CN102175823A - Evaluation method for in vitro dissolution analysis of traditional Chinese medicine - Google Patents
Evaluation method for in vitro dissolution analysis of traditional Chinese medicine Download PDFInfo
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- CN102175823A CN102175823A CN201010613644XA CN201010613644A CN102175823A CN 102175823 A CN102175823 A CN 102175823A CN 201010613644X A CN201010613644X A CN 201010613644XA CN 201010613644 A CN201010613644 A CN 201010613644A CN 102175823 A CN102175823 A CN 102175823A
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Abstract
The invention provides an evaluation method for in vitro dissolution analysis of traditional Chinese medicine, belonging to the technical field of traditional Chinese evaluation. The evaluation method provided by the invention comprises the following steps: step A: preparing a standard solution; step B: building an analysis measuring method; step C: performing dissolution experiment of a traditional Chinese medicine oral preparation; and step D: calculating a relatively accumulated dissolution rate. In the invention, a crude drug with multiple components is used as the 'standard substance'; the concentrations of various constituents in a releasing medium are calibrated; the difficulty that the in vitro dissolution experiment of traditional Chinese medicine with multiple components can not be performed without the standard substance is overcome; a new quality standard of traditional Chinese oral preparation with process characteristics can be formulated by the evaluation method provided by the invention; the in vitro dissolution of the traditional Chinese oral preparation is evaluated roundly; and a new method of quantitative analysis is supplied for the in vitro dissolution evaluation of more complex traditional Chinese oral preparation.
Description
Technical field
The invention belongs to the technical field that Chinese medicine is estimated, especially with the multi-component feedstock medicine as " standard items ", the concentration of each composition in the demarcation release medium, but the external stripping feature of thoroughly evaluating polycomponent Chinese medicine.
Background technology
The drug dissolution inspection is a kind of effective means of estimating the quality of the pharmaceutical preparations and technological level, the difference that can reflect crystal formation, granularity, prescription group, auxiliary material kind and the character and the production technology etc. of main ingredient to a certain extent, it also is a kind of effective means of estimating preparation active component bioavilability and preparation uniformity coefficient, can indicate on certain degree with distinguish with the different preparations of a kind of medicine between the difference of bioavilability, so the medicine dissolution rate is one of drug quality project of controlling necessary inspection.Traditional Chinese traditional compound medicine is many based on decoction, does not have the dissolution rate problem.And the modern Chinese herbal medicine of making through modern technology is many based on solid pharmaceutical preparations such as tablet, capsule, pills, and the stripping of its effective constituent is the systemic prerequisite of body, also will influence its performance drug effect.Therefore, the dissolution test of solid preparation of traditional Chinese medicine also is the important parameter that traditional Chinese medicine quality characterizes.But because the characteristic of Chinese medicine preparation, chemical constitution is various and complicated, and some active constituent content is lower, has the part chemical constitution water-soluble bad, and this has brought certain degree of difficulty for its dissolution test.Increase Chinese medicine determination of dissolution rate project, can control the quality of Chinese medicine better, for reasonable, effective medication provides foundation.The report that existing relevant at present Chinese medicine dissolution in vitro is measured, but only select 1-2 index components to measure.From traditional traditional Chinese medicine viewpoint, the control of index components is difficult to really control the effect of Chinese medicine, and especially compound preparation detects the whole curative effect that any index components can not reflect that all it embodies.Some index components are carried out assay, can reach the purpose of control " matter " hardly by " amount ", and many index components are not that a certain medicinal material is exclusive, by single index components control of quality, its specificity is also relatively poor, can't reflect the actual mass situation of Chinese medicine preparation comprehensively.
Summary of the invention
External stripping of Chinese medicine provided by the invention and evaluation method, be a kind of with the Chinese medicine material medicine as " standard items ", each composition in the dissolution medium is carried out assay, and then obtains the dissolution rate of each composition.
The present invention divides following step:
(1) preparation of standard solution;
(2) analysis determining method is set up;
(3) oral preparation of Chinese traditional medicinal dissolution test;
(4) measure external stripping sample;
(5) calculate the Chinese medicine dissolution rate in vitro.
