CN101843884B - Method for testing quality of antiviral oral liquid for treating hand-foot-and-mouth disease - Google Patents
Method for testing quality of antiviral oral liquid for treating hand-foot-and-mouth disease Download PDFInfo
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- CN101843884B CN101843884B CN2010101830088A CN201010183008A CN101843884B CN 101843884 B CN101843884 B CN 101843884B CN 2010101830088 A CN2010101830088 A CN 2010101830088A CN 201010183008 A CN201010183008 A CN 201010183008A CN 101843884 B CN101843884 B CN 101843884B
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000012360 testing method Methods 0.000 title claims abstract description 24
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- KFFCKOBAHMGTMW-LGQRSHAYSA-N Forsythin Chemical compound C1=C(OC)C(OC)=CC=C1[C@H]1[C@@H](CO[C@@H]2C=3C=C(OC)C(O[C@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)=CC=3)[C@@H]2CO1 KFFCKOBAHMGTMW-LGQRSHAYSA-N 0.000 claims abstract description 28
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Abstract
The invention discloses a method for testing the quality of antiviral oral liquid for treating the hand-foot-and-mouth disease and relates to the technical field of medicaments. In the method for testing the quality, the quality is tested by using a high performance liquid chromatogram single-test multi-evaluation method. 10 ml of antiviral oral liquid contains no less than 60 mu g of (R,S)-goitrin, no less than 1 mg of forsythoside A, no less than 0.25 mg of forsythin and no less than 0.12 mg of forsythingenin. The method has the advantages that: the method is simple and convenient; the content of four active ingredients of the antiviral oral liquid can be tested at the same time; the quality of the antiviral oral liquid and the curative effect of the antiviral oral liquid on the hand-foot-and-mouth disease can be comprehensively evaluated by establishing a quantitative analysis result of the active ingredients of the antiviral oral liquid, so the antiviral oral liquid has a truly-controllable standard; and simultaneously, the medicinal material basis of a Chinese medicinal preparation, namely, the antiviral oral liquid in the aspect of curing the hand-foot-and-mouth disease is put forward in China for the first time.
Description
Technical field
The present invention relates to medical technical field, relate to a kind of quality determining method of Chinese patent drug, specifically is a kind of quality determining method that is used to treat the antiviral oral liquor of hand-foot-and-mouth disease.
Background technology
Antiviral oral liquor records in " Drug Standard of Ministry of Public Health of the Peoples Republic of China new drug become a full member standard second " WS
3-(X-39)-92 (z), (pharmacopoeia commission of Ministry of Health of the People's Republic of China compiles, published in 1992).Loaded 2010 at present one one of version pharmacopeia (the formal execution on October 1st, 2010).Product is a compound preparation, and it is that water extract by Radix Isatidis 129g, gypsum 57g, reed rhizome 61g, glutinous rehmannia 32g, root tuber of aromatic turmeric 25g, wind-weed 25g, grass-leaved sweetflag 25g, Pogostemon cablin 29g, capsule of weeping forsythia 46g adds the antiviral oral liquor that medicinal auxiliary material and water are processed 1000ml.Have clearing heat and expelling damp, the effect of removing pattogenic heat from the blood and toxic material from the body is used for anemopyretic cold, the warm disease heating and the infection of the upper respiratory tract, virus infectious diseases such as influenza, mumps.Be used for the viral infection illness such as the infection of the upper respiratory tract, influenza and mumps that the heating of anemopyretic cold, warm disease causes clinically, have curative effect preferably.
