CN113759059B - Process evaluation method of substance reference substance or preparation of traditional Chinese medicine compound - Google Patents
Process evaluation method of substance reference substance or preparation of traditional Chinese medicine compound Download PDFInfo
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Abstract
The invention provides a process evaluation method of a substance reference substance or preparation of a traditional Chinese medicine compound, which comprises the step of evaluating a product obtained in any process step in the preparation process by adopting evaluation indexes, wherein the evaluation indexes at least comprise key quality attribute similarity coefficients S of a characteristic spectrum or a fingerprint cqa (ii) a Screening out the largest number of S cqa The value is closer to the value 1, namely the characteristic spectrum or the fingerprint spectrum corresponding to the process; and discloses S of the characteristic spectrum or the fingerprint spectrum cqa The acquisition process of (2). The invention has the advantages of reducing the difference of the material basis between the prepared product and the traditional decoction, ensuring the curative effect.
Description
Technical Field
The invention relates to the field of traditional Chinese medicine preparation, in particular to a process evaluation method of a substance reference substance or a preparation of a traditional Chinese medicine compound.
Background
The Chinese herbal compound is a prescription which is composed of two or more than two medicinal herbs, has a relatively specified processing method and a relatively specified using method and is designed aiming at relatively determined diseases and symptoms, and is a main component of a Chinese herbal prescription. The use of Chinese herbs for treating diseases has been in history for thousands of years, and with the release of the latest drug registration management method and simplified registration, examination and approval management regulation of ancient classic famous prescription Chinese herbal compound preparation of the State food and drug administration, the traditional Chinese medicine research and development mode is gradually returning to rationality.
The traditional Chinese medicine classic famous prescriptions mainly refer to Qing dynasty and ancient classic famous prescriptions before, have rich clinical application bases, are still used by Chinese medicine workers at home and abroad till now, and have the advantages of definite curative effect and small adverse reaction proved by clinical practice.
For classical famous Chinese medicinal prescriptions, the existing pharmaceutical research thinking is inconsistent with clinical practical application, and although the existing extraction method of a meridian prescription preparation is based on an ancient decoction method, the process is generally researched by taking the maximum value of an ointment yield and an index component transfer rate as guidance, and the traditional Chinese medicinal preparation is not compared with the specific component composition of a clinical decoction. As can be seen from the original descriptions of the ancient prescriptions of the menstruation formula, each prescription has different decoction requirements, so that the extraction method of the menstruation formula preparation in the prior art is greatly different from the ancient decoction method, and the clinical curative effects of the menstruation formula preparation and the ancient decoction method are sometimes greatly different. Therefore, the obtained finished product of the conventional meridian prescription preparation is inconsistent with the material basis contained in clinical decoction, the consistency of clinical curative effect cannot be ensured, and the hidden troubles of safety and effectiveness exist.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defect that the prior art does not disclose a process evaluation method which can make the composition and content of a substance reference substance object or a substance basis contained in a preparation of a traditional Chinese medicine compound basically consistent with those of a traditional decoction and can not keep the clinical curative effect consistent, thereby providing a process evaluation method which can effectively obtain process steps and parameters for reducing the substance basis difference between the prepared substance reference substance object or the preparation of the traditional Chinese medicine compound and the traditional decoction.
A method for evaluating substance reference substance or preparation of Chinese medicinal composition comprises:
evaluating the product obtained in any process step in the preparation process by adopting evaluation indexes, wherein the evaluation indexes at least comprise key quality attribute similarity coefficients S of characteristic spectrums or fingerprint spectrums cqa (ii) a Screening out the largest amount of S cqa The value is closer to the value 1, namely the characteristic spectrum or the fingerprint spectrum corresponding to the process;
s of the characteristic spectrum or fingerprint spectrum cqa The acquisition process comprises the following steps: respectively obtaining a standard decoction, a test sample and a reference sample, wherein the standard decoction is a decoction of a Chinese herbal compound, the test sample is a product obtained in any process step in the preparation process, and the reference sample is at least one component in the standard decoction; one component in a reference substance is adopted as an index component, a characteristic peak corresponding to the index component is marked in a characteristic spectrum or a fingerprint spectrum of a standard decoction and a test sample, the characteristic peak corresponding to the index component is adopted as an S peak, the relative peak area of each characteristic peak relative to the S peak displayed in the characteristic spectrum or the fingerprint spectrum is obtained, then the ratio of the relative peak areas of each corresponding characteristic peak in the test sample and the standard decoction is calculated, and the ratio is the S peak of the characteristic spectrum or the fingerprint spectrum cqa 。
S using characteristic or fingerprint spectrum cqa Evaluating all processes of a substance reference substance or a preparation of the traditional Chinese medicine compound; the method comprises the following steps: all the process steps of obtaining substance reference substance or preparation of Chinese herbal compound are carried out, the detection of characteristic spectrum or fingerprint spectrum is carried out on the product generated in each step according to the sequence of all the process steps, and the characteristic spectrum or S of the fingerprint spectrum of the product in the corresponding step is obtained cqa According to characteristic spectrum or fingerprint spectrum S cqa Screening out the process steps corresponding to the characteristic spectrums or the fingerprint spectrums with the largest number and closer to the numerical value 1.
The substance reference substance of the traditional Chinese medicine compound is any one of concentrated solution, extract or powder; the Chinese medicinal compound preparation is any one of tablets, pills, powder, granules, injections, tinctures, solutions, extracts and ointments.
