CN117761172A - Method for researching effective components of six-ingredient qi-tonifying formula and application - Google Patents
Method for researching effective components of six-ingredient qi-tonifying formula and application Download PDFInfo
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Abstract
The invention provides a method for researching effective components of a six-ingredient qi-tonifying formula, which comprises the following steps: the research method of the invention highlights clinical application, reveals the biological essence corresponding to the six qi-tonifying formulas as a tie, actively discusses the core molecular mechanism of the six qi-tonifying formulas for treating COPD, has definite research target and innovativeness. The scheme design takes the prevention and treatment of the slow-retention lung as the primary, reflects the intervention and management of the slow-retention lung in stages and symptoms, highlights the clinical application, and reflects the diagnosis and treatment based on syndrome differentiation and the original thinking of the disease in combination with the traditional Chinese medicine. The UPLC-Q/TOF-MS technology is adopted to characterize the extract and blood entering components of the six-ingredient qi-tonifying prescription, the effective component group of the Xinan six-ingredient qi-tonifying prescription is panoramically depicted, the pharmacodynamics study of slow-resistance lung and urine metabonomics are combined, the action mechanism is explained, and the pharmacodynamic substance basis of the traditional Chinese medicine is revealed from the component-pharmacodynamic combination layer.
Description
Technical Field
The invention relates to the technical field of traditional Chinese medicine component researches, in particular to a method for researching effective components of a six-ingredient qi-tonifying formula and application thereof.
Background
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD, simply slow obstructive pulmonary) is a major disease with high global morbidity, disability rate and mortality. According to the Chinese chronic obstructive pulmonary disease grading diagnosis and treatment report (2020), nearly 1 hundred million chronic obstructive pulmonary patients exist in China, the proportion of the high risk group with chronic obstructive pulmonary disease of 40 years old and older is 20.51%, and the prevalence of the chronic obstructive pulmonary disease of the high risk group is 33.4%. The prevalence of slow lung resistance is obviously rising, and the prevention and treatment situation is severe.
The syndrome of lung qi deficiency is the fundamental factor of the occurrence and development of lung diseases such as COPD, and the symptoms of persistent disease and qi impairment due to chronic disease, which causes qi deficiency of the lung and kidney, loss of lung to treat joint, loss of kidney to seal and accumulation, blood stasis due to the non-circulation of blood, phlegm-fluid retention due to abnormal metabolism of body fluid, blood stasis, turbid phlegm and water retention with staggering. The method takes the root-strengthening and primordial qi-banking ideas as guidance, takes the root-strengthening and primordial qi-banking as a method, has the root-strengthening key on lung, spleen and kidney, has the root-strengthening key on qi-tonifying, mainly on qi of lung, spleen and kidney, and has a certain curative effect on lung diseases such as COPD by six qi-tonifying formulas developed under the guidance of the root-strengthening and primordial qi-banking ideas.
The traditional Chinese medicine effectiveness research is guided by the dialectical ideas of traditional Chinese medicine, and is usually carried out by extracting effective part compound groups or monomer compounds in the traditional Chinese medicine by adopting a phytochemistry method, determining the effective part compound groups or monomer compounds through pharmacological experiments, and finally transitioning to clinical experiments. Because of the complex and diverse ingredients in the traditional Chinese medicine formula, the drug effect substance base is complex, thereby causing the blurring of the action mechanism of the traditional Chinese medicine. Therefore, the treatment effect of the effective components in the six qi tonifying formulas on related diseases is comprehensively studied, and the method has important clinical significance; and the basic research of the substances which play a key medicinal effect is particularly important for deeply analyzing the mechanism researches such as target paths of the disease treatment, so that technical support is provided for secondary development of traditional Chinese medicines and research and development of innovative medicines, and modernization of the traditional Chinese medicines is promoted.
Disclosure of Invention
The technical problem solved by the invention is to provide a method for researching effective components of the six-ingredient qi-tonifying formula, and reveal the correlation of the basic-activity-efficacy of the effective substances of the six-ingredient qi-tonifying formula for treating COPD so as to solve the problems in the prior art.