Concrete technical scheme is as follows:
A kind of evaluation method that is used for the external stripping analysis of Chinese medicine has preparation, the foundation of B step analysis determining method, C step oral preparation of Chinese traditional medicinal dissolution test, the D step of A step standard solution to calculate relative cumulative leaching rate, and detailed process is as follows:
The preparation of described A step standard solution is standard items with the Chinese medicine material medicine, the preparation raw material drug solns; Be diluted to variable concentrations respectively with same solvent again,, as labelled amount, measure the relative concentration of each component in each series standard solution with the total concentration of raw material medicine solution as series standard solution;
Described B step analysis determining method is set up, and utilizes the mode of mass spectral Q1 employing full scan, obtains the m/z data of Chinese medicine material medicinal substances group; Set up the chromatography-mass spectroscopy analysis condition, select interior mark, by the requirement that existing general analytical approach is proved conclusively, the quantitative analysis method of setting up Chinese medicine material medicinal substances group;
Described C step oral preparation of Chinese traditional medicinal dissolution test carries out according to the dissolution method of Chinese Pharmacopoeia version in 2010 regulation, and oral preparation of Chinese traditional medicinal dissolution test method adopts the oar method, changes basket method or little agar diffusion method; The dissolution medium of oral preparation of Chinese traditional medicinal dissolution test adopts acid, aqueous slkali, surfactant or the cosolvent of deionized water, variable concentrations;
Described D step is calculated relative cumulative leaching rate, measure external stripping sample, be to be that the oral preparation of Chinese traditional medicinal of W is dissolved in the dissolution medium with unit formulation weight, dissolution fluid, dissolution fluid is measured the peak area A of each component under the liquid chromatography-mass spectrography condition of B step; Other gets precision and claims that deciding weight is W
iOral preparation of Chinese traditional medicinal, carry out according to C step oral preparation of Chinese traditional medicinal dissolution test, the dissolution fluid that different time collects is measured the peak area A of each component under the liquid chromatography-mass spectrography condition of B step
i, by formula
Calculate accumulation stripping percent relatively.
Solvent for use of the present invention can adopt suitable solvents such as methyl alcohol, acetonitrile or mixed solvent.
The determination and analysis method of sample of the present invention can be taked spectroscopic methodology (infrared spectrum, ultraviolet spectrum, fluorescence spectrum, derivative spectrum, nuclear magnetic resonance), chromatogram (gas phase, liquid phase, Capillary Electrophoresis, thin layer scanning) and hyphenated techniques chromatography analytical approachs such as (LC-MS, LC-MS/MS, GC-MS, GS-MS/MS), obtains the component population analysis collection of illustrative plates or the image that can characterize the sample chemical feature.
The present invention with the multi-component feedstock medicine as " standard items ", demarcate the concentration of each composition in the release medium, having overcome the Chinese medicine polycomponent does not have standard items can't carry out the difficulty of external dissolution test, realized evaluation, the new approaches of quantitative test are provided for the external stripping evaluation of more complicated Chinese medicine preparation the multi-component stripping feature of Chinese medicine.
The external stripping analysis of Chinese medicine provided by the present invention and evaluation method are compared with traditional method of just passing judgment on traditional Chinese medicine quality with index components content, it is advantageous that more exclusively, comprehensive, can scientifically reflect the total quality of this complex system preparation of Chinese medicine.Utilize the external stripping evaluation method of Chinese medicine of the present invention can make the quality new standard of the oral preparation of Chinese traditional medicinal that comprises operational characteristic, can comprehensively estimate the external stripping of oral preparation of Chinese traditional medicinal.
Description of drawings
Fig. 1. uncommon bright graceful stripping curve figure.
Embodiment
Embodiment 1: uncommon bright graceful external stripping research
1 instrument
Triple quadrupole bar tandem mass spectrometer; High performance liquid chromatography.
The preparation of 2 drug solutions
The preparation of rattletop bulk drug standard serial solution: accurately take by weighing rattletop bulk drug 10.0mg, methanol constant volume as storing solution, is used methanol-water (80: 20 to 10mL, v/v) solvent progressively is diluted to 0.5,2.0,10,50,200,800 μ g/mL are as standard serial solution.