Hand-foot-and-mouth disease is claimed brothers' mouth syndrome again, is the acute dermexanthesis infectious disease that is caused by enterovirus, and Acute onset, heating clinically is characteristic with mucous membrane of mouth and hand-foot skin generation bleb.According to its symptom and characteristic, hand-foot-and-mouth disease surely belongs to categories such as " epidemic disease ", " warm disease " in traditional Chinese medicine.From the clinical research result of our company, find that the antiviral oral liquor of our company has the supplemental treatment effect to hand-foot-and-mouth disease.Because compound Chinese patent medicine is to be formed by the multi-flavor medicinal material extract; Its effective constituent is complicated, content of effective especially with the place of production, acquisition time, the preservation quality of medicinal material, multiple factors such as the method for distilling of medicinal material and process control condition are relevant; Like Radix Isatidis is the monarch drug in a prescription in this drug prescription; The amount of the quality of its medicinal material and the active component of extraction has substantial connection, and Radix Isatidis has rhizoma et Radix Baphicacanthis Cusiae and northern Radix Isatidis, and its contained effective constituent is different again.It is blue that the north Radix Isatidis derives from the crucifer ancient name for Chinese cabbage, contain antiviral characteristic chemical constituent (R, S)-accuse according to the spring (claiming epigoitrin again).Rhizoma et Radix Baphicacanthis Cusiae derives from acanthaceous vegetable acanthaceous indigo, do not contain (R, S)-to accuse according to the spring, its antiviral pharmacologically active is far below northern Radix Isatidis.The capsule of weeping forsythia different according to its picking time, can be divided into green grass or young crops and stick up and stick up two kinds always, but be the capsule of weeping forsythia.Gather during the just ripe band still of fruit green, boil for a moment or after cooking with boiling water and dry, practise and claim " green grass or young crops sticks up "; Gather when fruit is well-done and dry, practise and claim " sticking up always ".Research in recent years shows, green grass or young crops sticks up middle general flavone, forsythin content and all is higher than always and sticks up, and forsythin content is low in sticking up always.
The present manufacturing enterprise of antiviral oral liquor is numerous, and dragons and fishes jumbled together to cause product quality, even the enterprise product that has feeds intake not according to standard-required, and then the quality of product just more can't guarantee to have clinically the result of treatment of pair hand-foot-and-mouth disease.
Radix Isatidis is the monarch drug in a prescription in the antiviral oral liquor prescription, and consumption is maximum in the side, and its antiviral pharmacologically active is obvious.But standard is not set up its assay index at present.According to document " blue root chemical constitution and pharmacology activity research progress thereof; 2008 the 29th the 13rd phases of volume of Qiqihar Medical College's journal; 1609 pages ", reported that Radix Isatidis all has inhibiting effect to coxsackie B 3 viruses, hemorrhagic fever with renal syndrome virus, japanese encephalitis virus, mumps virus, herpes simplex virus and hepatitis type B virus.Document " capsule of weeping forsythia chemical constitution and bioactivity research. Northwest University; Science of Chinese materia medica (specialty) 2008 years of Master's thesis " to have reported: forsythia suspense extraction has the effect of anti-CBV and ECHO virus.The chicken idiosome is tested the proof capsule of weeping forsythia outward also has resistancing action to Asia influenza A virus, rhinovirus 17 types etc.Experiment shows that forsythin, Forsythoside have stronger external resistance virus function.
Research according to the inventor; (R in the antiviral oral liquor; S)-accuse height according to spring, forsythin, Forsythoside, four component contents of Forsythingenin; Can directly influence antiviral oral liquor to treating the curative effect of hand-foot-and-mouth disease, so the method that must set up a kind of quality determination to the antiviral oral liquor that is used to treat hand-foot-and-mouth disease is controlled the patent of product, guarantee clinical curative effect.Therefore, press for a kind of easy quality determining method can be simultaneously qualitative with the quantitative measurement antiviral oral liquor in (R, S)-accuse according to spring, forsythin, Forsythoside, four compositions of Forsythingenin.
Summary of the invention
The objective of the invention is to through four main active (R in the antiviral oral liquor; S)-and accuse qualitative, quantitative test according to spring, forsythin, Forsythoside, Forsythingenin, a kind of quality determining method that is used to treat the antiviral oral liquor of hand-foot-and-mouth disease is provided.
The said antiviral oral liquor of the present invention is for being added the antiviral oral liquor that medicinal auxiliary material and water are processed 1000ml by the water extract of medicinal material Radix Isatidis 129g, gypsum 57g, reed rhizome 61g, glutinous rehmannia 32g, root tuber of aromatic turmeric 25g, wind-weed 25g, grass-leaved sweetflag 25g, Pogostemon cablin 29g, capsule of weeping forsythia 46g
Its measuring method is to survey the method for commenting with high performance liquid chromatography one to measure more; Contain (R in the antiviral oral liquor of 10ml; S)-accuse according to the spring (being epigoitrin) and must not be lower than 60 μ g; Contain forsythiaside A and must not be lower than 1mg, contain forsythin and must not be lower than 0.25mg, contain Forsythingenin and must not be lower than 0.12mg.