When the substance reference substance of the traditional Chinese medicine compound is a concentrated solution or an extract, all the process steps for preparing the substance reference substance of the traditional Chinese medicine compound sequentially comprise an extraction step and a concentration step; firstly, extracting to obtain extractive solution, and obtaining S of the extractive solution cqa According to S cqa Screening out the optimal process of the extraction step; then using the best work of the extraction stepConcentrating the obtained extractive solution to obtain concentrated solution or extract, and obtaining S of the concentrated solution or extract cqa According to S cqa Screening out the optimal process of the concentration step.
When the substance reference substance of the traditional Chinese medicine compound is powder, all the process steps for preparing the substance reference substance of the traditional Chinese medicine compound sequentially comprise an extraction step, a concentration step and a drying step; firstly, extracting to obtain extractive solution, and obtaining S of the extractive solution cqa According to S cqa Screening out the optimal process of the extraction step; then concentrating the extractive solution obtained by the optimal extraction process to obtain concentrated solution, and obtaining S of the concentrated solution cqa According to S cqa Screening out the optimal process of the concentration step; finally drying the concentrated solution obtained by the optimal process of the concentration step to obtain powder, and obtaining S of the powder cqa According to S cqa And screening out the optimal process of the drying step.
When the Chinese herbal compound preparation is a granule, all the process steps for preparing the Chinese herbal compound preparation sequentially comprise an extraction step, a concentration step, a drying step and a granulation step; firstly, extracting to obtain extractive solution, and obtaining S of the extractive solution cqa According to S cqa Screening out the optimal process of the extraction step; secondly, concentrating the extract obtained by the optimal process of the extraction step to obtain a concentrated solution, and obtaining S of the concentrated solution cqa According to S cqa Screening out the optimal process of the concentration step; then drying the concentrated solution obtained by the optimum process of the concentration step to obtain powder, and obtaining S of the powder cqa According to S cqa Screening out the optimal process of the drying step; finally granulating the powder obtained by the optimum process of the drying step to obtain granules, and obtaining S of the granules cqa According to S cqa Screening out the optimal process of the granulation step.
The detection method of the characteristic spectrum or the fingerprint spectrum is a high performance liquid chromatography, the number of characteristic peaks in the characteristic spectrum or the fingerprint spectrum obtained by detecting the standard decoction and the test sample is not less than 60 percent of the total number of the total characteristic peaks, and the relative retention time of the characteristic spectrum or the fingerprint spectrum of the test sample is within +/-10 percent of the relative retention time of the corresponding characteristic peaks in the characteristic spectrum or the fingerprint spectrum of the standard decoction.
The method for acquiring the characteristic spectrum or fingerprint spectrum of the standard decoction comprises the following steps: is prepared from the raw materials in the same batch as the material reference substance or preparation of the Chinese herbal compound.
The method for acquiring the characteristic spectrum or fingerprint spectrum of the standard decoction comprises the following steps: the method comprises the steps of detecting multiple batches of ancient decoction prepared from multiple batches of traditional Chinese medicine raw materials, obtaining characteristic spectrums or fingerprint spectrums of the multiple batches of ancient decoction, and obtaining standard characteristic spectrums or fingerprint spectrums by calculating the mean value of the characteristic spectrums or fingerprint spectrums of the multiple batches of ancient decoction, wherein the standard characteristic spectrums or fingerprint spectrums are the characteristic spectrums or fingerprint spectrums of the standard decoction.
The evaluation index also comprises one or more of cream yield, powder collection rate, volatile oil, pH value, index component content, index component transfer rate, characteristic spectrum or fingerprint spectrum similarity, infrared fingerprint spectrum similarity and ultraviolet spectrum consistency.
The paste yield of the substance reference substance or preparation is 70-130% of the paste yield of the standard decoction;
the content of the index component of the material reference substance or the preparation is 70-130% of the content of the index component in the standard decoction;
the transfer rate of the index component of the substance reference substance or the preparation is 70-130% of the transfer rate of the index component in the standard decoction;
the evaluation method of the volatile oil comprises the following steps: calculating the yield of volatile oil in the standard decoction, separately obtaining volatile oil in the process step of preparing the substance reference substance or preparation of the Chinese medicinal compound, and supplementing the content of volatile oil in the substance reference substance or preparation of the Chinese medicinal compound according to the yield of volatile oil in the standard decoction.
The evaluation indexes also comprise key quality attribute similarity coefficients of cream yield, powder collection rate, volatile oil, pH value, index component content and index component transfer rateS cqa (ii) a S using corresponding evaluation index cqa The process of evaluating the process is as follows: comparing the value of the evaluation index of the reference substance or preparation with the value of the corresponding evaluation index of the standard decoction, and selecting S with a value closer to 1 cqa The corresponding process is the best process.
The technical scheme of the invention has the following advantages:
1. the invention provides a process evaluation method of a substance reference substance object or a preparation of a traditional Chinese medicine compound, wherein a new evaluation index-key quality attribute similarity coefficient S is provided cqa The S of cqa S including at least a characteristic spectrum or a fingerprint spectrum cqa And S using characteristic spectrum or fingerprint spectrum cqa Procedure for evaluating process steps, and S of characteristic or fingerprint spectra cqa The acquisition process of (1). The invention passes through S of the characteristic spectrum or the fingerprint spectrum cqa The value can effectively evaluate the difference between the material basis contained in the product prepared by different production process steps and the material basis contained in the standard decoction, so as to realize the comprehensive evaluation of the contained material basis; due to S cqa The closer to the value 1, the smaller the difference in the corresponding material basis between the product and the standard decoction, and therefore, by employing the screening method, the most abundant and S cqa The process corresponding to the characteristic spectrum or the fingerprint spectrum with the value closer to the value 1 is used as an evaluation method, so that the comprehensive material basis comparison between each product and the standard decoction can be realized;
by performing a characteristic or fingerprint S on the product of each process step cqa The evaluation of the method can effectively reduce the difference between the substance basis of each product and the standard decoction in the intermediate process, further reduce the difference between the substance basis real object or preparation of the finally prepared traditional Chinese medicine compound and the substance basis of the traditional decoction, improve the consistency of clinical curative effect, and further improve the safety and the effectiveness of the substance basis real object or preparation of the prepared traditional Chinese medicine compound.
