as need testing solution; Algoscopy, precision is measured reference substance solution and each 10 μ l of offerings solution respectively, injects chromatograph of liquid, measures, and calculates promptly;
B. determination of chlorogenic acid, measure according to high performance liquid chromatography (" appendix VID of Chinese pharmacopoeia nineteen ninety-five version), chromatographic condition and system suitability test, with octadecylsilane chemically bonded silica is filler, 1% 75-85: 15-25 aqueous acetic acid one methanol is mobile phase, the detection wavelength is 327nm, and theoretical cam curve is calculated by the chlorogenic acid honeybee should be not less than 3000; The preparation of reference substance solution, precision take by weighing chlorogenic acid reference substance 6mg, put in the 100ml measuring bottle, add 1%0.5-1.5: 0.5-1.5 aqueous acetic acid one dissolve with methanol also is diluted to scale, shakes up, promptly; This compositions ejection preparation 1mL is measured in the preparation of need testing solution, precision, puts in the 100ml measuring bottle, adds 1%0.5-1.5: 0.5-1.5 aqueous acetic acid one dissolve with methanol also is diluted to scale, shakes up, promptly; Algoscopy, precision is measured reference substance solution and each 10 μ l of need testing solution respectively, injects chromatograph of liquid, measures, and calculates, promptly.
Inspection comprises following method:
The n-butyl alcohol determination of residual amount: by " Chinese pharmacopoeia appendix gas chromatography of version in 2000 and alcohol determining method are measured; Chromatographic condition and system suitability test, chromatographic column: SUPELCO company: SLMPLICLTY-WAX capillary quartz column (30m * 530 μ m * 1.0 μ m) chromatographic condition: carrier gas: N
2, shunt mode sample introduction not, injector temperature: 200 ℃, constant voltage mode: the average linear speed of pressure 10Kpa is 14cm/sec; Column temperature: 80 ℃ kept 1.5 minutes, rose to 120 ℃ with 5 ℃/min again, rose to 200 ℃ with 20 ℃/min again, kept 10 minutes; Number of theoretical plate calculates by the ethanol peak should be not less than 1500;
Reference substance solution preparation: precision is measured n-butyl alcohol 0.1ml and is put in the 100ml measuring bottle, adds ethanol dilution to scale, shakes up, and precision is measured 0.1ml, puts in the 100ml measuring bottle, adds ethanol dilution to scale, shakes up, as n-butyl alcohol contrast liquid;
Standard curve is drawn, accurate n-butyl alcohol contrast liquid 1 μ l, 2 μ l, 3 μ l, 4 μ l, the inject gas chromatograph drawn, record chromatographic peak trap integrated value is an abscissa with reference substance concentration, is vertical coordinate with the trap score value, the drawing standard curve gets the n-butyl alcohol standard curve;
The need testing solution preparation: get 1 bottle of this combination injection, inclining injection, puts in the conical flask, shakes up, as need testing solution;
Algoscopy: the accurate need testing solution 1 μ l that draws, inject gas chromatograph, record test sample chromatographic peak trap integrated value, the substitution standard curve calculates content; This combination injection contains n-butyl alcohol must not cross 10/1000000ths.
The present composition is being controlled antiviral, good effect is being arranged on antibiotic, analgesic, and said composition toxicity is very little, and clinical practice is safe and reliable.
Present composition preparation (pyretic toxicity injection for curing) refrigeration function that tool is stronger, and can be by rising and the interior life of giving birth to pyrogen IL-1 of inhibition that suppresses cAMP in heating animal brain spinal fluid, the blood; Various respiratory road Strain is caused the cultured cell pathological changes obvious inhibitory action is all arranged; Growth to the various bacteria bacterial strain also has certain inhibitory action; In addition tool antiinflammatory, enhancing body's immunological function preferably improves premunition.High, middle dosage also can be had an analgesic effect.
Present composition preparation production technique advanced person, method of quality control can carry out effective and stable control to the quality of product.
Following experimental example is used to further specify the present invention.
The refrigeration function of experimental example 1 pyretic toxicity injection for curing
Experiment material: 1, analgin injection, 2ml/ props up, 0.25g/ml, Jiangxi Pharmaceutical Factory, lot number 9805032,2,4-f dinitrophenol,DNP, Beijing Chemical Plant, lot number 980,726 3, typhoid fever, paratyphoid fever first and second triple vaccinies, Lanzhou biological factory, 990327
Experimental technique: the refrigeration function that triple vaccine is caused fever in rabbits, adopt the healthy male rabbit of the about 2kg of body weight, survey normal anus temperature 3 times preceding 2 day every day in experiment, choosing body temperature is no more than 0.2 ℃ 50 of animals in the fluctuation of 38.5-39.3 ℃ and every day and uses for experiment, be divided into 5 groups at random, experimentize under 20 ℃ of environment of room temperature.Auricular vein injection triple vaccine 0.8ml/kg body weight causes the hyperpyrexia pathological model, surveys body temperature behind the 1h, with the person that raises more than 0.5 ℃ as laboratory animal.3 test group are used pyretic toxicity injection for curing 5.08g/kg, 2.4g/kg and 1.27g/kg respectively, positive controls is given analgin injection 0.20g/kS, and blank group is given normal saline, all intravenous administration, injection speed is＜0.2ml/min that injection back 1-5h surveys the anus temperature.Other gets 40 of qualified rabbit, experimental technique and animal grouping are the same, 3 test group are irritated stomach with the dosage of 5.08g/kg, 2.54g/kg and 1.27g/kg respectively with pyretic toxicity injection for curing dry powder respectively, and positive controls irritates stomach for analgin tablet 0.20g/kg, and blank group is given isopyknic normal saline.
Experimental result: L causes the refrigeration function of fever in rabbits to triple vaccine
Three dosage of pyretic toxicity injection for curing 1h after the iv administration begins that fever in rabbits due to the triple vaccine is had tangible refrigeration function, and with normal saline group ratio, animal heat decline statistical analysis has significant difference, and more rapid-action than gastric infusion, action effect is obvious.Analgin injection 0.20g/kg also has tangible antipyretic effect, shown in the table 1,2.
Table 1 pyretic toxicity injection for curing iV causes refrigeration function (n=10, the x ± s) of fever in rabbits to triple vaccine
Compare * p＜0.05 with the normal saline group
Table 2 pyretic toxicity injection for curing ig causes refrigeration function (n=10, the x ± s) of fever in rabbits to triple vaccine
Compare * p＜0.05 with the normal saline group
Conclusion: the peaceful large, medium and small dosage of vein heat injection poison all has refrigeration function in various degree, and peaceful oral more rapid-action than pyretic toxicity, effect is strong.The QINGKAILING group also has the better antipyretic effect.Rather big or middle dosage group of intravenous injection pyretic toxicity and QINGKAILING group there was no significant difference.The peaceful analgesic system of pyretic toxicity may with reduce brain ji spinal fluid in suck blood in cAMP content and the blood content of IL-1 relevant.