High-efficient liquid phase chromatogram condition: with the octadecylsilane chemically bonded silica is filling agent; Wash-out is to be mobile phase A with the acetonitrile, and the gradient eluent that uses phosphoric acid to transfer the water of pH value to 2.7～2.9 to form as Mobile phase B carries out gradient elution, and detections wavelength is 236nm, and number of theoretical plate is by (R S)-accuse according to spring peak calculating, must not be lower than 20000.
Said high performance liquid chromatography one is surveyed and is commented method to comprise the steps: more
(1) preparation of reference substance solution: forsythin, Forsythingenin, (R decided in accurate respectively title; S)-accuse according to spring, forsythiaside A reference substance; Adding methyl alcohol respectively processes every 1ml and contains that forsythin 0.2mg, every 1ml contain Forsythingenin 0.25mg, every 1ml contains (R; S)-and accuse the solution that contains forsythiaside A 0.1mg according to spring 0.02mg, every 1ml, shake up, promptly get four reference substance solution;
(2) preparation of need testing solution: get antiviral oral liquor 25ml, put in the 125ml separating funnel, add ethyl acetate 25ml, shaking out 3～6 times; Combined ethyl acetate liquid, evaporate to dryness, residue add 70% dissolve with methanol, put in the 10ml measuring bottle; Add 70% methyl alcohol to scale, shake up, promptly get need testing solution;
(3) draw respectively (R, S)-accuse according to each 10 μ l of spring, forsythin, Forsythoside, four contrast solutions of Forsythingenin and antiviral oral liquor need testing solution, inject high performance liquid chromatograph, promptly get;
(4) calculate: measure the peak area of composition to be measured in reference substance solution and the need testing solution, calculate content with external standard method.
The concentration expressed in percentage by volume of preferred two moving phases of said gradient elution and time relationship according to the form below program are carried out wash-out
| Time (minute) | Mobile phase A (%) (v/v) | Mobile phase B (%) (v/v) |
| 0～22 | 7→18 | 93→82 |
| 22～29 | 18 | 82 |
| 29～31 | 18→23 | 82→77 |
| 31～40 | 23 | 77 |
| 40～53 | 23→40 | 77→60 |
| 53～60 | 40 | 60 |
| 60～65 | 40→7 | 60→93 |
Advantage of the present invention is that method is easy; Can once measure the content of four active components in the antiviral oral liquor; The quantitative analysis results of the active component through setting up antiviral oral liquor; The quality of comprehensive evaluation antiviral oral liquor and the drug effect aspect the treatment hand-foot-and-mouth disease thereof make antiviral oral liquor that real controlled standard arranged, and have also proposed the medical substance basis of Chinese patent medicine preparation antiviral oral liquor aspect the treatment hand-foot-and-mouth disease simultaneously at home first.
Description of drawings
Fig. 1 be reference substance of the present invention (R, S)-accuse high performance liquid chromatography chromatogram according to the spring;
Fig. 2 is the high performance liquid chromatography chromatogram of reference substance forsythiaside A of the present invention;
Fig. 3 is the high performance liquid chromatography chromatogram of reference substance forsythin of the present invention;
Fig. 4 is the high performance liquid chromatography chromatogram of reference substance Forsythingenin of the present invention;
Fig. 5 is the high-efficient liquid phase chromatogram of antiviral oral liquor provided by the present invention (A sample);
Fig. 6 is the high-efficient liquid phase chromatogram of antiviral oral liquor provided by the present invention (B sample);
Fig. 7 is the high-efficient liquid phase chromatogram of antiviral oral liquor provided by the present invention (C sample);
Fig. 8 is the high-efficient liquid phase chromatogram that the present invention adopts gradient elution program 1 gained;
Fig. 9 is the high-efficient liquid phase chromatogram that the present invention adopts gradient elution program 2 gained;
Figure 10 is the high-efficient liquid phase chromatogram that the present invention adopts gradient elution program 3 gained.