2. The evaluation index provided by the invention not only relates to the S of the characteristic spectrum or the fingerprint spectrum cqa And can also compriseThe consistency between the prepared material reference substance, compound preparation and traditional decoction can be ensured by paste rate, effective index component transfer rate, infrared fingerprint spectrum, ultraviolet spectrum, etc., or/and key quality attribute similarity coefficient S of paste yield, powder collection rate, volatile oil, pH value, index component content, index component transfer rate, etc cqa (ii) a The process steps are evaluated by adopting multidimensional evaluation indexes, so that the consistency of the material basis between a material reference substance or preparation prepared by the optimal process and the standard decoction can be better ensured, and the consistency of clinical curative effect is further improved.
Meanwhile, the process evaluation method can also monitor the quality of the substance reference substance or the preparation of the Chinese herbal compound, and ensure the stability of the quality between batches, thereby ensuring the safety and the effectiveness of the substance reference substance or the preparation of the Chinese herbal compound to the maximum extent.
3. The invention further provides a process for obtaining the standard decoction, and the standard decoction obtained by the evaluation method of the invention better conforms to the traditional Chinese medicine theory, can represent the clinical practical situation and further ensures the consistency of the clinical curative effect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a fingerprint of a standard decoction of the GANJIANGLINGZHU decoction of the present invention;
FIG. 2 is a control plot at different concentration temperatures for example 1 of the present invention;
FIG. 3 is a control spectrum for different drying modes in example 2 of the present invention;
FIG. 4 is a control map at various stages in example 3 of the present invention;
FIG. 5 shows the comparison spectra of infrared fingerprint spectra at different stages in example 3 of the present invention;
FIG. 6 is a comparative UV spectrum at various stages in example 3 of the present invention;
FIG. 7 shows S at different concentration temperatures in example 4 of the present invention cqa A line graph;
FIG. 8 is a control spectrum for different drying regimes in example 5 of the present invention;
FIG. 9 shows S in different drying modes in example 5 of the present invention cqa A line graph;
FIG. 10 is the standard fingerprint spectrum of the standard decoction of Linggui shugan decoction of the present invention.
Detailed Description
Example 1
The embodiment provides a process evaluation method of a substance reference substance of a traditional Chinese medicine compound, wherein the traditional Chinese medicine compound is gan Jiang Zhi Zhu Tang, the substance reference substance is a concentrated solution, and evaluation indexes comprise key quality attribute similarity coefficients S of a characteristic spectrum or a fingerprint spectrum cqa . Using an evaluation index S cqa The process for evaluating the preparation process of the substance reference substance comprises the following steps:
weighing liquorice, dried ginger, bighead atractylodes rhizome and poria cocos according to the dosage of the prescription of the gan Jiang Ling Zhu decoction, preparing the extract according to the extraction process of the ancient decoction, measuring 600ml of the extract to obtain 4 parts, setting the pressure to be 40Pa, respectively concentrating at 50 ℃,60 ℃, 70 ℃ and 80 ℃, respectively setting the theoretical value of the concentration volume to be 100ml (90-110 ml), respectively recording the concentration volume, and measuring S of the comparison map of the concentrated solution and the gan Jiang Ling Zhu decoction standard decoction cqa 。
In this embodiment, the extraction process of the extractive solution is the same as that of decoction of ancient formula, and S of the extractive solution is not required cqa However, when the extraction process of the extract is different from that of the ancient formula decoction, S of the extract needs to be obtained cqa And evaluating the extraction process to obtain the optimal extraction process. In the embodiment, the concentrated solution is only used as a test sample to carry out high performance liquid chromatography fingerprint detection on effective index components, and the detection process is as follows:
a chromatographic column which takes octadecylsilane chemically bonded silica as a filler is adopted, the length of the chromatographic column is 100mm, the inner diameter of the chromatographic column is 2.1mm, the granularity of the chromatographic column is 1.6 mu m, acetonitrile is taken as a mobile phase A, and a phosphoric acid solution with the volume concentration of 0.05 percent is taken as a mobile phase B; the sample amount is 5 mul; the column temperature is 30 ℃; the flow rate was 0.3ml per minute; detection wavelength: 237nm; the number of theoretical plates is not less than 8000 according to the peak of 6-gingerol. Gradient elution was performed as specified in table 1 below:
TABLE 1
Control solution: 6-gingerol was used as a control, and methanol was used to prepare a control solution with a concentration of 90. Mu.g/ml.
The preparation method of the test solution comprises the following steps: precisely measuring 2ml of the concentrated solution, placing in a 10ml measuring flask, adding methanol with appropriate solubility to scale, and making the alcohol content of the solution reach 45%, shaking, filtering, and collecting the filtrate.
The standard decoction is prepared from the same batch of raw materials, and the processing mode of the standard decoction before the machine detection is the same as that of a test sample.
Performing on-machine detection with the above test solution and standard decoction, obtaining fingerprint spectrum shown in fig. 1-2 by the above evaluation method, and calculating to obtain S of characteristic peaks with different numbers in table 2 according to the spectrum of fig. 1-2 cqa . Wherein, fig. 1 is a fingerprint obtained from a standard solution, and S1-S5 in fig. 2 are, from bottom to top: standard decoction at 50 deg.C, 60 deg.C, 70 deg.C, 80 deg.C.
