Traditional Chinese medicine has a history of thousands of years in China, has a wide range of clinical application value and has formed a unique theoretical system. The law of the People'sRepublic ofChina on traditional Chinese medicine points out that the cause of traditional Chinese medicine should inherit the essence, keep the integrity and innovate. Therefore, how to maintain the traditional characteristics of traditional Chinese medicine while accelerating its modernization has become the key to the reform and innovation of traditional Chinese medicine. Traditional Chinese medicine new drugs integrate the basic theory of traditional Chinese medicine and modern technology to meet the urgent needs of the innovation and development of traditional Chinese medicine.

Measures for the administration of drug registration2007The registration of traditional Chinese medicine and natural drugs is classified into9Class, where1～6Class A is a new drug of traditional Chinese medicine, including single and compound preparations.6Class I new drugs, i.e. traditional Chinese medicine compound new drugs, are composed of multiple herbs, mostly derived from clinical experience or hospital preparations, and are the new drug category that best reflects the characteristics and advantages of traditional Chinese Medicine^[1]。

Pharmaceutical research on new drugs of traditional Chinese medicine compound includes research and extraction of medicinal materialsPurification process research, formulation process research, quality standards and stability research are not only the guarantee of controllable drug quality, but also the premise of safety and effectiveness test. Due to the wide source of traditional Chinese medicine, complex chemical composition and researchers' understanding of laws and policiesThere are some problems in pharmaceutical research, such as the source and origin of medicinal materials are not fixed, the selection of process route is unreasonable, the quality standard is not standardized, and the stability research is not comprehensive. This paper analyzes and discusses these problems according to the specific situation encountered in the development of new drugs of traditional Chinese medicine, in order to make full use of the theory and practical experience of traditional Chinese medicine, and provide references for scientific, standardized and reasonable research on new drugs of traditional Chinese medicine.

1  Issues needing attention in the research of medicinal materials

1.1  Origin and origin of medicinal materials

The original is the attribute source of medicinal materials, and the accuracy of the original is the basis for the stability of the quality of traditional Chinese medicine preparations^[2]Different species and genera of medicinal materials contain different chemical components and different contents, which will lead to different pharmacodynamic effects. The place of origin is also another important factor affecting the quality of medicinal materials, which has always been valued by doctors. "Shennong materia medica classic" says: "the land comes from, the authenticity is new, and each has its own method". It points out the importance of the place of origin of medicinal materials, and the growth environment such as temperature, humidity, light, soil conditions will have an impact on the content of active ingredients and drug efficacy of medicinal materials from different places of origin.

According to statistics, 《Chinese Pharmacopoeia》2015The original multi base plant of the annual edition of one drug has115species^[3]There are great differences in the content of many basic crude drugs and varieties from different origins, but the pharmacopoeia standard stipulates the same limit, so that the content of some basic crude drugs cannot meet the requirements of the Pharmacopoeia. The author once participated in the research and development of a new compound Chinese medicine. When determining the origin and origin of epimedium in pharmaceutical research, many batches of medicinal materials failed to meet the requirements of the Pharmacopoeia. For such problems, aitiemin^[3]It is suggested that the principle of "one name for one thing, one name for one thing" should be implemented for the traditional Chinese medicine of multi base original plants to ensure the uniqueness of the name and standard.

When there are genuine medicinal materials, the first choice is genuine medicinal materials; . For example, the main production area of peppermint in the herbal medicine of past dynasties is Jiangsu. With the change of times, Anhui has become a thinThe main production area of Holland. The dominant components of peppermint in different production areas are different. The content of menthone in Jiangsu and Anhui production areas is relatively high, the content of menthol in Anhui production area is relatively high, and the content of piperone in other production areas is relatively high^[4]，The difference of its efficacy needs further study. 《Chinese Pharmacopoeia》2015The annual edition only stipulates that the leaf content of peppermint should not be less than30%. the oil content of medicinal materials shall not be less than0.8%And the oil content of the decoction pieces shall not be less than0.4%The specific composition of volatile oil is not clearly specified. Therefore, in the process of pharmaceutical research, the origin of medicinal materials should not only meet the requirements of Chinese Pharmacopoeia, but also be comprehensively evaluated in combination with the functional indications and relevant pharmacodynamic results of the prescription.