Experimental example 2 pyretic toxicity injection for curing preventing respiratory viruses effects
The effect of pyretic toxicity injection for curing treatment mice influenza toxicity pneumonia, with 60 of NIH mices, body weight 14-16 gram, divide 6 groups at random: virus control, normal control, positive control is pressed the high, medium and low dosage group of pyretic toxicity injection for curing.In infecting the first two day beginning intravenous administration, the 3rd day animal under the slight anesthesia of ether, every mice intranasal vaccination FM115xLD50 virus liquid, the pyretic toxicity injection for curing of intravenous injection every day variable concentrations, once a day, continuous five days; The blank group gives the equal-volume normal saline, and the positive controls virazole is administered once every day, each 0.07g/kg.Cutd open mice extremely on the 6th, getting lung after weighing weighs, calculate lung exponential quantity (the lung weight in every 100g body weight) and lung index suppression ratio ([the average lung index of the average lung index-experimental group of virus control group] the average lung index of ÷ virus control group * 100%) one by one, compare with matched group, organize a t check.See Table 3
Table 3 pyretic toxicity injection for curing is to the effect (n=10) of mice influenza virus property pneumonia
Annotate: P value system compares with the virus control group
The antibacterial action of experimental example 3 pyretic toxicity injection for curing
The preparation of Carnis Bovis seu Bubali cream soup body culture medium: take by weighing Carnis Bovis seu Bubali cream 0.3g, peptone 1.0g, sodium chloride 0.5g.Put into beaker, add a small amount of distilled water heat fused after, adding distil water is to 100ml again, 20g/dl hydrochlorinate sodium solution is regulated its pH value to 7.2-7.6 then, uses filter paper filtering.Package 103.4kPa (15 pounds) sterilization 20 minutes with conical flask.The preparation of pharmaceutical liquid culture medium: because experimental strain is more, be the formality that simplifies the operation, test with being sub-packed in small test tube behind the Boiling tube dilute liquid medicine more earlier.Get 10 Boiling tube number consecutivelies, put in vitro every pipe 10ml with pipette, extract Carnis Bovis seu Bubali cream soup body culture medium by the sterile working.Reuse pipette, extract pyretic toxicity injection for curing (2.6g/ml) 10ml puts into the 1st pipe, shake up repeatedly: then draw 10ml and put into the 2nd pipe from the 1st pipe, shake up repeatedly, the same 10mi that draws puts into the 3rd pipe ... medicinal liquid is diluted as 1: 2 successively, 1: 4,1: 8 ... 1: 1024, drug level was followed successively by 1.3000,0.6500,0.3250 ... 0.0010g/ml.Get aseptic small test tube numbering again, every kind of bacterial strain is with 11 test tubes, manages for 1-10 number and to put into successively by serial dilution medicinal liquid 1ml, and No. 11 test tubes are put into the Carnis Bovis seu Bubali cream soup body culture medium 1ml that does not contain medicine and managed in contrast.
The inoculation of bacterial strain and cultivation: each experimental strain is inoculated in the Carnis Bovis seu Bubali cream soup body culture medium in 37 ℃ of incubators cultivated 16-18 hour, be diluted to 10-3 concentration with Carnis Bovis seu Bubali cream soup body culture medium or normal saline.Every kind of bacterial strain suspension inoculates 11 test tubes (containing 1 of 10 of variable concentrations medication tube and control tube), every pipe 0.1ml.In 37 ℃ of incubators, cultivated 24 hours, take out the bacterial growth situation of observing.As the drug liquid tube clarification, represent no bacterial growth, then this pipe medicine has antibacterial action; As be muddy, the expression antibacterial grows, and this pipe Chinese medicine does not have antibiotic effect.With the lowest concentration of drug of integral asepsis growth as the MIC of medicine to this bacterial strain.Experimental result shows that the pyretic toxicity injection for curing all has stronger bacteriostasis to various bacteria, to its minimal inhibitory concentration difference of different bacterium, sees Table 4
The antibacterial action (test tube method) of table 4 pyretic toxicity injection for curing
Experimental example 4 pyretic toxicity injection for curing are to the influence of mice specific humoral immunity
Adopt the chicken red blood cell immunization, choose 50 of healthy NIH mices, male and female half and half are divided into 5 groups.Grouping and administering mode are the same.Vein is got blood under the chicken wing, with normal saline Washed Red Blood Cells 3 times, makes 5% chicken erythrocyte suspension, and every mouse peritoneal injection 0.2ml carries out immunity, immunity administration after 2 days, and successive administration 5d, 7d plucks eyeball and gets blood.Get 20111 immune serums in clean tube, add the 2ml normal saline, and add 5% chicken red blood cell 0.5ml, it is standby to put into refrigerator.Other gets 2 of Cavia porcelluss, gets serum and makes 10% NS complement solution, gets its 0.5ml and adds in the refrigerated chicken red blood cell one immune serum test tube, reacts 30min in 37 ℃ of water-baths, takes out and puts into the frozen water cessation reaction, and is centrifugal, gets supernatant and surveys the OD value in the 540nm place.Experimental result proves that high, medium and low three the dosage groups of pyretic toxicity injection for curing all can obviously improve the hemolysin level of mice, with the analysis of matched group comparative statistics significant difference are arranged.Illustrate and be subjected to test product that there is potentiation in the humoral immunity of organism system.The results are shown in Table 5.
Table 5 pyretic toxicity injection for curing is to the influence of specific humoral immunity function (n=10, x ± s)
* p＜0.05, * * p＜0.01 and the comparison of normal saline group.
The analgesic activity of experimental example 5 pyretic toxicity injection for curing
Get 50 of white mice, be divided into 5 groups at random, 10 every group: blank group, aspirin group, high, medium and low three the dosage groups of pyretic toxicity injection for curing.Each group is by the corresponding dosage intravenously administrable, and positive drug ig aspirin 0.2g/kg, 30 minutes lumbar injection 0.3% acetic acid after the administration, 0.2ml/ only observe each treated animal in 30 minutes and turn round the body number by what acetic acid brought out.Experiment shows, causes more persistent pain stimulation behind the mouse peritoneal injection acetic acid.Each group all has the pain reaction that reduces mice in various degree after the administration, and the analgesic activity of pyretic toxicity injection for curing high dose 10.15g/kg and aspirin group is remarkable, and animal is turned round the body number and obviously is less than matched group.
The analgesic activity of table 6 pyretic toxicity injection for curing (n=10, x ± s)
Compare with the normal saline group: * p＜0.05, * * p＜0.01
The following example all can be realized the effect of above-mentioned experimental example.