S of control map cqa = relative peak area of S peak corresponding to each characteristic peak in sample/relative peak area of S peak corresponding to each characteristic peak in standard decoction; specifically, when the peak 18 shown in fig. 1 is used as the characteristic peak S, the relative peak areas of the characteristic peak and the peak S of each number in the corresponding fingerprint are calculated respectively, and then the relative peak area of one number in the fingerprint of the test sample is divided by the relative peak area of the corresponding number in the fingerprint of the standard decoction, for example, the relative peak area of the peak 1 in the fingerprint of the test sample and the relative peak area of the standard decoction are calculatedThe ratio of the relative peak areas of the No. 1 peak in the texture atlas is the S of the No. 1 peak cqa 。
TABLE 2 different concentration temperatures S cqa
The combination of the detection results shows that: at a concentration temperature of 60 deg.C, with S having a maximum amount and closer to a value of 1 cqa Therefore, for gan Jiang Ling Zhu Tang, the optimal process parameters at the concentration temperature of 60 ℃ were evaluated by the evaluation method of the present invention.
Example 2
The embodiment provides a process evaluation method of a substance reference substance of a traditional Chinese medicine compound, wherein the traditional Chinese medicine compound is gan Jiang Zhi Zhu Tang, the substance reference substance is dry powder, and evaluation indexes comprise key quality attribute similarity coefficients S of a characteristic spectrum or a fingerprint spectrum cqa . The process of evaluating the preparation process of the substance reference substance by adopting the evaluation indexes comprises the following steps:
weighing 16 parts of four ingredients of liquorice, dried ginger, bighead atractylodes rhizome and poria cocos according to the prescription dose of the gan Jiang Zhi Zhu Tang, preparing a concentrated solution according to the optimal process parameters preferably selected in the embodiment 1, measuring 3 parts of 300ml of the concentrated solution, and carrying out tests. And respectively measuring the fingerprint spectrums of the dried powder under different drying modes. The drying method in this example includes vacuum drying, atmospheric drying, and freeze drying.
Wherein, the temperature of the reduced pressure drying oven is set to 60 ℃ and the pressure is-0.1 MPa, 300ml of concentrated solution is loaded into a tray, and the equipment is opened for concentration. Drying under normal pressure, setting the temperature of a drying oven at 60 ℃, loading 300ml of concentrated solution into a tray under normal pressure, starting the equipment, and concentrating. Freeze drying sets control parameters, and starts the equipment. 300ml of the concentrated solution is filled into a freeze-drying tray and freeze-dried, and the main process parameters of the freeze-drying are shown in the following table 3:
TABLE 3
The product prepared by adopting the different drying processes is used as a test sample, and the fingerprint spectrum is detected by adopting the following method:
gradient elution was carried out using a chromatographic column having a column length of 150mm, an inner diameter of 2.1mm and a particle size of 1.9 μm, acetonitrile as a mobile phase A and a phosphoric acid solution of 0.05% by volume as a mobile phase B, according to the specifications in Table 4 below; the column temperature is 30 ℃; flow rate 0.6ml per minute; the sample amount is 2 mul; detection wavelength: 237nm. The number of theoretical plates is not less than 8000 according to the peak of 6-gingerol.
TABLE 4
Preparation of control solutions: 6-gingerol is used as a reference substance, and methanol is used for preparing a reference substance solution with the concentration of 100 mu g/ml.
Preparation of a test solution: taking about 0.3g of the rhizoma zingiberis and rhizoma atractylodis soup substance reference substance (dry powder), precisely weighing, placing in a conical flask with a plug, precisely adding 10ml of 50% methanol in volume concentration, weighing, ultrasonically treating for 10 minutes, cooling, weighing again, supplementing the lost weight with 50% methanol, shaking up, filtering, and taking the subsequent filtrate.
The fingerprint shown in FIG. 3 is obtained by the above detection method, and S of products obtained by different drying processes is calculated cqa As shown in table 5. In fig. 3, from bottom to top: standard decoction pattern, vacuum drying, drying under normal pressure, and freeze drying.
TABLE 5 different drying modesS cqa
The detection results show that: when the drying method is freeze drying, the product has S with the largest amount and closer to value 1 cqa Therefore, for gan jiang ling zhu tang, the method of the present invention is used to evaluate the optimal process when the drying method is freeze drying.
By adopting the same evaluation method as the embodiment, the technical parameters of the pre-freezing time, the temperature rise temperature, the temperature rise time and the like of the freeze drying can be effectively inspected, and the technical parameter conditions which enable the substance basis contained in the substance reference substance object of the traditional Chinese medicine compound to be basically consistent with the standard decoction are obtained. The optimal drying step can be obtained by the evaluation method of the invention under the following process conditions: freeze drying, and effective pre-freezing time is 5h, temperature rise is 30 ℃, and temperature rise time is 35h.
Example 3
This example uses different stages of material reference material obtained under the best conditions in examples 1 and 2 for validation. The optimal conditions are as follows: during concentration, the relative density of concentration at 60 ℃ is 1.04, and the concentration time is 2h; during freeze drying, the effective pre-freezing time is 5h, the temperature rise is 30 ℃, and the temperature rise time is 35h.
In this embodiment, the content of the effective index components of the substance reference material entity of three batches of gan jiang ling zhu tang in different stages (extraction, concentration, drying) is detected under the condition of the optimal parameters, and the detection process is as follows:
octadecylsilane chemically bonded silica is used as a filler; the column length of the content determination chromatographic column is 150mm, the inner diameter is 4.6mm, the granularity is 3.0 mu m, and the column temperature is 25 ℃; gradient elution was performed as specified in table 6 below; the sample amount is 5 mul; detection wavelength: 280nm; the flow rate was 1.0ml/min. In gradient elution, the mobile phase A is acetonitrile; the mobile phase B is a 0.05% concentration by volume phosphoric acid solution. The number of theoretical plates is not less than 5000 calculated by 6-gingerol peak.