Further set forth technical scheme of the present invention below in conjunction with embodiment and accompanying drawing.
Embodiment
Embodiment 1: the preparation of antiviral oral liquor
(A) sample:
Prescription: Radix Isatidis 129g, gypsum 57g, reed rhizome 61g, glutinous rehmannia 32g, root tuber of aromatic turmeric 25g, wind-weed 25g, grass-leaved sweetflag 25g, Pogostemon cablin 29g, capsule of weeping forsythia 46g
Method for making: above nine flavor medicinal materials, the extracting in water secondary adds 8 times of water gagings for the first time, decocts 3 hours, collects volatile oil and volatile oil emulsion simultaneously, adds the HP-inclusion; For the second time add 6 times of water gagings, decocted 1 hour 20 minutes, merge decoction liquor, be concentrated into relative density 1.08 (60 ℃), add ethanol 85% or more and make and contain pure measuring and reach 70%; Left standstill 24 hours, and filtered, collect filtrating,, be concentrated into relative density 1.10 (60 ℃) decompression filtrate recycling ethanol; Filter, add volatile oil clathrate compound and honey, sucrose, etc., add purified water to 1000ml, mixing; Filter to clarification, embedding, sterilization promptly gets.
Crude drug source: Radix Isatidis: be the dry root of cruciferae isatis, produce in Anhui.The capsule of weeping forsythia: be the dry fruit of the Oleaceae plant capsule of weeping forsythia, gather during the just ripe band still of fruit in autumn green that practise and claim that green grass or young crops sticks up, produce in Henan.Gypsum: be Sulfates mineral muriacite family gypsum.Reed rhizome: be the dry rhizome of grass reed, produce in Hebei.Glutinous rehmannia: be radix rehmanniae recen, the dried root of scrophulariaceae rehmannia glutinosa plant, produce in Henan.Root tuber of aromatic turmeric: be the dried root of zingiberaceous plant turmeric, practise and claim " yellow silk root tuber of aromatic turmeric " that is produced from Sichuan.The wind-weed: the dry rhizome of the liliaceous plant wind-weed, produce in Hebei.Grass-leaved sweetflag: be the dry rhizome of acorus gramineus araceae plant, produce in Zhejiang.Pogostemon cablin: be the dry aerial parts of labiate Pogostemon cablin, produce in Guangzhou.
(B) sample:
Prescription and method for making are all with sample A.Be that Radix Isatidis, the capsule of weeping forsythia medicinal material place of production are different, the Radix Isatidis place of production: Sichuan, the capsule of weeping forsythia place of production: Shanxi with the difference of sample A.
(C) sample:
Prescription and method for making are all with sample A.Be that the Radix Isatidis source is different with the season of gathering with the place of production, the capsule of weeping forsythia medicinal material place of production, Radix Isatidis: derive from the dry rhizome of acanthaceous vegetable acanthaceous indigo, the place of production: Zhejiang with the difference of sample A.The capsule of weeping forsythia place of production: for the dry fruit of the Oleaceae plant capsule of weeping forsythia, gather when fruit is well-done, practise and claiming: stick up the place of production always: Hubei.
1, instrument and reagent
Instrument and reagent Agilent 1200 high performance liquid chromatographs, antiviral oral liquor is provided by the applicant, and acetonitrile is a chromatographically pure, and water is ultrapure water.(R, S)-accuse and to provide by Nat'l Pharmaceutical & Biological Products Control Institute according to contrast medicines such as spring, forsythin, forsythiaside A, Forsythingenins.