Supplementary Provisions on the administration of registration of traditional Chinese Medicine2008For the first time, the year edition proposed that the source, place of origin and technological parameters of medicinal materials should be clarified, and should be included in the control link to ensure the quality of traditional Chinese Medicine^[5]For multi-source medicinal materials, it is necessary to systematically evaluate the medicinal materials' source after providing historical textual research on the source of the prescription, and fix the source by comparing the quality of medicinal materials between different sources. On this basis, it is also necessary to consider the actual growth environment, output and quality of medicinal materials sold in the market, so as to fix the origin of medicinal materials as much as possible.

1.2  Medicinal materials containing toxic ingredients

Toxic medicinal materials were first seen in the Shennong herbal classic, which can be divided into "big poison", "toxic" and "small poison" according to the degree of toxicity3level^[6]The previous editions of Chinese Pharmacopoeia contain toxic medicinal materials, and2015The annual edition contains83Species. Zhang Zhongjing's prescriptions in Treatise on Febrile Diseases and synopsis of the golden chamber also contain toxic medicinal materials such as aconite, aconite, Euphorbia, kansui, etc. these drugs play an important role in the treatment of some chronic diseases, but the resulting adverse reactions are also common. .

Review expert Wang Ting et al^[7]Once in2008It was pointed out in that "if the pharmacopoeia or ministerial standards or local standards consider that the medicinal materials contain toxic ingredients, if the toxic ingredients are not studied or limited in the standards, the methods for controlling the toxic ingredients should be increased and the corresponding application materials should be submitted".2019year6In August, the National Drug Examination Center released the draft for comments on the "technical guidelines for the research of quality standards of new Chinese medicines", which clearly stated that "if the decoction pieces in the prescription are derived from toxic medicinal materials... Their limit inspection items should be formulated"^[8]It can be seen that the quality control of toxic medicinal materials has been put on the important agenda of new drug research of traditional Chinese medicine.

At present, there are still limitations in the quality standards of toxic medicinal materials contained in the pharmacopoeia or local standards, 《Chinese Pharmacopoeia》2015Included in1Planting toxic traditional Chinese medicine14Kinds of toxic traditional Chinese medicine18There is no content determination item for all kinds of small toxic traditional Chinese medicines^[9]Most toxic medicinal materials in local medicinal materials standards have not established quality control methods for toxic components. In addition, the limit inspection method of toxic medicinal materials is also limited by the shortage of reference materials. The legal reference substances provided by National Institutes for food and drug control (nifdc) only refer to the varieties with content determination items recorded in Chinese Pharmacopoeia. For the limit inspection of toxic components of other toxic medicinal materials, it is difficult and time-consuming to purchase reference substances from other commercial channels or to separate, identify and calibrate by yourself.

Therefore, if we can establish a unified classification standard of toxic traditional Chinese medicine, introduce advanced detection technology to improve the quality standard of traditional Chinese medicine, strengthen the supply of reference substances of toxic ingredients, and simplify the calibration rules, it is bound to promote the research of new traditional Chinese medicine containing toxic traditional Chinese medicine more effectively and reasonably.

1.3  Other issues

Drug research is the source of new drug research and development, and runs through the whole process of new drug research and development. Only by combining the source control of medicinal materials, the production process control and the quality control of final products can we ensure the uniformity and stability of drugs.

At present, the inadequate and incomplete research on the harvesting, processing and other processes of many medicinal materials makes the quality of medicinal materials unstable, which has become a major obstacle to the research of high-quality traditional Chinese medicine. ^[10]It was found that the content of effective components in Forsythia suspensa had a certain correlation with the harvest time: forsythin, forsythiasideAThe content of7The harvest was the highest in the first ten days of the month, and then showed a downward trend; Zhangshurong et al^[11]By gas chromatography8The oil yield andα-Pinene andβ-The content of pinene was also determined7It is the highest in the middle and late ten days of the month. Therefore, in the study of medicinal materials of compound new drugs, when the collection time has an impact on the quality of medicinal materials, we can increase the investigation of the collection time and clarify the collection time to ensure the quality of medicinal materials.