The technical problems solved by the invention are realized by adopting the following technical scheme: a method for researching effective components of six-ingredient qi-tonifying formula comprises the following steps: ginseng, astragalus root, fructus alpiniae oxyphyllae, fragrant solomonseal rhizome, dried orange peel and cinnamon, and the research comprises the following aspects:
basic research of drug effect substances of six-ingredient qi-tonifying formula:
(1) Six-flavor air supplementing method in vitro chemical component analysis based on UPLC-QE-Orbitrap-MS technology;
(2) Analysis of transitional components in the blood of the six-ingredient qi-tonifying prescription based on UPLC-Q-TOF-MS technology;
(3) Screening drug effect substances of six qi tonifying formulas based on network target analysis and molecular docking technology;
research on new medicine components of the six-ingredient qi-tonifying formula:
(1) Reproducing a slow-resistance lung evolution model of a lung organoid micro-physiological system;
(2) The systematic evaluation system of the slow-blocking lung organoid Chinese herbal compound is innovated, and the new medicine components are defined;
the quality evaluation of the effective components of the six-ingredient qi supplementing formula:
(1) Identifying and separating effective components and doped components of the traditional Chinese medicine by a Surface Enhanced Raman Spectroscopy (SERS) technology;
(2) The assignment of the peak spectrum of the traditional Chinese medicine is measured by a Surface Enhanced Raman Spectroscopy (SERS) technology.
As a further scheme of the invention: six-ingredient qi-tonifying prescription based on UPLC-QE-Orbitrap-MS technology is subjected to external chemical component analysis, the six-ingredient qi-tonifying prescription is ground, precisely weighed, and subjected to preliminary pretreatment such as dissolution, ultrasonic extraction, centrifugation, supernatant taking and the like to prepare a sample solution and a corresponding reference solution;
the method comprises the steps of (1) characterizing chemical components of two sides by adopting an ultra-high performance liquid chromatography-quaternary rod-electrostatic orbit tandem high resolution mass spectrometry (UPLC-QE-Orbitrap-MS) technology; the obtained RAW data in RAW format is processed by Compound Discoverer software, and is identified with the accurate quality, element composition, isotope spectrum and MS2 spectrum of the mzCloud database and the TCM library database, and each chromatographic peak is primarily identified; comparing the fragment ion information obtained by Xcalibur software with MS2 and MASBANK databases of the reference substances, further deducing and confirming the compounds, summarizing the cracking rule of the compounds, analyzing the chemical components of the six-ingredient qi-supplementing in vitro pharmacodynamic substances, and laying a foundation for screening the in-vivo components.
As a further scheme of the invention: the analysis of transitional components in the blood of the six-ingredient air-supplementing prescription based on the UPLC-Q-TOF-MS technology, the high-throughput rapid analysis of the chemical components of the six-ingredient air-supplementing prescription based on the UPLC-QE-Orbitrap-MS technology, the analysis of the retention time, the mass-to-core ratio, the fragment ion and other information of the blood components of the six-ingredient air-supplementing prescription combined with the ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) technology, and the comparison, calculation and estimation of the differential substances in the prescription are carried out with the information in a database or a literature to obtain the detailed information of the prototype components and the blood components, so that the potential metabolic pathways and targets of the six-ingredient air-supplementing prescription in vivo after oral administration are further estimated.
As a further scheme of the invention: the method comprises the steps of screening drug effect substances of six qi-tonifying formulas based on network target analysis and molecular docking technology, taking transitional components in blood as a basis, performing component-disease action target correlation analysis on blood components of the six qi-tonifying formulas and COPD diseases, predicting the material basis of the formulas for treating COPD by constructing a core target-component network, performing molecular docking on the predicted active components and targets for treating COPD, and selecting components with high matching degree as potential drug effect substances.
The UPLC-Q/TOF-MS technology is adopted to characterize the extracting solution and blood entering components of the six-ingredient qi-tonifying prescription, the effective component group of the six-ingredient qi-tonifying prescription is depicted in a panoramic manner, the pharmacodynamics study of the slow-resistance lung and the urine metabonomics are combined, the action mechanism is explained, and the pharmacodynamic substance basis of the traditional Chinese medicine is revealed from the component-pharmacodynamic combination level.
As a further scheme of the invention: a slow-drag lung evolution model for reproducing a lung organoid micro-physiological system, comprising the steps of:
(1) The manufacturing method of the micro-fluidic chip comprises the following steps: the microfluidic chip devices are all manufactured by using a classical soft lithography method, and the manufacturing process mainly comprises mask design, template manufacture and chip processing.
(2) And manufacturing a PDMS gasket: preparing PDMS working solution, drying, cutting into strips, dripping the working solution, baking, cutting, perforating, immersing in 75% alcohol solution, vacuumizing and airing for standby.
(3) Building a lung organoid 3D model: adding the primary cell suspension from the normal lung tissue into matrigel, then inoculating with matrigel mixed solution, solidifying, slowly adding into organoid complete culture medium, collecting organoids to microfluidic chip when organoids are all larger than 50 mu and the size is not increased, and performing subsequent experiments.