2, high performance liquid chromatography
Chromatographic condition: with the octadecylsilane chemically bonded silica is filling agent; With the acetonitrile is mobile phase A, is Mobile phase B with water (transferring pH value to 2.85 with phosphoric acid), and according to the form below carries out gradient elution, and the detection wavelength is 236nm.Number of theoretical plate is by (R S)-accuse according to the spring peak and calculate, must not be lower than 20000.
| Time (minute) | Mobile phase A (%) (v/v) | Mobile phase B (%) (v/v) |
| 0～22 | 7→18 | 93→82 |
| 22～29 | 18 | 82 |
| 29～31 | 18→23 | 82→77 |
| 31～40 | 23 | 77 |
| 40～53 | 23→40 | 77→60 |
| 53～60 | 40 | 60 |
| 60～65 | 40→7 | 60→93 |
(1) preparation method of reference substance solution: get forsythin, Forsythingenin, (R respectively; S)-announcement is an amount of according to spring, forsythiaside A reference substance; Accurate claim fixed, add respectively methyl alcohol process every 1ml contain forsythin 0.2mg, Forsythingenin 0.25mg, (R, S)-accuse four solution reference substance solution according to spring 0.02mg and forsythiaside A 0.1mg; Shake up, promptly get.
(2) preparation method of need testing solution: get antiviral oral liquor 25ml, put in the 125ml separating funnel, add ethyl acetate 25ml, shaking out 3～6 times; Combined ethyl acetate liquid, evaporate to dryness, residue add 70% dissolve with methanol, put in the 10ml measuring bottle; Add 70% methyl alcohol to scale, shake up, promptly get.
(3) determination method: absorption respectively (R, S)-accuse according to each 10 μ l of spring, forsythin, Forsythoside, four contrast solutions of Forsythingenin and antiviral oral liquor need testing solution, inject high performance liquid chromatograph, measure, get the high performance liquid chromatogram collection of illustrative plates, see accompanying drawing 1.
(4) calculate: measure the peak area of composition to be measured in reference substance solution and the need testing solution, calculate among the 10m l with external standard method and contain (R, S)-announcement is 208.5 μ g according to the spring, forsythiaside A 1.98mg, forsythin 0.49mg, Forsythingenin 0.37mg.
Embodiment 3: measure embodiment 1 sample (B) (R, S)-accuse content according to spring, forsythin, Forsythoside, four compositions of Forsythingenin.
Method step is with embodiment 2
Collection of illustrative plates is seen accompanying drawing 2
Calculate: every of antiviral oral liquor contain (R, S)-to accuse according to the spring be that 68.9 μ g/ prop up, forsythiaside A 1.47mg/ props up, forsythin 0.27mg/ props up, Forsythingenin 0.14mg/ props up.
Embodiment 4: measure embodiment 1 sample (C) (R, S)-accuse content according to spring, forsythin, Forsythoside, four compositions of Forsythingenin.
Method step is with embodiment 2
Collection of illustrative plates is seen accompanying drawing 3
Calculate: every of antiviral oral liquor contain (R, S)-to accuse according to the spring be that 0 μ g/ props up, forsythiaside A 1.1mg/ props up, forsythin 0.25mg/ props up, Forsythingenin 0.12mg/ props up.
Embodiment 5: the conditional filtering test of gradient elution
In the detection method research process, best for the degree of separation, the symmetry that guarantee each detected peaks, after the moving phase composition was confirmed, we studied the eluent gradient elution requirement.Compared of the influence of the moving phase ratio of variable concentrations respectively to the chromatographic peak degree of separation.At last selected best gradient according to the quantity of information and the peak degree of separation of collection of illustrative plates,
Gradient elution according to the form below program 1 is carried out, and the result sees accompanying drawing 8
| Time (minute) | Mobile phase A (%) (v/v) | Mobile phase B (%) (v/v) |
| 0～20 | 7→16 | 93→84 |
| 20～29 | 16 | 84 |
| 29～31 | 16→20 | 84→80 |
| 31～40 | 20 | 80 |
| 40～53 | 23→30 | 77→70 |
| 53～60 | 30 | 70 |
| 60～65 | 30→10 | 70→90 |
Gradient elution according to the form below program 2 is carried out, and the result sees accompanying drawing 9
| Time (minute) | Mobile phase A (%) (v/v) | Mobile phase B (%) (v/v) |
| 0～21 | 7→18 | 93→84 |
| 21～29 | 18 | 82 |
| 29～31 | 18→21 | 82→79 |
| 31～40 | 21 | 79 |
| 40～53 | 23→35 | 77→65 |
| 53～60 | 35 | 65 |
Gradient elution according to the form below program 3 is carried out, and the result sees accompanying drawing 10
| Time (minute) | Mobile phase A (%) (v/v) | Mobile phase B (%) (v/v) |
| 0～22 | 7→18 | 93→82 |
| 22～29 | 18 | 82 |
| 29～31 | 18→23 | 82→77 |
| 31～40 | 23 | 77 |
| 40～53 | 23→40 | 77→60 |
| 53～60 | 40 | 60 |
| 60～65 | 40→7 | 60→93 |
Below through the quality of Test Example proof antiviral oral liquor and the effect of treatment hand-foot-and-mouth disease, because of hand-foot-and-mouth disease from traditional Chinese medical science angle, belong to " warm disease " category.Therefore, pharmacodynamic experiment adopts the warm disease model of the traditional Chinese medical science to experimentize.