The specific embodiment
Embodiment 1:
Herba Artemisiae Annuae 1250g Flos Lonicerae 750g Fructus Gardeniae 600g
More than three flavors, Flos Lonicerae, Herba Artemisiae Annuae add 13-18 times of water gaging and soaked 3 hours, heating decocts distillation 2 times, each 2 hours, collect volatile oil simultaneously, standby.Merge decoction liquor, being evaporated to relative density is 1.03-1.08, and (it is 1.10-1.12 that ultrafiltrate is evaporated to 50 ℃ of relative densities to high speed centrifugation for 20000 commentaries on classics/min) get supernatant, classification ultrafiltration, and vacuum drying gets Flos Lonicerae, Herba Artemisiae Annuae dried cream powder.Fructus Gardeniae is ground into coarse powder, measures 80% alcohol heating reflux 1-3 time, each 1 hour with 6 times, merge medicinal liquid, filter, filtrate recycling ethanol also is concentrated into 1: 1, transfers pH4.0 with hydrochloric acid, 100 ℃ were heated 1 hour, cold preservation 12 hours filters, and it is 1.10-1.12 that filtrate is concentrated into 50 ℃ of relative densities, vacuum drying gets the Fructus Gardeniae dried cream powder.Get Herba Artemisiae Annuae and be, Flos Lonicerae volatile oil, add after 6g poloxamer 108 grinds mixings, add in the 900ml water for injection, stirring makes clear and bright, adds Flos Lonicerae, Herba Artemisiae Annuae dried cream powder again, stirs to make dissolving, transferring pH value with sodium hydroxide solution is 7.5-8.0, adds the injection water to 1000ml.Filter with the G4 sintered filter funnel, embedding in the 10ml ampoule, 100 ℃ of flowing steam sterilizations.Every 10ml, suitable crude drug 26 grams, intravenous drip, this product 10-20ml injection adds 5% must or 0.9% sodium chloride injection 250-500ml, and quiet, every day 1 time or follow the doctor's advice.
Embodiment 2:
Herba Artemisiae Annuae 1100g Flos Lonicerae 800g Fructus Gardeniae 700g
More than three flavors, Flos Lonicerae, Herba Artemisiae Annuae add 13-18 times of water gaging and soaked 3 hours, heating decocts distillation 2 times, each 2 hours, collect volatile oil simultaneously, standby.Merge decoction liquor, being evaporated to relative density is 1.03-1.08, and high speed centrifugation (20000 commentaries on classics/min) get supernatant, being evaporated to 50 ℃ of relative densities is 1.10-1.12, vacuum drying gets Flos Lonicerae, Herba Artemisiae Annuae dried cream powder.Fructus Gardeniae is ground into coarse powder, measures 80% alcohol heating reflux 1-3 time, each 1 hour with 6 times, merge medicinal liquid, filter, filtrate recycling ethanol also is concentrated into 1: 1, transfers pH4.0 with hydrochloric acid, 100 ℃ were heated 1 hour, cold preservation 12 hours filters, and it is 1.10-1.12 that filtrate is concentrated into 50 ℃ of relative densities, vacuum drying gets the Fructus Gardeniae dried cream powder.Get volatile oil and dried cream powder, add the edible vegetable oil that 0.5-1.5 doubly measures, grind, be pressed into 1000 of soft capsules through conventional technology, promptly get the soft capsule of compositions, every dress 0.55g is equivalent to crude drug 2.6g.Each 1-2 grain, 2-3 time/day.
Embodiment 3: this composite injection method of quality control:
Differentiate: a. gets this composite injection 5ml, is equivalent to crude drug 13g, adds 1%H
2SO
4Aqueous solution adjust pH 3 adds water saturated n-butanol extraction 2 times, and each 10ml merges butanol solution, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Extracting honeysuckle control medicinal material 0.5g adds water 20ml and refluxed 1 hour in addition, filters, and filtrate adds n-butyl alcohol according to the preparation of need testing solution preparation method, medical material solution in contrast; Get the chlorogenic acid reference substance again, add methanol and make the solution that every 1ml contains 2mg, in contrast product solution; According to thin layer chromatography (" appendix VIB of Chinese pharmacopoeia nineteen ninety-five version) test, draw each 4 μ l of above-mentioned three kinds of solution, put respectively on same silica gel H plate, with 8.5: 1: 0.5 ethyl acetate-formic acid-water was developing solvent, launched, and took out, dry, inspection is known under ultra-violet lamp 365nm; In the test sample chromatograph, respectively with Flos Lonicerae control medicinal material and the corresponding position of chlorogenic acid reference substance chromatograph on, show the speckle of same color;
B. get this composite injection 5ml, be equivalent to crude drug 13g, add water saturated n-butyl alcohol collection and drive 2 times, each 10ml merges n-butyl alcohol liquid, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Other gets Fructus Gardeniae control medicinal material 1g, adds water 20ml and refluxes 1 hour, filters, and filtrate adds n-butyl alcohol according to the preparation of need testing solution preparation method, medical material solution in contrast; Get the gardenoside reference substance again, add methanol and make the solution that every 1ml contains 4mg, in contrast product solution; According to thin layer chromatography (" appendix vIB of Chinese pharmacopoeia nineteen ninety-five version) test, draw each 5 μ l of above-mentioned three kinds of solution, put respectively on same high-efficient silica gel GF254 lamellae, with 7: 3: 2: 0.2 chloroform-acetonitrile-methanol-strong aqua ammonia was developing solvent, launch, take out, dry, inspection is known under ultra-violet lamp 254nm; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show identical color speckle; With the corresponding position of Fructus Gardeniae control medicinal material chromatograph on, show the speckle of same color;
C. get this composite injection 5ml, be equivalent to crude drug 13g, add 1%H
2SO
4Aqueous solution adjust pH 3 adds water saturated n-butanol extraction 2 times, and each 10ml merges butanol solution, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Other gets Herba Artemisiae Annuae control medicinal material 2g, adds water 20ml, and supersound extraction 1h filters, and filtrate adds the preparation method preparation of n-butyl alcohol according to need testing solution, medical material solution in contrast; According to thin layer chromatography (appendix VIB of (Chinese Pharmacopoeia) nineteen ninety-five version) test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica gel G thin plate, with 8: 2: 2: 0.2 chloroform-acetonitrile-methanol-strong aqua ammonia was developing solvent, launched, and took out, dry, inspection is known under ultra-violet lamp 365nm; In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color;
Assay: a. Fructus Gardeniae salidroside content is measured, the photograph high performance liquid chromatography (" appendix VID of Chinese pharmacopoeia nineteen ninety-five version) measure; Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, and the 0.05mol/L sodium hydrogen phosphate is transferred pH6.0 with phosphoric acid, and 88: 12 sodium hydrogen phosphate-acetonitriles are mobile phase; Detect wavelength 237nm, theoretical tower; The plate number calculates by the gardenoside peak should be not less than 2500; The preparation of reference substance solution, precision take by weighing gardenoside reference substance 6mg, put in the 100ml measuring bottle, add the dissolving of 50% methanol aqueous solution and are diluted to scale, shake up, promptly; This composite preparation solution 1ml is measured in the preparation of need testing solution, precision, is equivalent to crude drug 2.6g, puts in the 100ml measuring bottle, add 50% methanol aqueous solution and be diluted to scale, shake up, precision is got 5ml again, puts in the 10ml measuring bottle, add 50% methanol aqueous solution to scale, shake up, as need testing solution; Algoscopy, precision is measured reference substance solution and each 10 μ l of offerings solution respectively, injects chromatograph of liquid, measures, and calculates promptly.