3 set up rattletop total saponins LC-MS/MS polycomponent assay method
With " standard items " of rattletop bulk drug as the material group, the usefulness methanol-water (80: 20, v/v) it is diluted to suitable multiple:
(1) with syringe pump (FIA) sample introduction, mass spectral Q1 adopts the mode of full scan, obtains the m/z data of the higher rattletop material group of response;
(2) with these data respectively as the ion of the SIM of LC-MS/MS monitoring, input mass spectrum workstation;
(3) chromatogram adopts the mode of gradient elution, and mass spectrum is selected the quasi-molecular ion of [M-H]-signal stabilization;
(4) adopt the MS2 scan mode, seek the corresponding daughter ion of parent ion, and the mass spectrum parameter is optimized, select the ion pair highly sensitive, that specificity is strong to carry out quantitatively, input mass spectrum workstation; 14 kinds of component mass spectrum conditions see Table 1.
Table 1 is measured the mass spectrum condition of 14 kinds of compositions in the dissolution medium
(5) optimize chromatographiccondition, mark in selecting is by the requirement that has international analytical approach conclusive evidence now, the quantitative analysis method of setting up rattletop material group.Chromatographic column: C18 post, 4.6 μ m, 50 * 2.1mmI.D.; Moving phase: organic phase (B phase) is a methyl alcohol, and 0.2mM NH4F (A phase) adopts the gradient elution mode, T=0 (min): 60%A; T=0.5:25%A; T=2.5:5%A; T=7.5:60%A; T=10.5:60%A; Flow velocity is 0.4mL/min; Column temperature: 40 ℃; Sample size: 10 μ L.
4 set up typical curve
Precision takes by weighing uncommon bright graceful bulk drug reference substance 10mg, adds the water methanol constant volume in the 10mL measuring bottle, uses methanol-water (80: 20, v/v) progressively to be diluted to the bulk drug total concentration be 0.5 to solution, 2.0,10,50,200, the standard serial solution of 800 μ g/mL, with this concentration be " sign concentration " with each component concentrations in the mark standard solution, get 10 μ L solution, carry out the LC-MS/MS quantitative test, with concentration to peak area map 14 component typical curves.
5 a hundred per cent stripping quantities are measured
Get uncommon bright graceful 20 of same lot number, porphyrize, precision takes by weighing and is equivalent to the heavy sample size (W) of average sheet, puts in the 100ml dissolution medium, 37 ℃ of water-baths, rotating speed is 100rmin
-1, behind the 6h, get in right amount, filter, get subsequent filtrate is measured 14 kinds of components under above-mentioned LC-MS/MS condition peak area A, the amount of each component during as uncommon bright graceful a hundred per cent stripping.This value is calculated accumulation stripping percent relatively as hundred-percent content substitution following formula.
6 external dissolution tests
According to dissolution method [three therapeutic methods of traditional Chinese medicine in Chinese Pharmacopoeia version (two ones) in 2010 dissolution method], be dissolution medium with the aqueous solution, get each 250mL of dissolution medium, place respectively in each stripping rotor, after treating temperature balance, remain on 37 ± 0.5 ℃, adjusting rotating speed is 75 rev/mins.Choose 6 of uncommon bright graceful stripping standard films, precision is weighed and is placed 6 stripping rotors simultaneously after (Wi), picks up counting when stripping standard film contact dissolution medium, through 3,6,12,18,24,36 and 48h time sampling 5mL, add synthermal medium 5ml simultaneously, with 0.18 μ m filtering with microporous membrane, and the LC-MS/MS sample introduction, get 14 component peaks areas (Ai), ask the dissolution rate of effective ingredient by typical curve.The accumulative total dissolution rate sees Table 2.
The uncommon bright graceful different time accumulation of table 2 dissolution rate
In sum, each components contents is eliminated in dissolution rate calculates, thus the stripping that the present invention calculates each component with the bulk drug method be science accurately.In addition, from the dissolution rate result of 14 components as can be seen, because the dissolubility difference of different component, there is some difference to cause the dissolution rate of each component and dissolution rate, can not embody the preparation overall quality so only with one or more compounds polycomponent Chinese medicine is carried out external stripping investigation.Chinese medicine is multi-component synergy, and the prerequisite that guarantees the oral preparation of Chinese traditional medicinal curative effect is exactly medicine stripping from preparation earlier.The polycomponent assay method is more suitable for the multi-component characteristics of Chinese medicine, can wholely embody oral preparation of Chinese traditional medicinal in-vitro evaluation and quality control.