TABLE 6
Preparation of control solutions: liquiritin, glycyrrhizic acid and 6-gingerol are used as reference substances, and methanol is used for preparing a reference substance solution with the concentration of 80 mug/ml.
The preparation method of the test solution comprises the following steps: precisely measuring 2ml of a substance reference substance (liquid or fluid extract) of GANJIANGLINGZHU decoction, placing in a 10ml measuring flask, adding methanol with appropriate solubility to scale to make the alcohol content of the solution reach 80%, shaking, filtering, and collecting the filtrate;
preparation of a test solution: taking about 0.5g of rhizoma Zingiberis recens-rhizoma Atractylodis decoction substance reference substance (semi-solid or solid state), precisely weighing, placing in a conical flask with a plug, precisely adding 20ml of 80% methanol, weighing, ultrasonically treating (power 200W, frequency 40 kHz) for 25 min, cooling, weighing again, supplementing the lost weight with 80% methanol, shaking, filtering, and taking the subsequent filtrate. Obtaining the transfer rates of the liquiritin, the glycyrrhizic acid and the 6-gingerol.
Under the condition of optimal parameters, the method for the characteristic spectrum or the fingerprint spectrum of the substance reference real object of the ganjiang ling shu decoction at different stages comprises the following steps:
gradient elution was carried out using a chromatographic column having a column length of 150mm, an inner diameter of 2.1mm and a particle size of 1.7 μm, acetonitrile as a mobile phase A and a phosphoric acid solution of 0.05% by volume as a mobile phase B, according to the specifications given in Table 7 below; the column temperature was 40 ℃; the flow rate was 0.2ml per minute; the sample injection amount is 4 mul; detection wavelength: 237nm. The number of theoretical plates is not less than 8000 according to the peak of 6-gingerol.
TABLE 7
Preparation of control solutions: 6-gingerol is used as a reference substance, and methanol is used for preparing a reference substance solution with the concentration of 80 mug/ml.
The preparation method of the test sample comprises the following steps: precisely measuring 2ml of substance reference substance (liquid or fluid extract) of GANJIANGLINGZHU decoction, placing in 10ml measuring flask, adding methanol with appropriate solubility to scale until the alcohol content of the solution reaches 50%, shaking, filtering, and collecting filtrate.
Preparation of a test solution: taking about 0.3g of a Ganjianling decoction substance reference substance (in a semi-solid or solid state), precisely weighing, placing in a conical flask with a plug, precisely adding 10ml of 50% methanol in volume concentration, weighing, ultrasonically treating for 10 minutes, cooling, weighing again, supplementing the weight loss with 50% methanol, shaking up, filtering, and taking a subsequent filtrate.
The characteristic spectrum or fingerprint spectrum of the three batches of gan Jiang Zhi Shu soup substance reference substance is obtained by the detection method, as shown in figures 4-6. In fig. 4, S1 to S4 are, from bottom to top: standard decoction map, decoction and filtration stage map, concentration stage map, and drying stage map; in fig. 5, from bottom to top: standard decoction, extracted, concentrated and dried infrared fingerprint spectrum contrast spectrum; in fig. 6, from bottom to top: standard decoction, extraction, concentration and drying.
Through detection, the following results are obtained: in the embodiment, the total powder recovery rates of the three batches of the substance reference material objects of the gan Jiang Ling Zhu Tang are respectively 19.52%, 19.86% and 20.49%, and the average value is 19.96%; the total transfer rates of liquiritin obtained by content detection and conversion of effective index components are 71.32%, 63.34% and 77.02%, respectively, and the average value is 70.56%; the total transfer rates of glycyrrhizic acid obtained by content detection and conversion of effective index components are 57.13%, 56.64% and 59.60%, respectively, and the average value is 57.79%; the total transfer rates of 6-gingerol obtained by conversion of content detection of effective index components are respectively 29.93%, 31.79% and 33.10%, and the average value is 31.61%. The results are all within the parameter range of quality control, so that the process evaluation method provided by the invention can be effectively used for evaluating the process steps to obtain the optimal process basically consistent with the material basis of the standard decoction.
Example 4
The embodiment is providedProvides a process evaluation method of a substance reference substance of a traditional Chinese medicine compound, wherein the traditional Chinese medicine compound is a tuckahoe, cinnamon, rhizoma glycyrrhizae decoction, the substance reference substance is a concentrated solution, and evaluation indexes comprise key quality attribute similarity coefficient S of a characteristic spectrum or a fingerprint spectrum cqa . S using evaluation index feature spectrum or fingerprint cqa The process for evaluating the preparation process of the substance reference substance comprises the following steps:
weighing Glycyrrhrizae radix, ramulus Cinnamomi, atractylodis rhizoma, and Poria according to the prescription of LINGGUISHUGUOGANTANG, adding 1200ml water, soaking for 30min before decocting, decocting with cover, boiling with strong fire, decocting with slow fire for 150min, decocting once, and filtering while hot to obtain filtrate. Mixing filtrates obtained by decocting for several times, weighing total 4 parts of mixed filtrate 600ml, concentrating at 50 deg.C, 60 deg.C, 70 deg.C and 80 deg.C respectively until the volume theoretical value is 100ml (90-110 ml), recording the concentrated volume respectively, and determining characteristic spectrum or S of fingerprint of the concentrated solution cqa 。
The detection method and chromatographic conditions of the characteristic spectrum or fingerprint spectrum detected by the concentrated solution in the embodiment are as follows:
and (3) chromatographic column: a chromatographic column using octadecylsilane chemically bonded silica as a filler; detection wavelength: 254nm; elution was carried out using acetonitrile as mobile phase a and 0.05% by volume phosphoric acid solution as mobile phase B according to the gradient elution procedure of table 8 below:
TABLE 8
The content of the mobile phase A is verified to be changed within +/-5% gradient by experiments, and the characteristic spectrum is not influenced.