Test Example one antiviral oral liquor is to warm disease humidifier fever experimental study of animal model
Test method: with the Wistar rat, male and female half and half, body weight 180～220g.Under normal humiture environment (25 ℃ of temperature, relative humidity 55%), raised 10 days with the high glucose and high fat feed, then rat is placed modeling case (35 ℃ of temperature, relative humidity 95%), modeling every day 9 hours).Irritate stomach behind the 96h and give bacillus typhi murium 10
9/ ml (2ml/200g), 120h infects once (2ml/200g) again, shifts out then to place physical environment to raise and the grouping administration.At once that model group 10 rat chambeies arterial blood extracting and separation of serum is subsequent use after the grouping.All the other each group difference gastric infusions every day 2 times, after 7 days that rat chamber arterial blood extracting and separation of serum is subsequent use.Adopt distinct methods to detect index of correlation.Animal random packet after the modeling success, is respectively by 12 every group: damp and hot model group, damp and hot model treatment control group, ganlu xiaodu micropills positive controls, three kinds of antiviral oral liquor ABC (it is as shown in the table that each forms the content that divides :).
| Numbering | (R, S)-accuse according to spring content (μ g/10ml) | Forsythiaside A content (mg/10ml) | Forsythin content (mg/10ml) | Forsythingenin content (mg/10ml) |
| A | 208.5 | 1.98 | 0.49 | 0.37 |
| B | 68.9 | 1.47 | 0.27 | 0.14 |
| |
0 | 1.1 | 0.25 | 0.12 |
Other gets 10 of rats, places physical environment, normal diet to raise, and is made as the normal control group.Adopt double antibodies sandwich ELISA method, measure by the kit instructions and respectively organize rat blood serum G-CSF content; Detect rat blood serum NO content with the nitrate reductase method;
Test findings: see table 1,2,3
The content of G-CSF, NO in table 2 rat blood serum
Annotate: compare with normal group
*＞0.05
*＜0.05
* *＜0.01
Compare △＞0.05 △ △＜0.05 △ △ △＜0.01 with model control group
Compare #＞0.05 ##＜0.05 ###＜0.01 with the ganlu xiaodu micropills group
The content of diastase and D-wood sugar in table 3 rat blood serum
Annotate: compare with normal group
*＞0.05
*＜0.05
* *＜0.01
Compare △＞0.05 △ △＜0.05 △ △ △＜0.01 with model control group
Compare #＞0.05 ##＜0.05 ###＜0.01 with the ganlu xiaodu micropills group
The test brief summary:
1, behind the successive administration 7d, antiviral oral liquor A, B group G-CSF level have been recovered near normal level, show effectively control infection of antiviral oral liquor.Each treated animal serum NO level does not have significant change before and after the treatment, points out this index related not strong.
2, after the modeling, model group animal blood serum D-wood sugar content obviously increases, and explains that the high glucose and high fat diet can cause that rat blood serum D-wood sugar level rises.Behind the successive administration 7 days, antiviral oral liquor is respectively organized serum D-wood sugar content and is obviously descended, and B, C group serum D-wood sugar content have recovered normal level.
3, antiviral oral liquor is to warm disease humidifier fever animal model, and effectively control infection reduces G-CSF level in the serum, and wherein the C group does not contain that (R, S)-accuse according to the spring, the serum G-CSF level descends the slowest, almost suitable with model control group.