This composite preparation solution 1ml is equivalent to crude drug 2.6g, contains Fructus Gardeniae with gardenoside (C
17H
24O
11) meter, should be 9.0mg-14g0mg;
B. determination of chlorogenic acid, measure according to high performance liquid chromatography (" appendix VID of Chinese pharmacopoeia nineteen ninety-five version), chromatographic condition and system suitability test, with octadecylsilane chemically bonded silica is filler, 1% 80: 20 aqueous acetic acids, one methanol is mobile phase, the detection wavelength is 327nm, and theoretical cam curve is calculated by the chlorogenic acid honeybee should be not less than 3000; The preparation of reference substance solution, precision take by weighing chlorogenic acid reference substance 6mg, put in the 100ml measuring bottle, add 1: 1 aqueous acetic acid-dissolve with methanol of 1% and are diluted to scale, shake up, promptly; This compositions ejection preparation 1mL is measured in the preparation of need testing solution, precision, puts in the 100ml measuring bottle, adds 1%1: 1 aqueous acetic acid-dissolve with methanol and is diluted to scale, shakes up, promptly; Algoscopy, precision is measured reference substance solution and each 10 μ l of need testing solution respectively, injects chromatograph of liquid, measures, and calculates, promptly.
This product formulation soln 1ml is equivalent to crude drug 2.6g, contains Flos Lonicerae with chlorogenic acid (C
16H
18O
4) meter, should be 6.4mg-9.6mg.
Check:
The n-butyl alcohol determination of residual amount: by " Chinese pharmacopoeia appendix gas chromatography of version in 2000 and alcohol determining method are measured; Chromatographic condition and system suitability test, chromatographic column: SUPELCO company: SLMPLICLTY-WAX capillary quartz column (30m * 530 μ m * 1.0 μ m) chromatographic condition: carrier gas: N
2, shunt mode sample introduction not, injector temperature: 200 ℃, constant voltage mode: the average linear speed of pressure 10Kpa is 14cm/sec; Column temperature: 80 ℃ kept 1.5 minutes, rose to 120 ℃ with 5 ℃/min again, rose to 200 ℃ with 20 ℃/min again, kept 10 minutes; Number of theoretical plate calculates by the ethanol peak should be not less than 1500;
Reference substance solution preparation: precision is measured n-butyl alcohol 0.1ml and is put in the 100ml measuring bottle, adds ethanol dilution to scale, shakes up, and precision is measured 0.1ml, puts in the 100ml measuring bottle, adds ethanol dilution to scale, shakes up, as n-butyl alcohol contrast liquid;
Standard curve is drawn, accurate n-butyl alcohol contrast liquid 1 μ l, 2 μ l, 3 μ l, 4 μ l, the inject gas chromatograph drawn, record chromatographic peak trap integrated value is an abscissa with reference substance concentration, is vertical coordinate with the trap score value, the drawing standard curve gets the n-butyl alcohol standard curve;
The need testing solution preparation: get 1 bottle of this combination injection, inclining injection, puts in the conical flask, shakes up, as need testing solution;
Algoscopy: the accurate need testing solution 1 μ l that draws, inject gas chromatograph, record test sample chromatographic peak trap integrated value, the substitution standard curve calculates content; This combination injection contains n-butyl alcohol must not cross 10/1000000ths.
Embodiment 4: the preparation of composition intermediates
Flos Lonicerae, the preparation of Herba Artemisiae Annuae dried cream powder: extracting honeysuckle 750g extracting in water secondary (90 ℃), (amount of water was 15 times in each one hour, 10 times), extracting solution is put in addition, after getting Herba Artemisiae Annuae 1250g and adding 4 times of water gagings and run through, vapor distillation extracted volatile oil in 6 hours, volatile oil is put in addition, extracts Flos Lonicerae and Herba Artemisiae Annuae extracting solution, filters, being evaporated to relative density is 1.10 (60 ℃), add ethanol and make that to contain the alcohol amount be 75%, left standstill 24 hours, filter, it is 1.20 (60 ℃) that filtrate decompression is concentrated into relative density, transferring pH value with hydrochloric acid is about 2.0, uses equivalent ethyl acetate extraction 10 times, gets extract, be evaporated to no ethyl acetate flavor, inclining concentrated solution, and vacuum drying gets Flos Lonicerae, the Herba Artemisiae Annuae dried cream powder.
The preparation of Fructus Gardeniae dried cream powder: Fructus Gardeniae 600g was ground into coarse powder, with 6 times of amount 80% alcohol heating reflux secondaries, each 1 hour, merge medicinal liquid, filter, filtrate recycling ethanol also is concentrated into 1: 1, transfer pH3.0 with hydrochloric acid, 100 ℃ were heated 1 hour, added the hard paraffin of 1% medical material amount, stir evenly, cold preservation 12 hours filters, the n-butanol extraction of filtrate usefulness equivalent 6 times, concentrating under reduced pressure is to no n-butyl alcohol flavor, and vacuum drying gets the Fructus Gardeniae dried cream powder.
Embodiment 5: the method for quality control of composition intermediates (described intermediate is prepared with embodiment 4 methods)
One, the quality standard of Herba Artemisiae Annuae, Flos Lonicerae intermediate:
This product 1g is got in [discriminating] (1), adds dissolve with methanol, filters, and is settled to 10ml, as need testing solution.Other gets the chlorogenic acid reference substance, adds methanol and makes the solution that every 1ml contains 2mg, in contrast product solution.According to thin layer chromatography (" an appendix VI of Chinese pharmacopoeia version in 2000 B) test, draw each 4 μ l of above-mentioned two kinds of solution, put respectively on same silica gel H plate, with ethyl acetate-formic acid-water (8.5: 1: 0.5) is developing solvent, launches, and takes out, dry, inspection is known under ultra-violet lamp 365nm.In the test sample chromatograph, with the corresponding position of chlorogenic acid reference substance chromatograph on, show the speckle of same color.
(2) get [discriminating] (1) following need testing solution as need testing solution.Other gets Herba Artemisiae Annuae control medicinal material 2g, adds water 20ml, and supersound extraction 1h filters, and filtrate adds the preparation method preparation of n-butyl alcohol according to need testing solution, medical material solution in contrast.According to thin layer chromatography (" an appendix VI of Chinese pharmacopoeia version in 2000 B) test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica gel G thin plate, with chloroform-acetonitrile-methanol-strong aqua ammonia (8: 2: 2: 0.2) be developing solvent, launch, take out, dry, inspection is known under ultra-violet lamp 365nm.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
[assay]
Determination of chlorogenic acid: the photograph high performance liquid chromatography (" an appendix VI of Chinese pharmacopoeia nineteen ninety-five version D) measure.