(4) Slow-blocking lung organoid platform construction: based on a lung organoid 3D model, a modern technical means is adopted to construct a chronic obstructive pulmonary organoid model of the COPD lung-kidney qi deficiency syndrome.
As a further scheme of the invention: the systematic evaluation system of the slow-blocking lung organoid Chinese herbal compound is innovated, and the new medicine components are defined, and the method comprises the following steps:
(1) The UPLC-QTOF/MS is adopted to screen the blood active ingredients of the six-ingredient qi supplementing prescription, and the drug effect is defined based on the lung organoid level of COPD: and screening active monomer components with higher blood content and stable property by adopting UPLC-QTOF/MS results, detecting the drug effect of candidate components through a COPD lung organoid model, retaining the components with obvious drug effect, eliminating the components with insignificant effect or no drug effect, and locking the components into the blood active components.
(2) Optimizing the combination arrangement of the active ingredients of the traditional Chinese medicine, and defining the efficacy: the active ingredients are combined by adopting network pharmacology, bioinformatics and orthogonal design means, and pharmacodynamics detection is carried out through a COPD lung organoid model, so that the optimal effective ingredient group of the 'synergistic' COPD resisting effect is screened.
(3) The system reveals the relationship between the pharmacodynamic substance basis, activity and efficacy of the traditional Chinese medicine compound for treating COPD: through a small molecule binding experiment, a protein target point of the action of the related active pharmaceutical ingredients is clear; and the structural biological method can be used for analyzing the crystal structure of the medicinal component-protein complex, and simultaneously combining related mutants to explore the influence of the active component on the target function.
As a further scheme of the invention: the method comprises the steps of identifying and separating active ingredients and doped ingredients of traditional Chinese medicines by a Surface Enhanced Raman Spectroscopy (SERS) technology, respectively separating chemical ingredients of the six-ingredient air supplementing formula by adopting a preferable silver sol as an enhanced substrate and adopting TCL as a detection method, identifying the separated microelements by using the SERS technology, and detecting the doped chemical ingredients of the six-ingredient air supplementing formula by adopting the TCL-SERS technology.
As a further scheme of the invention: measuring the attribution of the peak spectrum of the traditional Chinese medicine by a Surface Enhanced Raman Spectroscopy (SERS) technology, respectively detecting the samples of the six qi supplementing formulas by using a gold film, silver nano particles and a gold film-silver nano particle enhanced substrate, and observing the Raman signal of the medicine by using the SERS technology to obtain the attribution of the initial peak spectrum of the samples.
As a further scheme of the invention: the six-ingredient qi-supplementing formula also comprises the following steps of:
(1) Rationality study of the formulation: carrying out literature analysis and research on six qi tonifying formulas, carrying out systematic summary and inductive analysis on the aspects of clinical information, chemical components, extraction and separation methods, pharmacological actions and the like of the six qi tonifying formulas, and determining the rationality of the formulas from the aspect of literature analysis; the content change of main chemical components in the compatibility process of the six-ingredient qi-tonifying formula is researched, and the rationality of the six-ingredient qi-tonifying formula is researched from the angle of the component change of compatibility indexes;
(2) And (3) preparation process research: the water absorption of the inspected traditional Chinese medicine decoction pieces is optimized by a comprehensive evaluation method; the method comprises the steps of taking the dry paste yield and the content of certain index components of a six-ingredient qi supplementing formula as evaluation indexes, comparing the impurity removal effects of different methods of the water extract, selecting the optimal refining process, and screening the most effective drying method based on the optimal refining process; through examining the novel auxiliary materials, taking particle formability, moisture absorption rate, bulk density and repose angle as indexes, optimizing the optimal auxiliary materials and proper auxiliary material dosage, and screening the most effective granulating method;
(3) Quality standard research: carrying out thin-layer identification research on the six medicinal materials in the recipe of tonifying qi, and simultaneously preparing corresponding odor-lacking negative control solution to prove the specificity of the method; checking the moisture, the difference of the filling amount, the disintegration time limit, the heavy metal, the salt and the microorganism limit checking method of the six-ingredient qi-tonifying formula according to various regulations related to the capsule item in Chinese pharmacopoeia; referring to the Chinese pharmacopoeia and related literature data, a plurality of components are quantified simultaneously by adopting an HPLC method, and fingerprint patterns of the six-ingredient qi tonifying formula are researched;
(4) Preliminary stability test: according to the relevant regulations of the technical requirement of the quality stability research of the new traditional Chinese medicine in the technical requirement of the research of the new traditional Chinese medicine issued by the national food and drug administration, the stability test is carried out on the six qi tonifying formulas, and the key investigation items comprise the investigation of the appearance, the color and luster of the content, the related substances, the disintegration time limit or dissolution, the moisture and the like of the product;
(5) Homogeneity inspection: and (3) measuring and analyzing the uniformity of the quality of the six-ingredient qi supplementing formula among different batches by adopting an HPLC method.