In the detection of the characteristic map, the number of theoretical plates is not less than 5000 calculated according to glycyrrhizic acid, and the column temperature is 25 ℃; the sample amount is 2 mul; the flow rate was 0.2ml/min.
The results obtained by the above-described detection and calculation are shown in table 9 and fig. 7.
TABLE 9 concentration temperature investigation S cqa
The detection results show that: at a concentration temperature of 60 deg.C, with S having a maximum amount and closer to a value of 1 cqa Therefore, for the tuckahoe, cinnamon, rhizoma atractylodis and rhizoma glycyrrhizae decoction, the method for evaluating the tuckahoe, cinnamon, rhizoma atractylodis and rhizoma glycyrrhizae decoction is adopted to evaluate that the concentration temperature is 60 ℃ which is the best process parameter.
By adopting the quality control method, the invention can also effectively evaluate the process parameters such as the concentration volume, the concentration time and the like, and the optimal concentration process determined by the evaluation method of the invention is as follows: the concentration temperature is 60 ℃, the extract is concentrated from 600ml to 100ml, and the concentration time is not longer than 3h.
Example 5
The embodiment provides a process evaluation method of a substance reference substance of a traditional Chinese medicine compound, wherein the traditional Chinese medicine compound is a poria and cassia twig and rhizoma glycyrrhizae decoction, the substance reference substance is dry powder, and evaluation indexes comprise key quality attribute similarity coefficients S of characteristic spectrum or fingerprint spectrum cqa . The process of evaluating the preparation process of the substance reference substance by adopting the evaluation indexes comprises the following steps:
the mixed filtrate obtained in the embodiment 4 is concentrated at 60 ℃, each 600ml of the mixed filtrate is concentrated to a theoretical volume value of 100ml to obtain a concentrated solution, 3 parts of the concentrated solution are respectively dried in a 60 ℃ electric heating air blast drying oven, a 60 ℃ reduced pressure drying oven and a vacuum freeze dryer to obtain dry powder of the poria and cassia twig dry decoction, the fingerprint of the dry powder obtained by adopting the detection method same as the embodiment 4 is shown in a figure 8, and in the figure 8, S1, S2, S3 and S4 are respectively a standard decoction reference map, a normal pressure drying, a reduced pressure drying and a freeze drying substance reference physical feature map. Detecting fingerprint of dry powder obtained by different drying modes and standard decoction of LINGGUISHUGAN decoction, and calculating S cqa The results are shown in FIG. 9 and Table 10。
TABLE 10 examination of drying Pattern-S cqa
The detection results show that: when the drying method is freeze drying, the product has S with the largest amount and closer to value 1 cqa Therefore, for the linggui zhu gan tang, the best process step is to evaluate the drying method as freeze drying by the evaluation method of the present invention.
The invention also carries out repeated verification tests on the concentrated solution and the dry powder under the condition of the same process parameters for a plurality of times, and the verification proves that: the verified characteristic spectrums among multiple batches of concentrated solutions and among multiple batches of dry powders are consistent with the components of the characteristic spectrum of the standard decoction of the tuckahoe, cinnamon, atractylodes rhizome and licorice decoction, and the extraction, concentration and freeze-drying processes are stable and have reproducibility.
In conclusion: the invention can adopt fingerprint spectrum S cqa The consistency of the material basis between the product prepared by the preparation process and the standard decoction is evaluated, and the safety performance is improved.
In this embodiment, the method is used for calculating the fingerprint spectrum S cqa The number of the characteristic peaks can be all characteristic peaks marked in the fingerprint of the standard decoction, or part of characteristic peaks marked in the fingerprint of the standard decoction, and is used for calculating the fingerprint S cqa Should be no less than 60%, preferably 80% or more of the total number of all the characteristic peaks marked in the fingerprint of the standard decoction. In this embodiment, the method is used for calculating the fingerprint spectrum S cqa Should not be less than 100% of the total number of all characteristic peaks labeled in the fingerprint of the standard decoction.
Example 6
This example provides two methods for obtaining the fingerprint of the standard decoction, one method is to directly use the same batch of raw materials as the material standard substance or preparation of the herbal compound, such as the fingerprint of the standard decoction used in examples 1-3. Meanwhile, the fingerprint of the standard decoction can also be detected by using multiple batches of ancient decoction prepared from multiple batches of traditional Chinese medicine raw materials, the obtained characteristic spectrum or fingerprint of the multiple batches of ancient decoction is obtained, and a standard characteristic spectrum or fingerprint is obtained by performing mean value calculation on the characteristic spectrum or fingerprint of the multiple batches of ancient decoction, wherein the standard characteristic spectrum or fingerprint is the characteristic spectrum or fingerprint of the standard decoction, such as the fingerprint of the standard decoction adopted in the embodiment 4-5.
The specific acquisition process of the fingerprint of the standard decoction adopted in the embodiment 4-5 is as follows:
after the 15 batches of standard decoction of linguizhu gan decoction are detected by the same characteristic spectrum or fingerprint detection method in example 4, the average value of the relative peak areas of 20 characteristic peaks in the 15 batches of linguizhu gan decoction standard decoction is calculated, and the average value of the relative peak areas of the 15 batches of linguizhu gan decoction standard decoction is used as the relative peak area of the standard characteristic spectrum or fingerprint of the linguizhu gan decoction standard decoction, as shown in the following tables 11 and 12:
TABLE 11
TABLE 12
The standard fingerprint obtained from the above 15 batches of standard decoction of LINGGUISHUGAN decoction is shown in FIG. 10.