Test Example two antiviral oral liquors are to the refrigeration function of fever in rabbits due to the endotoxin
Experimental technique:
Get healthy new zealand rabbit, place in 22 ± 2 ℃ of laboratories, every survey altogether 4 times at a distance from 1 hour measurement anus temperature 1 time, 4 body temperature is all in 38.9-39.5 ℃ scope, and the highest minimum body temperature difference is no more than 0.3 ℃ rabbit and continues to employ.The animal fasting begins experiment after 12 hours, every rabbit is surveyed anus temperature 2 times, and each 45 minutes at interval, twice temperature difference must not be above 0.3 ℃, with the mean value of the twice body temperature normal body temperature as this rabbit.Each rabbit normal body temperature is in 38.9-39.5 ℃ of scope, and auricular vein is injected endotoxin 150EU/kg, take temperature after 60 minutes, and the normal rabbit of fervescence more than 0.5 ℃ is the modeling success.The 1st body temperature is surveyed in administration after the random packet after 30 minutes, whenever surveyed body temperature 1 time at a distance from 1 hour, surveys continuously 4 times.Subtract the normal body temperature of same animals with different time body temperature after the administration, the difference of fervescence difference between each group relatively, and do the t check.4h is subsequent use from tame rabbit ear edge arterial blood extracting and separation of serum after the administration.
Experimental result:
1, endotoxin is caused the influence of fever in rabbits body temperature, each organizes the average basal body temperature of rabbit does not have significant difference, is 38.9～39.2 ℃; Quiet notes endotoxin after 60 minutes the body temperature difference that on average raises also do not have significant difference, scope is 0.78-0.94 ℃.After the random packet administration, the model control group animal heat continues obviously to raise, and keeps more than 4 hours.The administration of antiviral oral liquor A group after 1 hour body temperature do not have obvious reduction, administration had the trivial solution heat effect to rabbit heating due to the endotoxin after 2 hours, with model control group significant difference (P＜0.05) was arranged relatively, each time point effect is proportionate; Antiviral oral liquor A group reduces difference with each time point mean body temperature of positive controls does not have significant difference (P＞0.05), shows that the two action intensity is approaching.After the administration 4 hours, antiviral oral liquor A group and positive controls body temperature reduce difference and model control group relatively still has significant difference (P＜0.05), shows that refrigeration function can keep more than 4 hours.See table 5 for details.
2, each is organized the influence of TNF-a in rabbit anteserum
Testing result shows that antiviral oral liquor A, B dose groups and positive controls all can significantly reduce TNF-a content in the rabbit fever models serum, with the model control group ratio significant difference (P＜0.05) are arranged; Antiviral oral liquor A group and positive controls action intensity are near (P＞0.05).See table 6 for details.
Table 6 antiviral oral liquor is to the influence
of rabbit fever model TNF-a due to the bacterial endotoxin
Compare with model control group
*P＞0.05
*P＜0.05
* *P＜0.01
Compare #p＞0.05 ##p＜0.05 ###p＜0.01 with the QINGKAILING positive controls
Test Example is summed up:
1, antiviral oral liquor A, B can obviously improve rat warm disease humidifier fever symptom for two groups, make rat blood serum granulocyte colony stimulating factor G-CSF, serum D-wood sugar content return to normal level, and approaching with ganlu xiaodu micropills positive controls action intensity.
2, antiviral oral liquor A group can significantly reduce the body temperature that endotoxin causes rabbit fever models, and refrigeration function can be kept more than 4 hours; Antiviral oral liquor A, B dose groups all can reach the heat-clearing effect through generation and the release that suppresses TNF-a, and approaching with the positive controls action intensity.
The prompting of above test findings, antiviral oral liquor can improve the resistibility of body, removes the influence of virulence factor, has effect analgesic and alleviate clinical symptoms simultaneously, and hand-foot-and-mouth disease is had certain therapeutic action.Its drug action intensity is just relevant with four active component contents.Four component contents are high more, and its pharmacologically active is strong more.