Compared with the prior art, the invention has the beneficial effects that: the six Chinese medicinal herbs for tonifying qi comprise ginseng, astragalus root, fructus alpiniae oxyphyllae, rhizoma polygonati, dried orange peel and cinnamon, and are mainly used for treating the lung-kidney qi deficiency syndrome of COPD, and clinical observation shows that the Chinese medicinal herbs can delay the lung function decline of patients to different degrees, enhance the immunity, reduce the lung inflammatory response and reduce the acute exacerbation times.
The research method of the invention highlights clinical application, reveals the biological essence corresponding to the six qi-tonifying formulas as a tie, actively discusses the core molecular mechanism of the six qi-tonifying formulas for treating COPD, has definite research targets and innovative research ideas. The scheme design takes the prevention and treatment of the slow-retention lung as the primary, reflects the intervention and management of the slow-retention lung in stages and symptoms, highlights the clinical application, and reflects the diagnosis and treatment based on syndrome differentiation and the original thinking of the disease in combination with the traditional Chinese medicine. The UPLC-Q/TOF-MS technology is adopted to characterize the extracting solution and blood entering components of the six-ingredient qi-tonifying prescription, the effective component group of the six-ingredient qi-tonifying prescription is depicted in a panoramic manner, the pharmacodynamics study of the slow-resistance lung and the urine metabonomics are combined, the action mechanism is explained, and the pharmacodynamic substance basis of the traditional Chinese medicine is revealed from the component-pharmacodynamic combination level. The new medicine component researches reproduce a lung organoid slow resistance lung evolution model, pharmacodynamics detection is carried out through a COPD lung organoid model, and then the optimal effective component for resisting COPD effect is screened, and the pharmacodynamic substance basis-activity-efficacy relevance of the traditional Chinese medicine compound for treating COPD is revealed; surface enhanced raman spectroscopy evaluates the overall effective components.
Drawings
FIG. 1 is a technical roadmap of the content of the study of the present invention.
Detailed Description
The invention is further described with reference to the following detailed drawings in order to make the implementation, the creation characteristics, the achievement of the purpose and the effect of the invention easy to understand.
As shown in fig. 1, the embodiment provides a method for researching effective components of six-ingredient qi-tonifying formula, wherein the traditional Chinese medicine composition of the six-ingredient qi-tonifying formula is as follows: ginseng, astragalus root, fructus alpiniae oxyphyllae, fragrant solomonseal rhizome, dried orange peel and cinnamon, and the research comprises the following aspects:
basic research of drug effect substances of six-ingredient qi-tonifying formula:
(1) Six-flavor air supplementing method in vitro chemical component analysis based on UPLC-QE-Orbitrap-MS technology;
(2) Analysis of transitional components in the blood of the six-ingredient qi-tonifying prescription based on UPLC-Q-TOF-MS technology;
(3) Screening drug effect substances of six qi tonifying formulas based on network target analysis and molecular docking technology;
research on new medicine components of the six-ingredient qi-tonifying formula:
(1) Reproducing a slow-resistance lung evolution model of a lung organoid micro-physiological system;
(2) The systematic evaluation system of the slow-blocking lung organoid Chinese herbal compound is innovated, and the new medicine components are defined;
the quality evaluation of the effective components of the six-ingredient qi supplementing formula:
(1) Identifying and separating effective components and doped components of the traditional Chinese medicine by a Surface Enhanced Raman Spectroscopy (SERS) technology;
(2) The assignment of the peak spectrum of the traditional Chinese medicine is measured by a Surface Enhanced Raman Spectroscopy (SERS) technology.