Example 7
In order to better evaluate the process steps and the process parameters, the method of the invention not only passes through the S of the characteristic spectrum or the fingerprint spectrum of the product in each process step cqa Besides the process evaluation, the process steps and the process parameters can be evaluated through other evaluation indexes.
The evaluation indexes of the supplementary evaluation include, but are not limited to, cream yield, powder collection rate, volatile oil, pH value, index component content, index component transfer rate, feature spectrum or fingerprint spectrum similarity, infrared fingerprint spectrum similarity, ultraviolet spectrum consistency and the like. Wherein, when the cream yield is adopted for evaluation, the cream yield of the substance reference substance or the preparation is 70-130% of the standard decoction cream yield; when the content of the index components is adopted for evaluation, the content of the index components of the material reference substance or the preparation is 70% -130% of the content of the index components in the standard decoction; when the transfer rate of the index components is adopted for evaluation, the transfer rate of the index components of the substance reference substance or the preparation is 70-130% of the transfer rate of the index components in the standard decoction; when volatile oil is adopted for evaluation: respectively calculating the yields of the essential oil in the substance reference substance or preparation and the standard decoction, if the yield of the essential oil in the substance reference substance or preparation is reduced, separately obtaining the essential oil in the process step of preparing the substance reference substance or preparation of the Chinese medicinal compound, and then supplementing the content of the essential oil in the substance reference substance or preparation of the Chinese medicinal compound according to the yield of the essential oil in the standard decoction.
Meanwhile, the evaluation indexes of the supplementary evaluation can also comprise key quality attribute similarity coefficients S of cream yield, powder collection rate, volatile oil, pH value, index component content and index component transfer rate cqa . The key quality attribute similarity coefficient S cqa Dividing the numerical value of one evaluation index of the substance reference substance or preparation with the numerical value of the corresponding evaluation index of the standard decoction; for example: cream yield S cqa = product removal in process stepPaste rate/standard decoction yield; powder collection rate S cqa = powder yield of product in process step/powder yield of standard decoction; volatile oil S cqa = the volatile oil content of the product in the process step/the volatile oil content of the standard decoction; pH value S of the product cqa = pH of product in process step/pH of standard decoction; index component content S cqa = index ingredient content of product in process step/index ingredient content of standard decoction; index component transfer rate S cqa = index component transfer rate of product in process step/index component transfer rate of standard decoction. S using corresponding evaluation index cqa The process of evaluating the process is as follows: selecting S with closer value to 1 cqa The corresponding process is the best process.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. And obvious variations or modifications derived therefrom are intended to be within the scope of the invention.
Claims (11)
1. A process evaluation method for substance reference substance or preparation of Chinese herbal compound is characterized by comprising the step of evaluating products obtained in any process step in the preparation process by adopting evaluation indexes, wherein the evaluation indexes at least comprise key quality attribute similarity coefficients S of characteristic spectrum or fingerprint cqa (ii) a Screening out the largest amount of S cqa The value is closer to the value 1, namely the characteristic spectrum or the fingerprint spectrum corresponding to the process;
s of the characteristic spectrum or fingerprint spectrum cqa The acquisition process comprises the following steps: respectively obtaining a characteristic spectrum or a fingerprint spectrum of a standard decoction, a test sample and a reference substance, wherein the standard decoction is a decoction of a Chinese herbal compound, the test sample is a product obtained by any process step in the preparation process, and the reference substance is at least one component in the standard decoction; one component in the reference substance is used as indexMarking a characteristic peak corresponding to the index component in a characteristic spectrum or a fingerprint spectrum of a standard decoction and a test sample, adopting the characteristic peak corresponding to the index component as an S peak, obtaining the relative peak area of each characteristic peak relative to the S peak displayed in the characteristic spectrum or the fingerprint spectrum, then calculating the ratio of the relative peak areas of each corresponding characteristic peak in the test sample and the standard decoction, wherein the ratio is the S peak of the characteristic spectrum or the fingerprint spectrum cqa ；
When the traditional Chinese medicine compound is Ganyang Lingzhu decoction, in the detection of characteristic spectrum or fingerprint spectrum, a chromatographic column using octadecylsilane chemically bonded silica as a filler is adopted, the length of the chromatographic column is 100mm, the inner diameter is 2.1mm, the granularity is 1.6 mu m, acetonitrile is used as a mobile phase A, and a phosphoric acid solution with the volume concentration of 0.05% is used as a mobile phase B; gradient elution was performed as specified in the following table:
when the traditional Chinese medicine compound is the poria and cassia twig decoction, in the detection of the characteristic spectrum or the fingerprint spectrum, a chromatographic column which takes octadecylsilane chemically bonded silica as a filler, acetonitrile as a mobile phase A and a phosphoric acid solution with the volume concentration of 0.05 percent as a mobile phase B are adopted; gradient elution was performed as specified in the following table:
2. the method for evaluating substance-based substance or preparation of Chinese herbal compound according to claim 1, wherein S of characteristic spectrum or fingerprint spectrum is adopted cqa Evaluating all processes of a substance reference substance or a preparation of the traditional Chinese medicine compound; the method comprises the following steps: all the process steps of obtaining substance reference substance or preparation of Chinese herbal compound are carried out, the detection of characteristic spectrum or fingerprint spectrum is carried out on the product generated in each step according to the sequence of all the process steps, and the characteristic spectrum or S of the fingerprint spectrum of the product in the corresponding step is obtained cqa According to the characteristic spectrum or fingerprint spectrum S cqa And screening the process steps corresponding to the characteristic spectrum or the fingerprint spectrum with the largest quantity and closer to the numerical value 1.