Through above-mentioned evidence: the present invention is through setting up (R in the antiviral oral liquor; S)-accuse content assaying method according to spring, forsythin, Forsythoside, four kinds of main active of Forsythingenin; Characterized four main active components that improve rat warm disease humidifier fever and treated the dose-effect relationship between the hand-foot-and-mouth disease curative effect, quality and the curative effect of estimating antiviral oral liquor are practicable.
Claims (1)
1. quality determining method that is used to treat the antiviral oral liquor of hand-foot-and-mouth disease; Said antiviral oral liquor is for being added the antiviral oral liquor that medicinal auxiliary material and water are processed 1000ml by the water extract of medicinal material Radix Isatidis 129g, gypsum 57g, reed rhizome 61g, glutinous rehmannia 32g, root tuber of aromatic turmeric 25g, wind-weed 25g, grass-leaved sweetflag 25g, Pogostemon cablin 29g, capsule of weeping forsythia 46g
It is characterized in that: survey the method commented with high performance liquid chromatography one more and measure; Contain in the antiviral oral liquor of 10ml (R, S)-accuse according to the spring and must not be lower than 60 μ g, contain forsythiaside A and must not be lower than 1mg; Contain forsythin and must not be lower than 0.25mg, contain Forsythingenin and must not be lower than 0.12mg;
High-efficient liquid phase chromatogram condition: with the octadecylsilane chemically bonded silica is filling agent; Wash-out is to be mobile phase A with the acetonitrile, and the gradient eluent that uses the water of phosphoric acid adjust pH to 2.7～2.9 to form as Mobile phase B carries out gradient elution, and detections wavelength is 236nm, and number of theoretical plate is by (R S)-accuse according to spring peak calculating, must not be lower than 20000;
Said gradient elution according to the form below program is carried out:
Said high performance liquid chromatography one is surveyed and is commented method to comprise the steps: more
(1) preparation of reference substance solution: forsythin, Forsythingenin, (R decided in accurate respectively title; S)-accuse according to spring, forsythiaside A reference substance; Adding methyl alcohol respectively processes every 1ml and contains that forsythin 0.2mg, every 1ml contain Forsythingenin 0.25mg, every 1ml contains (R; S)-and accuse the solution that contains forsythiaside A 0.1mg according to spring 0.02mg, every 1ml, shake up, promptly get four reference substance solution;
(2) preparation of need testing solution: get antiviral oral liquor 25ml, put in the 125ml separating funnel, add ethyl acetate 25ml, shaking out 3～6 times; Combined ethyl acetate liquid, evaporate to dryness, residue add 70% dissolve with methanol, put in the 10ml measuring bottle; Add 70% methyl alcohol to scale, shake up, promptly get need testing solution;
(3) draw respectively (R, S)-accuse according to each 10 μ l of spring, forsythin, Forsythoside, four reference substance solution of Forsythingenin and antiviral oral liquor need testing solution, inject high performance liquid chromatograph, promptly get;
(4) calculate: measure the peak area of composition to be measured in reference substance solution and the need testing solution, calculate content with external standard method.
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| CN102716245B (en) * | 2011-03-31 | 2014-05-28 | 丽珠医药集团股份有限公司 | Application of traditional Chinese medicine composition in preparing medicines for resisting enterovirus 71 |
| CN103675189B (en) * | 2012-09-05 | 2016-06-29 | 亚宝药业集团股份有限公司 | A kind of quality determining method of Folium Forsythiae medical material |
| CN103245737A (en) * | 2013-04-17 | 2013-08-14 | 杭州老桐君制药有限公司 | Detection method of anti-viral oral liquid |
| CN104181241A (en) * | 2013-05-28 | 2014-12-03 | 河北以岭医药研究院有限公司 | Determination method of forsythiaside A and forsythin content in fructus forsythiae leaves |
| CN106950289B (en) * | 2016-01-07 | 2019-10-29 | 陕西步长制药有限公司 | A kind of coronary disease treatment capsule one is surveyed comments detection method of content more |
| CN112168940A (en) * | 2020-10-22 | 2021-01-05 | 佛山市高明区(中国科学院)新材料产业研究院 | Method for extracting water-soluble effective components of oral liquid for treating tetanus septicemia |
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