In addition, the processing of the same decoction piece generally has the phenomenon of "one drug with multiple methods" and "different methods in different places", and the standards for processing technology judgment are also different. For example, the processing specification of Radix Scrophulariae decoction pieces in Zhejiang, Tianjin and other provinces is slicing, the processing specification of traditional Chinese medicine decoction pieces in Jiangsu, Shandong and other provinces stipulates slicing, Hunan and Jiangxi provinces require oblique slicing, and Beijing and Zhejiang provinces require thick slicing. The specifications of Radix Scrophulariae pieces circulating in the national market are relatively chaotic. Different processing methods lead to great differences in properties. Different processing methods also lead to different contents of effective components in the pieces, such as the content determination index components in Zhejiang Province and Tianjin and the Chinese Pharmacopoeia2015Consistent with the annual edition, it is stipulated that the total amount of harpagoside and harpagoside shall not be less than0.45%In Hubei and Guangdong provinces, the amount of harpagoside shall not be less than0.05%Shanghai stipulates that harpagoside shall not be less than0.04%^[12].

In addition, the research of medicinal materials should also be carried out according to the supplementary provisions on the registration and administration of traditional Chinese Medicine^[5]According to the requirements of "ensuring the stability of the source of Chinese medicinal materials and the sustainable utilization of resources... Those involving endangered wild animals and plants should comply with the relevant national regulations", the Chinese government pays attention to the sustainable utilization of medicinal materials resources and the legitimacy and necessity of using wild medicinal materials.

2  Issues needing attention in process research

2.1  Determination of extraction process route

The chemical composition of each flavor in the prescription of traditional Chinese medicine compound new drugs is complex, and the physical and chemical properties are different. In order to improve the curative effect, reduce the dose, and facilitate the formation of the preparation, the medicinal materials need to be extracted and purified. Technical guidelines for research on Extraction and purification process of traditional Chinese medicine and natural medicine2005According to the annual edition, the design of technological route should be based on the premise of ensuring safety and effectiveness. Generally, the characteristics of prescription and the nature of medicinal materials, the type of preparation and clinical medication requirements, the feasibility and cost of large-scale production, and the requirements of environmental protection should be considered^[13]The route design of extraction process is directly related to the utilization rate of medicinal materials and the difficulty and ease of preparation process. In the process of research and development of new Chinese medicine, the following problems should be paid attention to: ① the extraction process of volatile oil from medicinal materials containing volatile components in the prescription was not studied; ② The extraction process was determined only on the basis of chemical indexes.

For the prescription of medicinal materials containing volatile components, if it is clear that it has a pharmacodynamic effect, the volatile oil should be extracted separately in the modern process route design, and the process parameters should be confirmed. . The requirements for the collection device of volatile oil during production scale extraction are very high. When the atmospheric pressure or condensation effect is not good, the oil-water separation is difficult, the extraction yield of volatile oil is low, or even only aromatic perfume can be collected. Therefore, in pharmaceutical research, different methods can be used to extract volatile oil according to the physicochemical properties of medicinal materials, such as supercriticalCO₂Extraction, oil adsorption, etc. Zheng Peng et al^[14]Steam distillation was compared（SD）Method and extraction-Azeotropic distillation coupling technology（WER）The volatile oil from Fructus aurantii Immaturus and Rhizoma Cyperi was extracted, and it was found that the volatile oil from Fructus aurantii Immaturus and Rhizoma Cyperi Immaturus was similar toSDCompared with France,WERThe volatile oil extracted by this method has better phase, higher yield and higher content of chemical components. butSDIt has the advantages of simple equipment, safe operation and low cost. If it can be applied on the basis of slightly improving the extraction device and improving the yield and quality of volatile oil, it is also very economical and feasible.