3. The method for evaluating the process of the substance reference substance or the preparation of the traditional Chinese medicine compound according to claim 1 or 2, wherein the substance reference substance of the traditional Chinese medicine compound is any one of a concentrated solution, an extract or a powder; the Chinese medicinal compound preparation is any one of tablets, pills, powder, granules, injections, tinctures, solutions, extracts and ointments.
4. The method for evaluating the substance reference substance or the preparation of the compound traditional Chinese medicine according to claim 3, wherein when the substance reference substance of the compound traditional Chinese medicine is a concentrated solution or an extract, all the process steps for preparing the substance reference substance of the compound traditional Chinese medicine sequentially comprise an extraction step and a concentration step; firstly, extracting to obtain extractive solution, and obtaining S of the extractive solution cqa According to S cqa Screening out the optimal process of the extraction step; then adopting the extract obtained by the optimal process of the extraction step to concentrate to obtain concentrated solution or extract, and obtaining S of the concentrated solution or extract cqa According to S cqa Screening out the optimal process of the concentration step.
5. The method for evaluating the process of a substance reference substance or a preparation of a traditional Chinese medicine compound according to claim 3, wherein when the substance reference substance of the traditional Chinese medicine compound is powder, all the process steps for preparing the substance reference substance of the traditional Chinese medicine compound sequentially comprise an extraction step, a concentration step and a drying step; firstly, extracting to obtain extractive solution, and obtaining S of the extractive solution cqa According to S cqa Screening out the optimal process of the extraction step; then concentrating the extract obtained by the optimal extraction process to obtain a concentrated solution, and obtaining S of the concentrated solution cqa According to S cqa Optimum process for screening out concentration step(ii) a Finally drying the concentrate obtained by the optimum process of the concentration step to obtain powder, and obtaining S of the powder cqa According to S cqa And screening out the optimal process of the drying step.
6. The method for evaluating the substance reference substance or the preparation of the compound traditional Chinese medicine according to claim 3, wherein when the preparation of the compound traditional Chinese medicine is a granule, all the process steps for preparing the preparation of the compound traditional Chinese medicine sequentially comprise an extraction step, a concentration step, a drying step and a granulation step; firstly, extracting to obtain extractive solution, and obtaining S of the extractive solution cqa According to S cqa Screening out the optimal process of the extraction step; then concentrating the extract obtained by the optimal extraction process to obtain a concentrated solution, and obtaining S of the concentrated solution cqa According to S cqa Screening out the optimal process of the concentration step; then drying the concentrated solution obtained by the optimum process of the concentration step to obtain powder, and obtaining S of the powder cqa According to S cqa Screening out the optimal process of the drying step; finally granulating the powder obtained by the optimum process of the drying step to obtain granules, and obtaining S of the granules cqa According to S cqa Screening out the optimal process of the granulation step.
7. The method for evaluating substance reference substance or preparation of Chinese herbal compound according to claim 1 or 2,
the detection method of the characteristic spectrum or the fingerprint spectrum is a high performance liquid chromatography, and the relative retention time of the characteristic spectrum or the characteristic peak in the fingerprint spectrum of the test sample is within +/-10% of the relative retention time of the corresponding characteristic peak in the characteristic spectrum or the fingerprint spectrum of the standard decoction.
8. The method for evaluating the process of the substance reference substance or the preparation of the compound traditional Chinese medicine according to claim 1 or 2, wherein the method for acquiring the characteristic spectrum or the fingerprint spectrum of the standard decoction comprises the following steps: is prepared by adopting raw materials with the same batch as the material reference substance or preparation of the Chinese herbal compound;
or detecting multiple batches of decoction prepared from multiple batches of traditional Chinese medicine raw materials to obtain characteristic spectrums or fingerprint spectrums of the multiple batches of decoction, and calculating the mean value of the characteristic spectrums or fingerprint spectrums of the multiple batches of decoction to obtain standard characteristic spectrums or fingerprint spectrums, wherein the standard characteristic spectrums or fingerprint spectrums are the characteristic spectrums or fingerprint spectrums of the standard decoction.
9. The method for evaluating the substance-based substance or preparation of a herbal compound according to claim 1 or 2, wherein the evaluation index further comprises one or more of cream yield, powder collection rate, volatile oil, pH value, index component content, index component transfer rate, feature spectrum or fingerprint similarity, infrared fingerprint similarity, and ultraviolet spectrum consistency.
10. The method for evaluating the process of a substance-based substance or a preparation of a compound Chinese medicine according to claim 9, wherein the cream yield of the substance-based substance or the preparation is 70% -130% of the cream yield of a standard decoction;
the content of the index component of the substance reference substance or the preparation is 70-130% of the content of the index component in the standard decoction;
the transfer rate of the index component of the substance reference substance or the preparation is 70-130% of the transfer rate of the index component in the standard decoction;
the evaluation method of the volatile oil comprises the following steps: calculating the yield of volatile oil in the standard decoction, separately obtaining volatile oil in the process step of preparing the substance reference substance or preparation of the Chinese medicinal compound, and supplementing the content of volatile oil in the substance reference substance or preparation of the Chinese medicinal compound according to the yield of volatile oil in the standard decoction.
11. The method for evaluating the substance reference substance or preparation of Chinese herbal compound according to claim 1 or 2, wherein the evaluation is performedThe indexes also comprise key quality attribute similarity coefficient S of one or more of cream yield, powder collecting rate, volatile oil, pH value, index component content and index component transfer rate cqa (ii) a Selecting S with a value closer to 1 cqa The corresponding process is the best process.
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