Six-ingredient qi-tonifying prescription based on UPLC-QE-Orbitrap-MS technology is subjected to external chemical component analysis, the six-ingredient qi-tonifying prescription is ground, precisely weighed, and subjected to preliminary pretreatment such as dissolution, ultrasonic extraction, centrifugation, supernatant taking and the like to prepare a sample solution and a corresponding reference solution;
the method comprises the steps of (1) characterizing chemical components of two sides by adopting an ultra-high performance liquid chromatography-quaternary rod-electrostatic orbit tandem high resolution mass spectrometry (UPLC-QE-Orbitrap-MS) technology; the obtained RAW data in RAW format is processed by Compound Discoverer software, and is identified with the accurate quality, element composition, isotope spectrum and MS2 spectrum of the mzCloud database and the TCM library database, and each chromatographic peak is primarily identified; comparing the fragment ion information obtained by Xcalibur software with MS2 and MASBANK databases of the reference substances, further deducing and confirming the compounds, summarizing the cracking rule of the compounds, analyzing the chemical components of the six-ingredient qi-supplementing in vitro pharmacodynamic substances, and laying a foundation for screening the in-vivo components.
The analysis of transitional components in the blood of the six-ingredient air-supplementing prescription based on the UPLC-Q-TOF-MS technology, the high-throughput rapid analysis of the chemical components of the six-ingredient air-supplementing prescription based on the UPLC-QE-Orbitrap-MS technology, the analysis of the retention time, the mass-to-core ratio, the fragment ion and other information of the blood components of the six-ingredient air-supplementing prescription combined with the ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) technology, and the comparison, calculation and estimation of the differential substances in the prescription are carried out with the information in a database or a literature to obtain the detailed information of the prototype components and the blood components, so that the potential metabolic pathways and targets of the six-ingredient air-supplementing prescription in vivo after oral administration are further estimated.
The method comprises the steps of screening drug effect substances of six qi-tonifying formulas based on network target analysis and molecular docking technology, taking transitional components in blood as a basis, performing component-disease action target correlation analysis on blood components of the six qi-tonifying formulas and COPD diseases, predicting the material basis of the formulas for treating COPD by constructing a core target-component network, performing molecular docking on the predicted active components and targets for treating COPD, and selecting components with high matching degree as potential drug effect substances.
The UPLC-Q/TOF-MS technology is adopted to characterize the extracting solution and blood entering components of the six-ingredient qi-tonifying prescription, the effective component group of the six-ingredient qi-tonifying prescription is depicted in a panoramic manner, the pharmacodynamics study of the slow-resistance lung and the urine metabonomics are combined, the action mechanism is explained, and the pharmacodynamic substance basis of the traditional Chinese medicine is revealed from the component-pharmacodynamic combination level.
A slow-drag lung evolution model for reproducing a lung organoid micro-physiological system, comprising the steps of:
(1) The manufacturing method of the micro-fluidic chip comprises the following steps: the microfluidic chip devices are all manufactured by using a classical soft lithography method, and the manufacturing process mainly comprises mask design, template manufacture and chip processing.
(2) And manufacturing a PDMS gasket: preparing PDMS working solution, drying, cutting into strips, dripping the working solution, baking, cutting, perforating, immersing in 75% alcohol solution, vacuumizing and airing for standby.
(3) Building a lung organoid 3D model: adding the primary cell suspension from the normal lung tissue into matrigel, then inoculating with matrigel mixed solution, solidifying, slowly adding into organoid complete culture medium, collecting organoids to microfluidic chip when organoids are all larger than 50 mu and the size is not increased, and performing subsequent experiments.
(4) Slow-blocking lung organoid platform construction: based on a lung organoid 3D model, a modern technical means is adopted to construct a chronic obstructive pulmonary organoid model of the COPD lung-kidney qi deficiency syndrome.
The systematic evaluation system of the slow-blocking lung organoid Chinese herbal compound is innovated, and the new medicine components are defined, and the method comprises the following steps:
(1) The UPLC-QTOF/MS is adopted to screen the blood active ingredients of the six-ingredient qi supplementing prescription, and the drug effect is defined based on the lung organoid level of COPD: and screening active monomer components with higher blood content and stable property by adopting UPLC-QTOF/MS results, detecting the drug effect of candidate components through a COPD lung organoid model, retaining the components with obvious drug effect, eliminating the components with insignificant effect or no drug effect, and locking the components into the blood active components.
(2) Optimizing the combination arrangement of the active ingredients of the traditional Chinese medicine, and defining the efficacy: the active ingredients are combined by adopting network pharmacology, bioinformatics and orthogonal design means, and pharmacodynamics detection is carried out through a COPD lung organoid model, so that the optimal effective ingredient group of the 'synergistic' COPD resisting effect is screened.
(3) The system reveals the relationship between the pharmacodynamic substance basis, activity and efficacy of the traditional Chinese medicine compound for treating COPD: through a small molecule binding experiment, a protein target point of the action of the related active pharmaceutical ingredients is clear; and the structural biological method can be used for analyzing the crystal structure of the medicinal component-protein complex, and simultaneously combining related mutants to explore the influence of the active component on the target function.