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, and 1% aqueous acetic acid-methanol (80: 20) is a mobile phase, and the detection wavelength is 327nm, and theoretical cam curve is calculated by the chlorogenic acid peak should be not less than 3000.
The preparation of reference substance solution: precision takes by weighing chlorogenic acid reference substance 6mg, puts in the 100ml measuring bottle, adds 1% aqueous acetic acid-methanol (1: 1) and dissolves and be diluted to scale, shakes up, promptly.
The preparation of need testing solution: precision is measured this product 0.1g, puts in the 100ml measuring bottle, adds dissolve with methanol and is diluted to scale, and the accurate 1ml that draws puts in the 5ml measuring bottle, adds 1% aqueous acetic acid-methanol (1: 1) and dissolves and be diluted to scale, shakes up, promptly.Algoscopy: precision is measured reference substance solution and each 10 μ l of need testing solution respectively, injects chromatograph of liquid, measures, and calculates, promptly.Herba Artemisiae Annuae, Flos Lonicerae intermediate contain chlorogenic acid (C
16H
18O
4), should be 12-25%.
Two, Fructus Gardeniae dried cream powder method of quality control
[discriminating] gets this product 1g, adds dissolve with methanol, filters, and is settled to 10ml, as need testing solution.Other gets the gardenoside reference substance, adds methanol and makes the solution that every 1ml contains 4mg, in contrast product solution.According to thin layer chromatography (" an appendix VI of Chinese pharmacopoeia version in 2000 B) test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same high-efficient silica gel GF
254On the lamellae, (7: 3: 2: 0.2) be developing solvent, launch that taking-up is dried, inspection was known under ultra-violet lamp 254nm with chloroform-acetonitrile-methanol-strong aqua ammonia.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show identical color speckle.
[assay]
The gardenoside assay: high performance liquid chromatography (" appendix VID of Chinese pharmacopoeia nineteen ninety-five version) measure.
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, and 0.05mol/L sodium hydrogen phosphate (transferring pH6.0 with phosphoric acid)-acetonitrile (88: 12) is a mobile phase; Detect wavelength 237nm.Theoretical cam curve is calculated by the gardenoside peak should be not less than 2500.
The preparation of reference substance solution: it is an amount of that precision takes by weighing the gardenoside reference substance, adds the solution dissolving of methanol-water (1: 1), is prepared into the solution that every 1ml contains 0.06mg approximately, shakes up, promptly.
The preparation of need testing solution: precision is measured this product 0.1g, puts in the 100ml measuring bottle, adds 50% methanol aqueous solution and is diluted to scale, shakes up, and precision is got 1ml again, puts in the 10ml measuring bottle, adds 50% methanol aqueous solution to scale, shakes up, as need testing solution.
Algoscopy: precision is measured reference substance solution and each 10 μ l of offerings solution respectively, injects chromatograph of liquid, measures, and calculates promptly.Contain gardenoside (C in the Fructus Gardeniae intermediate
17H
24O
11), should be 25-40%.
Embodiment 6:
Get the Herba Artemisiae Annuae of embodiment 4 preparations, Flos Lonicerae intermediate and Fructus Gardeniae intermediate add injection water 1000ml, boil, drop into above-mentioned two intermediate, stir evenly, seethe with excitement after 4 minutes, be cooled to room temperature, cold preservation 24 hours filters, it is 2-3 that filtrate is transferred PH, adds 1% active carbon, boils 10 minutes, 24 hours after-filtration of cold preservation, filtrate is heated to boiling, transferring PH in the heating process is 5.05, the about 10 minutes cool to room temperature that seethe with excitement, cold preservation 48 hours, filter, add the 0.5g sodium sulfite, standardize solution stirs and gets solution 50ml to 1000ml, be heated to 65 ℃ and add tween 80 4ml, stir evenly, add volatile oil, stir evenly, (molecular weight is 30,000 to filter ultrafiltration, 10,000), cross the microporous filter membrane of 0.22 μ m, packing, flowing steam sterilization 45min.
Claims (9)
1, a kind of pharmaceutical composition with analgesic, antiviral, antibacterial action is characterized in that the ejection preparation of this pharmaceutical composition is made by following method:
Herba Artemisiae Annuae 1000-1400 weight portion Flos Lonicerae 600-900 weight portion Fructus Gardeniae 500-700 weight portion
The preparation of Flos Lonicerae, Herba Artemisiae Annuae dried cream powder: Flos Lonicerae extracting in water 1-3 time, 80-100 ℃, each 1-2 hour, amount of water was 9-16 times, extracting solution is put in addition; After Herba Artemisiae Annuae adds 3-6 times of water gaging and runs through, extracted volatile oil in vapor distillation 5-8 hour, volatile oil is put in addition, extract Flos Lonicerae extractive solution and Herba Artemisiae Annuae extracting solution, filter, being evaporated to 60 ℃ of relative densities is 1.10, adds ethanol and makes and contain the alcohol amount and be 70-80%, left standstill 20-36 hour, filter, filtrate decompression concentrate 60 ℃ to relative density be 1.20, transferring pH value with hydrochloric acid is 1.8-2.3, with equivalent ethyl acetate extraction 9-12 time, get extract, be evaporated to no ethyl acetate flavor, inclining concentrated solution, vacuum drying gets Flos Lonicerae, Herba Artemisiae Annuae dried cream powder;
The preparation of Fructus Gardeniae dried cream powder: Fructus Gardeniae is ground into coarse powder, doubly measures the 70-90% alcohol heating reflux 1-3 time with 5-8, each 1-2 hour, merge medicinal liquid, filter, filtrate recycling ethanol also is concentrated into 1: 1, transferring Ph with hydrochloric acid is 2.5-3.5, and 100 ℃ were heated 1-2 hour, added the hard paraffin of 1% medical material amount, stir evenly, cold preservation 10-14 hour, filter, the n-butanol extraction of filtrate usefulness equivalent 5-7 time, concentrating under reduced pressure is to no n-butyl alcohol flavor, and vacuum drying gets the Fructus Gardeniae dried cream powder;
Get water for injection 800-1200 parts by volume and boil, drop into and make two intermediate, stir evenly, seethe with excitement after 3-7 minute, be cooled to room temperature, cold preservation 20-36 hour, filter, it is 2-3 that filtrate is transferred PH, adds 1% active carbon, boiled cold preservation 20-36 hour after-filtration, filtrate 8-14 minute, be heated to boiling, transferring PH in the heating process is 5.05, and 9-13 minute cool to room temperature seethes with excitement, cold preservation 40-58 hour, filter, add 0.3-0.8 weight portion sodium sulfite, standardize solution 1000 parts by volume, solution 50 parts by volume are got in stirring, be heated to 65 ℃ and add tween 80 3-5 parts by volume, stir evenly, add volatile oil, stir evenly, filter ultrafiltration, molecular weight is 30,000,10,000, the microporous filter membrane of mistake 0.22 μ m, packing, flowing steam sterilization 35-50min.