Claims (2)
1. an evaluation method that is used for the external stripping analysis of Chinese medicine has preparation, the foundation of B step analysis determining method, C step oral preparation of Chinese traditional medicinal dissolution test, the D step of A step standard solution to calculate relative cumulative leaching rate, and detailed process is as follows:
The preparation of described A step standard solution is standard items with the Chinese medicine material medicine, the preparation raw material drug solns; Be diluted to variable concentrations respectively with same solvent again,, as labelled amount, measure the relative concentration of each component in each series standard solution with the total concentration of raw material medicine solution as series standard solution;
Described B step analysis determining method is set up, and utilizes the mode of mass spectral Q1 employing full scan, obtains the m/z data of Chinese medicine material medicinal substances group; Set up the chromatography-mass spectroscopy analysis condition, select interior mark, by the requirement that existing general analytical approach is proved conclusively, the quantitative analysis method of setting up Chinese medicine material medicinal substances group;
Described C step oral preparation of Chinese traditional medicinal dissolution test carries out according to the dissolution method of Chinese Pharmacopoeia version in 2010 regulation, and oral preparation of Chinese traditional medicinal dissolution test method adopts the oar method, changes basket method or little agar diffusion method; The dissolution medium of oral preparation of Chinese traditional medicinal dissolution test adopts deionized water, acid or aqueous slkali, surfactant or cosolvent;
Described D step is calculated relative cumulative leaching rate, measure external stripping sample, be to be that the oral preparation of Chinese traditional medicinal of W is dissolved in the dissolution medium with unit formulation weight, dissolution fluid, dissolution fluid is measured the peak area A of each component under the liquid chromatography-mass spectrography condition of B step; Other gets precision and claims that deciding weight is W
iOral preparation of Chinese traditional medicinal, carry out according to C step oral preparation of Chinese traditional medicinal dissolution test, the dissolution fluid that different time collects is measured the peak area A of each component under the liquid chromatography-mass spectrography condition of B step
i, by formula
Calculate accumulation stripping percent relatively.
2. the evaluation method that is used for the external stripping analysis of Chinese medicine according to claim 1 is characterized in that, the solvent of described preparing standard solution adopts methyl alcohol or acetonitrile.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105158188A (en) * | 2015-07-06 | 2015-12-16 | 长春中医药大学 | Release detection method of aniracetam sustained release tablet |
| CN107907640A (en) * | 2017-11-22 | 2018-04-13 | 杭州华东医药集团新药研究院有限公司 | The method of evaluating drug effect of fermentation winter worm summer bacterium powder piece |
| CN108007826A (en) * | 2016-11-02 | 2018-05-08 | 广东嘉博制药有限公司 | A kind of assay method of long-lasting liquid agent in vitro Accumulation dissolution |
| CN113075370A (en) * | 2021-03-12 | 2021-07-06 | 药都(本溪)一致科技有限公司 | Method, system, medium and application for measuring quality consistency of traditional Chinese medicine |
| CN117783459A (en) * | 2024-02-28 | 2024-03-29 | 沈阳科惠生物医药科技有限公司 | Drug dissolution curve determination method and system |
-
2010
- 2010-12-30 CN CN201010613644XA patent/CN102175823A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 陈立兵等: "中药制剂及给药系统的物质组释放/溶出动力学原理", 《中草药》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105158188A (en) * | 2015-07-06 | 2015-12-16 | 长春中医药大学 | Release detection method of aniracetam sustained release tablet |
| CN108007826A (en) * | 2016-11-02 | 2018-05-08 | 广东嘉博制药有限公司 | A kind of assay method of long-lasting liquid agent in vitro Accumulation dissolution |
| CN107907640A (en) * | 2017-11-22 | 2018-04-13 | 杭州华东医药集团新药研究院有限公司 | The method of evaluating drug effect of fermentation winter worm summer bacterium powder piece |
| CN113075370A (en) * | 2021-03-12 | 2021-07-06 | 药都(本溪)一致科技有限公司 | Method, system, medium and application for measuring quality consistency of traditional Chinese medicine |
| CN117783459A (en) * | 2024-02-28 | 2024-03-29 | 沈阳科惠生物医药科技有限公司 | Drug dissolution curve determination method and system |
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Application publication date: 20110907 |