The method comprises the steps of identifying and separating active ingredients and doped ingredients of traditional Chinese medicines by a Surface Enhanced Raman Spectroscopy (SERS) technology, respectively separating chemical ingredients of the six-ingredient air supplementing formula by adopting a preferable silver sol as an enhanced substrate and adopting TCL as a detection method, identifying the separated microelements by using the SERS technology, and detecting the doped chemical ingredients of the six-ingredient air supplementing formula by adopting the TCL-SERS technology.
Measuring the attribution of the peak spectrum of the traditional Chinese medicine by a Surface Enhanced Raman Spectroscopy (SERS) technology, respectively detecting the samples of the six qi supplementing formulas by using a gold film, silver nano particles and a gold film-silver nano particle enhanced substrate, and observing the Raman signal of the medicine by using the SERS technology to obtain the attribution of the initial peak spectrum of the samples.
In this embodiment, the six-ingredient qi-tonifying formulation further comprises a preliminary study of components, including the following steps:
(1) Rationality study of the formulation: carrying out literature analysis and research on six qi tonifying formulas, carrying out systematic summary and inductive analysis on the aspects of clinical information, chemical components, extraction and separation methods, pharmacological actions and the like of the six qi tonifying formulas, and determining the rationality of the formulas from the aspect of literature analysis; the content change of main chemical components in the compatibility process of the six-ingredient qi-tonifying formula is researched, and the rationality of the six-ingredient qi-tonifying formula is researched from the angle of the component change of compatibility indexes;
(2) And (3) preparation process research: the water absorption of the inspected traditional Chinese medicine decoction pieces is optimized by a comprehensive evaluation method; the method comprises the steps of taking the dry paste yield and the content of certain index components of a six-ingredient qi supplementing formula as evaluation indexes, comparing the impurity removal effects of different methods of the water extract, selecting the optimal refining process, and screening the most effective drying method based on the optimal refining process; through examining the novel auxiliary materials, taking particle formability, moisture absorption rate, bulk density and repose angle as indexes, optimizing the optimal auxiliary materials and proper auxiliary material dosage, and screening the most effective granulating method;
(3) Quality standard research: carrying out thin-layer identification research on the six medicinal materials in the recipe of tonifying qi, and simultaneously preparing corresponding odor-lacking negative control solution to prove the specificity of the method; checking the moisture, the difference of the filling amount, the disintegration time limit, the heavy metal, the salt and the microorganism limit checking method of the six-ingredient qi-tonifying formula according to various regulations related to the capsule item in Chinese pharmacopoeia; referring to the Chinese pharmacopoeia and related literature data, a plurality of components are quantified simultaneously by adopting an HPLC method, and fingerprint patterns of the six-ingredient qi tonifying formula are researched;
(4) Preliminary stability test: according to the relevant regulations of the technical requirement of the quality stability research of the new traditional Chinese medicine in the technical requirement of the research of the new traditional Chinese medicine issued by the national food and drug administration, the stability test is carried out on the six qi tonifying formulas, and the key investigation items comprise the investigation of the appearance, the color and luster of the content, the related substances, the disintegration time limit or dissolution, the moisture and the like of the product;
(5) Homogeneity inspection: and (3) measuring and analyzing the uniformity of the quality of the six-ingredient qi supplementing formula among different batches by adopting an HPLC method.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof. It is noted that relational terms such as first and second, and the like, if any, are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one … …" does not exclude the presence of other like elements in a process, method, article, or apparatus that comprises the element.
Claims (9)
1. A method for researching effective components of six-ingredient qi-tonifying formula comprises the following steps: ginseng, astragalus root, fructus alpiniae oxyphyllae, fragrant solomonseal rhizome, dried orange peel and cinnamon, and is characterized in that: the study included the following aspects:
basic research of drug effect substances of six-ingredient qi-tonifying formula:
(1) Six-flavor air supplementing method in vitro chemical component analysis based on UPLC-QE-Orbitrap-MS technology;
(2) Analysis of transitional components in the blood of the six-ingredient qi-tonifying prescription based on UPLC-Q-TOF-MS technology;
(3) Screening drug effect substances of six qi tonifying formulas based on network target analysis and molecular docking technology;
research on new medicine components of the six-ingredient qi-tonifying formula:
(1) Reproducing a slow-resistance lung evolution model of a lung organoid micro-physiological system;
(2) The systematic evaluation system of the slow-blocking lung organoid Chinese herbal compound is innovated, and the new medicine components are defined;
the quality evaluation of the effective components of the six-ingredient qi supplementing formula:
(1) Identifying and separating effective components and doped components of the traditional Chinese medicine by a Surface Enhanced Raman Spectroscopy (SERS) technology;
(2) The assignment of the peak spectrum of the traditional Chinese medicine is measured by a Surface Enhanced Raman Spectroscopy (SERS) technology.