2, pharmaceutical composition as claimed in claim 1 is characterized in that the ejection preparation of this pharmaceutical composition is made by following method:
Extracting honeysuckle 750g, extracting in water secondary, 90 ℃, each one hour, amount of water was 15 times, 10 times, extracting solution is put in addition, after getting Herba Artemisiae Annuae 1250g and adding 4 times of water gagings and run through, vapor distillation extracted volatile oil in 6 hours, and volatile oil is put in addition, extract Flos Lonicerae extractive solution and Herba Artemisiae Annuae extracting solution, filter, being evaporated to 60 ℃ of relative densities is 1.10, adds ethanol and makes that to contain the alcohol amount be 75%, left standstill 24 hours, filter, it is 60 ℃ 1.20 that filtrate decompression is concentrated into relative density, and transferring pH value with hydrochloric acid is 2.0, with equivalent ethyl acetate extraction 10 times, get extract, be evaporated to no ethyl acetate flavor, inclining concentrated solution, vacuum drying gets Flos Lonicerae, the Herba Artemisiae Annuae dried cream powder;
Fructus Gardeniae 600g was ground into coarse powder, with 6 times of amount 80% alcohol heating reflux secondaries, each 1 hour, merge medicinal liquid, filter, filtrate recycling ethanol also is concentrated into 1: 1, transfer pH3.0 with hydrochloric acid, 100 ℃ were heated 1 hour, added the hard paraffin of 1% medical material amount, stir evenly, cold preservation 12 hours filters, the n-butanol extraction of filtrate usefulness equivalent 6 times, concentrating under reduced pressure is to no n-butyl alcohol flavor, and vacuum drying gets the Fructus Gardeniae dried cream powder;
Get the Herba Artemisiae Annuae of preparation, Flos Lonicerae intermediate and Fructus Gardeniae intermediate are standby, add injection water 1000ml, boil, drop into above-mentioned two kinds of intermediate, stir evenly, seethe with excitement after 4 minutes, be cooled to room temperature, cold preservation 24 hours filters, it is 2-3 that filtrate is transferred PH, adds 1% active carbon, boils 10 minutes, 24 hours after-filtration of cold preservation, filtrate is heated to boiling, transferring PH in the heating process is 5.05, the about 10 minutes cool to room temperature that seethe with excitement, cold preservation 48 hours, filter, add the 0.5g sodium sulfite, standardize solution is to 1000ml, solution 50ml is got in stirring, be heated to 65 ℃ and add tween 80 4ml, stir evenly, add volatile oil, stir evenly, filter ultrafiltration, molecular weight is 30,000,10,000, the microporous filter membrane of mistake 0.22 μ m, packing, flowing steam sterilization 45min.
3, a kind of preparation method of ejection preparation of the pharmaceutical composition with analgesic, antiviral, antibacterial action is characterized in that this method is:
Herba Artemisiae Annuae 1000-1400 weight portion Flos Lonicerae 600-900 weight portion Fructus Gardeniae 500-700 weight portion
The preparation of Flos Lonicerae, Herba Artemisiae Annuae dried cream powder: Flos Lonicerae extracting in water 1-3 time, 80-100 ℃, each 1-2 hour, amount of water was 9-16 times, extracting solution is put in addition; After Herba Artemisiae Annuae adds 3-6 times of water gaging and runs through, extracted volatile oil in vapor distillation 5-8 hour, volatile oil is put in addition, extract Flos Lonicerae extractive solution and Herba Artemisiae Annuae extracting solution, filter, being evaporated to 60 ℃ of relative densities is 1.10, adds ethanol and makes and contain the alcohol amount and be 70-80%, left standstill 20-36 hour, filter, it is 1.20 that filtrate decompression is concentrated into 60 ℃ of relative densities, and transferring pH value with hydrochloric acid is 1.8-2.3, with equivalent ethyl acetate extraction 9-12 time, get extract, be evaporated to no ethyl acetate flavor, inclining concentrated solution, vacuum drying gets Flos Lonicerae, Herba Artemisiae Annuae dried cream powder;
The preparation of Fructus Gardeniae dried cream powder: Fructus Gardeniae is ground into coarse powder, doubly measures the 70-90% alcohol heating reflux 1-3 time with 5-8, each 1-2 hour, merge medicinal liquid, filter, filtrate recycling ethanol also is concentrated into 1: 1, transferring Ph with hydrochloric acid is 2.5-3.5, and 100 ℃ were heated 1-2 hour, added the hard paraffin of 1% medical material amount, stir evenly, cold preservation 10-14 hour, filter, the n-butanol extraction of filtrate usefulness equivalent 5-7 time, concentrating under reduced pressure is to no n-butyl alcohol flavor, and vacuum drying gets the Fructus Gardeniae dried cream powder;
Get water for injection 800-1200 parts by volume and boil, drop into and make two intermediate, stir evenly, seethe with excitement after 3-7 minute, be cooled to room temperature, cold preservation 20-36 hour, filter, it is 2-3 that filtrate is transferred PH, adds 1% active carbon, boiled cold preservation 20-36 hour after-filtration, filtrate 8-14 minute, be heated to boiling, transferring PH in the heating process is 5.05, and 9-13 minute cool to room temperature seethes with excitement, cold preservation 40-58 hour, filter, add 0.3-0.8 weight portion sodium sulfite, standardize solution 1000 parts by volume, solution 50 parts by volume are got in stirring, be heated to 65 ℃ and add tween 80 3-5 parts by volume, stir evenly, add volatile oil, stir evenly, filter ultrafiltration, molecular weight is 30,000,10,000, the microporous filter membrane of mistake 0.22 μ m, packing, flowing steam sterilization 35-50min.
4, the preparation method of the ejection preparation of pharmaceutical composition as claimed in claim 3 is characterized in that this method is:
Extracting honeysuckle 750g, extracting in water secondary, 90 ℃, each one hour, amount of water was 15 times, 10 times, extracting solution is put in addition, after getting Herba Artemisiae Annuae 1250g and adding 4 times of water gagings and run through, vapor distillation extracted volatile oil in 6 hours, and volatile oil is put in addition, extract Flos Lonicerae extractive solution and Herba Artemisiae Annuae extracting solution, filter, being evaporated to 60 ℃ of relative densities is 1.10, adds ethanol and makes that to contain the alcohol amount be 75%, left standstill 24 hours, filter, it is 60 ℃ 1.20 that filtrate decompression is concentrated into relative density, and transferring pH value with hydrochloric acid is 2.0, with equivalent ethyl acetate extraction 10 times, get extract, be evaporated to no ethyl acetate flavor, inclining concentrated solution, vacuum drying gets Flos Lonicerae, the Herba Artemisiae Annuae dried cream powder;
Fructus Gardeniae 600g was ground into coarse powder, with 6 times of amount 80% alcohol heating reflux secondaries, each 1 hour, merge medicinal liquid, filter, filtrate recycling ethanol also is concentrated into 1: 1, transfer pH3.0 with hydrochloric acid, 100 ℃ were heated 1 hour, added the hard paraffin of 1% medical material amount, stir evenly, cold preservation 12 hours filters, the n-butanol extraction of filtrate usefulness equivalent 6 times, concentrating under reduced pressure is to no n-butyl alcohol flavor, and vacuum drying gets the Fructus Gardeniae dried cream powder;
Get the Herba Artemisiae Annuae of preparation, Flos Lonicerae intermediate and Fructus Gardeniae intermediate are standby, add injection water 1000ml, boil, drop into above-mentioned two kinds of intermediate, stir evenly, seethe with excitement after 4 minutes, be cooled to room temperature, cold preservation 24 hours filters, it is 2-3 that filtrate is transferred PH, adds 1% active carbon, boils 10 minutes, 24 hours after-filtration of cold preservation, filtrate is heated to boiling, transferring PH in the heating process is 5.05, the about 10 minutes cool to room temperature that seethe with excitement, cold preservation 48 hours, filter, add the 0.5g sodium sulfite, standardize solution is to 1000ml, solution 50ml is got in stirring, be heated to 65 ℃ and add tween 80 4ml, stir evenly, add volatile oil, stir evenly, filter ultrafiltration, molecular weight is 30,000,10,000, the microporous filter membrane of mistake 0.22 μ m, packing, flowing steam sterilization 45min.
5, pharmaceutical composition as claimed in claim 1 or 2 is characterized in that the intermediate that makes carries out assay with high performance liquid chromatography, and Herba Artemisiae Annuae, Flos Lonicerae intermediate contain chlorogenic acid, should be 12～25%; Contain gardenoside in the Fructus Gardeniae intermediate, should be 25～40%.
6, the detection method of the ejection preparation of pharmaceutical composition as claimed in claim 1 or 2 is characterized in that discriminating in this method comprises one or more in the following method:
A. get this composite preparation solution 5ml, be equivalent to crude drug 13g, add 1%H
2SO
4Aqueous solution adjust pH 3 adds water saturated n-butanol extraction 1-3 time, and each 10ml merges butanol solution, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Extracting honeysuckle control medicinal material 0.5g adds water 20ml backflow 0.5-1.5 hour in addition, filters, and filtrate adds n-butyl alcohol according to the preparation of need testing solution preparation method, medical material solution in contrast; Get the chlorogenic acid reference substance again, add methanol and make the solution that every 1ml contains 2mg, in contrast product solution; According to thin layer chromatography test, draw each 4 μ l of above-mentioned three kinds of solution, put respectively on same silica gel H plate, with 8-9: 0.5-1.5: 0.5 ethyl acetate-formic acid-water is developing solvent, launches, and takes out, and dries, and inspection is known under ultra-violet lamp; In the test sample chromatograph, respectively with Flos Lonicerae control medicinal material and the corresponding position of chlorogenic acid reference substance chromatograph on, show the speckle of same color;
B. get this composite preparation solution 5ml, be equivalent to crude drug 13g, add water saturated n-butanol extraction 1-3 time, each 10ml merges n-butyl alcohol liquid, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Other gets Fructus Gardeniae control medicinal material 1g, adds water 15-25ml and refluxes 1 hour, filters, and filtrate adds n-butyl alcohol according to the preparation of need testing solution preparation method, medical material solution in contrast; Get the gardenoside reference substance again, add methanol and make the solution that every 1ml contains 4mg, in contrast product solution; According to the thin layer chromatography test, draw each 5 μ l of above-mentioned three kinds of solution, put respectively on same high-efficient silica gel GF254 lamellae, with 6-8: 2-4: 1-3: 0.1-0.3 chloroform-acetonitrile-methanol-strong aqua ammonia is developing solvent, launches, and takes out, dry, inspection is known under ultra-violet lamp; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show identical color speckle; With the corresponding position of Fructus Gardeniae control medicinal material chromatograph on, show the speckle of same color;
C. get this composite preparation solution 5ml, be equivalent to crude drug 13g, add 1%H
2SO
4Aqueous solution adjust pH 3 adds water saturated n-butanol extraction 2 times, and each 10ml merges butanol solution, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Other gets Herba Artemisiae Annuae control medicinal material 2g, adds water 20ml, and supersound extraction 1h filters, and filtrate adds the preparation method preparation of n-butyl alcohol according to need testing solution, medical material solution in contrast; According to thin layer chromatography test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica gel G thin plate, with 7-9: 1-3: 1-3: 0.1-3 chloroform-acetonitrile-methanol-strong aqua ammonia is developing solvent, launches, and takes out, and dries, and inspection is known under ultra-violet lamp; In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
7, the detection method of pharmaceutical composition ejection preparation as claimed in claim 6 is characterized in that discriminating in this method comprises one or more in the following method:
A. get this composite preparation solution 5ml, be equivalent to crude drug 13g, add 1%H
2SO
4Aqueous solution adjust pH 3 adds water saturated n-butanol extraction 2 times, and each 10ml merges butanol solution, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Extracting honeysuckle control medicinal material 0.5g adds water 20ml and refluxed 1 hour in addition, filters, and filtrate adds n-butyl alcohol according to the preparation of need testing solution preparation method, medical material solution in contrast; Get the chlorogenic acid reference substance again, add methanol and make the solution that every 1ml contains 2mg, in contrast product solution; According to the thin layer chromatography test, draw each 4 μ l of above-mentioned three kinds of solution, put respectively on same silica gel H plate, be developing solvent with 8.5: 1: 0.5 ethyl acetate-formic acid-water, launch, take out, dry, inspection is known under ultra-violet lamp 365nm; In the test sample chromatograph, respectively with Flos Lonicerae control medicinal material and the corresponding position of chlorogenic acid reference substance chromatograph on, show the speckle of same color;