2. The method for researching the effective components of the six-ingredient qi-tonifying formula according to claim 1, which is characterized in that: six-ingredient qi-tonifying prescription based on UPLC-QE-Orbitrap-MS technology is subjected to external chemical component analysis, the six-ingredient qi-tonifying prescription is ground, precisely weighed, and subjected to preliminary pretreatment such as dissolution, ultrasonic extraction, centrifugation, supernatant taking and the like to prepare a sample solution and a corresponding reference solution;
the method comprises the steps of (1) characterizing chemical components of two sides by adopting an ultra-high performance liquid chromatography-quaternary rod-electrostatic orbit tandem high resolution mass spectrometry (UPLC-QE-Orbitrap-MS) technology; the obtained RAW data in RAW format is processed by Compound Discoverer software, and is identified with the accurate quality, element composition, isotope spectrum and MS2 spectrum of the mzCloud database and the TCM library database, and each chromatographic peak is primarily identified; comparing the fragment ion information obtained by Xcalibur software with MS2 and MASBANK databases of the reference substances, further deducing and confirming the compounds, summarizing the cracking rule of the compounds, analyzing the chemical components of the six-ingredient qi-supplementing in vitro pharmacodynamic substances, and laying a foundation for screening the in-vivo components.
3. The method for researching the effective components of the six-ingredient qi-tonifying formula according to claim 2, which is characterized in that: the analysis of transitional components in the blood of the six-ingredient air-supplementing prescription based on the UPLC-Q-TOF-MS technology, the high-throughput rapid analysis of the chemical components of the six-ingredient air-supplementing prescription based on the UPLC-QE-Orbitrap-MS technology, the analysis of the retention time, the mass-to-core ratio, the fragment ion and other information of the blood components of the six-ingredient air-supplementing prescription combined with the ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) technology, and the comparison, calculation and estimation of the differential substances in the prescription are carried out with the information in a database or a literature to obtain the detailed information of the prototype components and the blood components, so that the potential metabolic pathways and targets of the six-ingredient air-supplementing prescription in vivo after oral administration are further estimated.
4. A method for studying the effective components of a six-ingredient qi-tonifying formulation according to claim 3, wherein: the method comprises the steps of screening drug effect substances of six qi-tonifying formulas based on network target analysis and molecular docking technology, taking transitional components in blood as a basis, performing component-disease action target correlation analysis on blood components of the six qi-tonifying formulas and COPD diseases, predicting the material basis of the formulas for treating COPD by constructing a core target-component network, performing molecular docking on the predicted active components and targets for treating COPD, and selecting components with high matching degree as potential drug effect substances.
5. The method for researching the effective components of the six-ingredient qi-tonifying formula according to claim 1, which is characterized in that: a slow-drag lung evolution model for reproducing a lung organoid micro-physiological system, comprising the steps of:
(1) The manufacturing method of the micro-fluidic chip comprises the following steps: the microfluidic chip devices are all manufactured by using a classical soft lithography method, and the manufacturing process mainly comprises mask design, template manufacture and chip processing.
(2) And manufacturing a PDMS gasket: preparing PDMS working solution, drying, cutting into strips, dripping the working solution, baking, cutting, perforating, immersing in 75% alcohol solution, vacuumizing and airing for standby.
(3) Building a lung organoid 3D model: adding the primary cell suspension from the normal lung tissue into matrigel, then inoculating with matrigel mixed solution, solidifying, slowly adding into organoid complete culture medium, collecting organoids to microfluidic chip when organoids are all larger than 50 mu and the size is not increased, and performing subsequent experiments.
(4) Slow-blocking lung organoid platform construction: based on a lung organoid 3D model, a modern technical means is adopted to construct a chronic obstructive pulmonary organoid model of the COPD lung-kidney qi deficiency syndrome.
6. The method for researching the effective components of the six-ingredient qi-tonifying formula according to claim 5, which is characterized in that: the systematic evaluation system of the slow-blocking lung organoid Chinese herbal compound is innovated, and the new medicine components are defined, and the method comprises the following steps:
(1) The UPLC-QTOF/MS is adopted to screen the blood active ingredients of the six-ingredient qi supplementing prescription, and the drug effect is defined based on the lung organoid level of COPD: and screening active monomer components with higher blood content and stable property by adopting UPLC-QTOF/MS results, detecting the drug effect of candidate components through a COPD lung organoid model, retaining the components with obvious drug effect, eliminating the components with insignificant effect or no drug effect, and locking the components into the blood active components.