B. get this composite preparation solution 5ml, be equivalent to crude drug 13g, add water saturated n-butanol extraction 2 times, each 10ml merges n-butyl alcohol liquid, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Other gets Fructus Gardeniae control medicinal material 1g, adds water 20ml and refluxes 1 hour, filters, and filtrate adds n-butyl alcohol according to the preparation of need testing solution preparation method, medical material solution in contrast; Get the gardenoside reference substance again, add methanol and make the solution that every 1ml contains 4mg, in contrast product solution; According to the thin layer chromatography test, draw each 5 μ l of above-mentioned three kinds of solution, put respectively on same high-efficient silica gel GF254 lamellae, with 7: 3: 2: 0.2 chloroform-acetonitrile-methanol-strong aqua ammonia is developing solvent, launches, and takes out, and dries, inspection is known under ultra-violet lamp 254nm; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show identical color speckle; With the corresponding position of Fructus Gardeniae control medicinal material chromatograph on, show the speckle of same color;
C. get this composite preparation solution 5ml, be equivalent to crude drug 13g, add 1%H
2SO
4Aqueous solution adjust pH 3 adds water saturated n-butanol extraction 2 times, and each 10ml merges butanol solution, and water-bath volatilizes, and residue adds methanol 5ml dissolving, as need testing solution; Other gets Herba Artemisiae Annuae control medicinal material 2g, adds water 20ml, and supersound extraction 1h filters, and filtrate adds the preparation method preparation of n-butyl alcohol according to need testing solution, medical material solution in contrast; According to the thin layer chromatography test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica gel G thin plate, with 8: 2: 2: 0.2 chloroform-acetonitrile-methanol-strong aqua ammonia is developing solvent, launches, and takes out, and dries, inspection is known under ultra-violet lamp 365nm; In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
8, as the detection method of pharmaceutical composition ejection preparation as described in claim 6 or 7, it is characterized in that this method also comprises one or both in the following assay:
A. the Fructus Gardeniae salidroside content is measured, according to high effective liquid chromatography for measuring; Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, and the 0.05mol/L sodium hydrogen phosphate is transferred pH6.0 with phosphoric acid, 80-90: 10-14 sodium hydrogen phosphate-acetonitrile is a mobile phase; Detect wavelength 237nm, theoretical tower; The plate number calculates by the gardenoside peak should be not less than 2500; The preparation of reference substance solution, precision take by weighing gardenoside reference substance 6mg, put in the 100ml measuring bottle, add the dissolving of 40-60% methanol aqueous solution and are diluted to scale, shake up, promptly; The preparation of need testing solution, precision is measured this composite preparation solution 1ml, be equivalent to crude drug 2.6g, put in the 100ml measuring bottle, add the 40-60% methanol aqueous solution and be diluted to scale, shake up, precision is got 5ml again, puts in the 10ml measuring bottle, adds the 40-60% methanol aqueous solution to scale, shake up, as need testing solution; Algoscopy, precision is measured reference substance solution and each 10 μ l of offerings solution respectively, injects chromatograph of liquid, measures, and calculates promptly;
B. determination of chlorogenic acid, according to high effective liquid chromatography for measuring, chromatographic condition and system suitability test, with octadecylsilane chemically bonded silica is filler, 1% 75-85: 15-25 aqueous acetic acid one methanol is mobile phase, the detection wavelength is 327nm, and theoretical cam curve is calculated by the chlorogenic acid honeybee should be not less than 3000; The preparation of reference substance solution, precision take by weighing chlorogenic acid reference substance 6mg, put in the 100ml measuring bottle, add 1%0.5-1.5: 0.5-1.5 aqueous acetic acid one dissolve with methanol also is diluted to scale, shakes up, promptly; This composite preparation oral liquid 1mL is measured in the preparation of need testing solution, precision, puts in the 100ml measuring bottle, adds 1%0.5-1.5: 0.5-1.5 aqueous acetic acid one dissolve with methanol also is diluted to scale, shakes up, promptly; Algoscopy, precision is measured reference substance solution and each 10 μ l of need testing solution respectively, injects chromatograph of liquid, measures, and calculates, promptly.
9,, it is characterized in that this method also comprises one or both in the following assay as the detection method of claim 6 or 7 described pharmaceutical composition ejection preparations:
A. the Fructus Gardeniae salidroside content is measured, according to high effective liquid chromatography for measuring; Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, and the 0.05mol/L sodium hydrogen phosphate is transferred pH6.0 with phosphoric acid, and 88: 12 sodium hydrogen phosphate-acetonitriles are mobile phase; Detect wavelength 237nm, theoretical tower; The plate number calculates by the gardenoside peak should be not less than 2500; The preparation of reference substance solution, precision take by weighing gardenoside reference substance 6mg, put in the 100ml measuring bottle, add the dissolving of 50% methanol aqueous solution and are diluted to scale, shake up, promptly; This composite preparation solution 1ml is measured in the preparation of need testing solution, precision, is equivalent to crude drug 2.6g, puts in the 100ml measuring bottle, add 50% methanol aqueous solution and be diluted to scale, shake up, precision is got 5ml again, puts in the 10ml measuring bottle, add 50% methanol aqueous solution to scale, shake up, as need testing solution; Algoscopy, precision is measured reference substance solution and each 10 μ l of offerings solution respectively, injects chromatograph of liquid, measures, and calculates promptly;
B. determination of chlorogenic acid, according to high effective liquid chromatography for measuring, chromatographic condition and system suitability test, with octadecylsilane chemically bonded silica is filler, 80: 20 aqueous acetic acid-methanol of 1% are mobile phase, the detection wavelength is 327nm, and theoretical cam curve is calculated by the chlorogenic acid honeybee should be not less than 3000; The preparation of reference substance solution, precision take by weighing chlorogenic acid reference substance 6mg, put in the 100ml measuring bottle, add 1%1: 1 aqueous acetic acid-dissolve with methanol and are diluted to scale, shake up, promptly; This composite preparation solution 1mL is measured in the preparation of need testing solution, precision, is equivalent to crude drug 2.6g, puts in the 100ml measuring bottle, adds 1%1: 1 aqueous acetic acid one dissolve with methanol and is diluted to scale, shakes up, promptly; Algoscopy, precision is measured reference substance solution and each 10 μ l of need testing solution respectively, injects chromatograph of liquid, measures, and calculates, promptly.
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| CN101721515B (en) * | 2008-10-28 | 2012-10-03 | 江苏康缘药业股份有限公司 | Application of traditional Chinese medicine composition in preparing medicine for treating hand, mouth and foot diseases |
| CN101773238B (en) * | 2010-02-02 | 2012-11-07 | 华南农业大学 | Application of artemisia apiacea extract |
| CN102233021B (en) * | 2010-04-30 | 2013-05-01 | 江苏康缘药业股份有限公司 | Content measurement method for Chinese patent medicine prepared from sweet wormwood, honeysuckle and gardenia jasminoides fruit |
| CN103076403B (en) * | 2012-10-07 | 2014-10-22 | 贵州远程制药有限责任公司 | Inspection method for capsule for treating lower urinary tract infection |
| CN106266078B (en) * | 2016-08-30 | 2019-08-16 | 江苏康缘药业股份有限公司 | A kind of control method and device of cape jasmine heat treatment process |
| CN109832397A (en) * | 2017-11-28 | 2019-06-04 | 苏州唐基生物科技有限公司 | Sweet wormwood pressed candy and preparation method thereof |
| CN107951941B (en) * | 2017-11-29 | 2019-12-24 | 江苏康缘药业股份有限公司 | Method for controlling refrigeration process of gardenia extract |
| CN114053343B (en) * | 2020-07-30 | 2023-06-09 | 江苏康缘药业股份有限公司 | Traditional Chinese medicine composition, preparation method and application |
| CN111973671B (en) * | 2020-09-07 | 2021-12-31 | 临沂大学 | Inhalation powder inhalation of "Reduning" and preparation method thereof |
| CN114533813A (en) * | 2022-02-16 | 2022-05-27 | 岳阳市中医医院 | Antibacterial and antiviral traditional Chinese medicine composition and preparation method thereof |
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