(2) Optimizing the combination arrangement of the active ingredients of the traditional Chinese medicine, and defining the efficacy: the active ingredients are combined by adopting network pharmacology, bioinformatics and orthogonal design means, and pharmacodynamics detection is carried out through a COPD lung organoid model, so that the optimal effective ingredient group of the 'synergistic' COPD resisting effect is screened.
(3) The system reveals the relationship between the pharmacodynamic substance basis, activity and efficacy of the traditional Chinese medicine compound for treating COPD: through a small molecule binding experiment, a protein target point of the action of the related active pharmaceutical ingredients is clear; and the structural biological method can be used for analyzing the crystal structure of the medicinal component-protein complex, and simultaneously combining related mutants to explore the influence of the active component on the target function.
7. The method for researching the effective components of the six-ingredient qi-tonifying formula according to claim 1, which is characterized in that: the method comprises the steps of identifying and separating active ingredients and doped ingredients of traditional Chinese medicines by a Surface Enhanced Raman Spectroscopy (SERS) technology, respectively separating chemical ingredients of the six-ingredient air supplementing formula by adopting a preferable silver sol as an enhanced substrate and adopting TCL as a detection method, identifying the separated microelements by using the SERS technology, and detecting the doped chemical ingredients of the six-ingredient air supplementing formula by adopting the TCL-SERS technology.
8. The method for researching the effective components of the six-ingredient qi-tonifying formula according to claim 7, which is characterized in that: measuring the attribution of the peak spectrum of the traditional Chinese medicine by a Surface Enhanced Raman Spectroscopy (SERS) technology, respectively detecting the samples of the six qi supplementing formulas by using a gold film, silver nano particles and a gold film-silver nano particle enhanced substrate, and observing the Raman signal of the medicine by using the SERS technology to obtain the attribution of the initial peak spectrum of the samples.
9. The method for researching the effective components of the six-ingredient qi-tonifying formula according to claim 1, which is characterized in that: the six-ingredient qi-supplementing formula also comprises the following steps of:
(1) Rationality study of the formulation: carrying out literature analysis and research on six qi tonifying formulas, carrying out systematic summary and inductive analysis on the aspects of clinical information, chemical components, extraction and separation methods, pharmacological actions and the like of the six qi tonifying formulas, and determining the rationality of the formulas from the aspect of literature analysis; the content change of main chemical components in the compatibility process of the six-ingredient qi-tonifying formula is researched, and the rationality of the six-ingredient qi-tonifying formula is researched from the angle of the component change of compatibility indexes;
(2) And (3) preparation process research: the water absorption of the inspected traditional Chinese medicine decoction pieces is optimized by a comprehensive evaluation method; the method comprises the steps of taking the dry paste yield and the content of certain index components of a six-ingredient qi supplementing formula as evaluation indexes, comparing the impurity removal effects of different methods of the water extract, selecting the optimal refining process, and screening the most effective drying method based on the optimal refining process; through examining the novel auxiliary materials, taking particle formability, moisture absorption rate, bulk density and repose angle as indexes, optimizing the optimal auxiliary materials and proper auxiliary material dosage, and screening the most effective granulating method;
(3) Quality standard research: carrying out thin-layer identification research on the six medicinal materials in the recipe of tonifying qi, and simultaneously preparing corresponding odor-lacking negative control solution to prove the specificity of the method; checking the moisture, the difference of the filling amount, the disintegration time limit, the heavy metal, the salt and the microorganism limit checking method of the six-ingredient qi-tonifying formula according to various regulations related to the capsule item in Chinese pharmacopoeia; referring to the Chinese pharmacopoeia and related literature data, a plurality of components are quantified simultaneously by adopting an HPLC method, and fingerprint patterns of the six-ingredient qi tonifying formula are researched;
(4) Preliminary stability test: according to the relevant regulations of the technical requirement of the quality stability research of the new traditional Chinese medicine in the technical requirement of the research of the new traditional Chinese medicine issued by the national food and drug administration, the stability test is carried out on the six qi tonifying formulas, and the key investigation items comprise the investigation of the appearance, the color and luster of the content, the related substances, the disintegration time limit or dissolution, the moisture and the like of the product;
(5) Homogeneity inspection: and (3) measuring and analyzing the uniformity of the quality of the six-ingredient qi supplementing formula among different batches by adopting an HPLC method.
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