In addition, when the prescription comes from the clinical experience of famous doctors or folk prescriptions, especially when the extraction method of the main effective chemical ingredients is contradictory to the traditional process preparation method, or there are few reports on the physicochemical properties and pharmacological effects of some drug flavors in the prescription, it is usually necessary to design multiple process routes, and determine the appropriate process route in combination with the preliminary pharmacodynamic experimental results. For example, "Jianpi Liqi Granule" is a commonly used prescription for the treatment of primary liver cancer in Fudan University Cancer Hospital, Wu Hongbin et al^[15]Designed5Effects of Jianpi Liqi granules onH₂₂. It can be seen that the pharmacodynamic indexes play an important guiding role in the screening of the technological route, and ensure the effectiveness of the developed drugs to a certain extent.

2.2  Selection of process evaluation index

The evaluation index of quality control in the process of process research is not only an important factor to investigate the rationality of the process route, but also the main means to determine the process parameters. It should be scientific, stable, controllable, and can make a reasonable judgment on the prescription process.

In the research of traditional Chinese medicine compound new drugs, there are mainly the following problems in the selection of process evaluation indicators: first, the prescription containing toxic herbs did not select the index components related to safety. Sophora flavescens is contained in the prescription of a compound new drug, in which the chemical components matrine and Oxymatrine may induce hepatotoxicity, neurotoxicity and gastrointestinal toxicity. When selecting the process evaluation index, the transfer rate of toxic components should be investigated, and the "toxicity effect balance" should be fully considered, and the extraction process route should be determined on this basis. 2008It was pointed out in the electronic journal in that "when the content of active ingredient or toxic ingredient is very low (less than 1 in 10000 of the preparation), its controllability as the index ingredient of the process route screening is poor, and it should not be selected"^[16]. But Feng Yi et al^[17]It was also pointed out that the more the better the index components, such as Ligusticum chuanxiong, radix paeoniae rubra and Fructus Ligustri Lucidi contained in a traditional Chinese medicine compound3The results showed that with the extension of decoction time, the transfer rate of ligustrin significantly increased, the transfer rate of paeoniflorin basically unchanged, but the transfer rate of ferulic acid decreased; .

In short, we need to firmly grasp the key quality attributes of traditional Chinese medicine preparations, carefully analyze and study the nature of each drug flavor and the interaction of the main components in the prescription around the process of traditional Chinese medicine extraction, concentration, alcohol precipitation, drying, etc., and comprehensively consider the safety and effectiveness of drugs, so as to make a reasonable choice of process evaluation indicators in the research of traditional Chinese medicine compound new drugs.

2.3  Selection of dosage forms

A reasonable dosage form can ensure the curative effect of drugs, and it is also an important factor affecting the stability of the quality of traditional Chinese medicine preparations. .

The traditional dosage forms of traditional Chinese medicine are the earliest, followed by pills, powders, ointments and alcoholic drinks. In recent years, tablets, capsules, films and other dosage forms have been developed, which has promoted the development of traditional Chinese medicine. However, due to the complex composition, unclear target effect and low bioavailability of traditional Chinese medicine, the choice of dosage forms is limited. For oral preparations, there is still a single dosage form, with granules and oral liquid in the majority. Due to the large dosage of traditional Chinese medicine compound, the extract is easy to absorb moisture and has high viscosity, so the tabletCapsules may have defects such as low drug loading, difficult formation and poor stability, which also restrict the application of other modern dosage forms such as microspheres and dropping pills in the field of traditional Chinese medicine. Therefore, if we can use some new excipients, new technologies and new equipment to strengthen the research of traditional Chinese medicine dosage forms, solve the problems existing in the preparation, and try to choose more suitable new dosage forms, it will open up more paths for the modernization development of traditional Chinese medicine preparations.

2.4  Other issues

Technological research determines the feasibility, stability and sustainability of industrialized production of new Chinese medicine compound preparations after marketing. The research process should also pay attention to the selection method of process conditions and the selection of excipients in the study of preparation molding process.

At present, in the process of research on the technology of traditional Chinese medicine compound new drugs, the screening method of technological conditions is relatively simple, and single factor investigation, orthogonal test and other methods are mostly used; We should go out of a single evaluation mode, use the technology and methods of other related disciplines for reference as much as possible, and conduct a comprehensive and comprehensive investigation of the process of traditional Chinese medicine compound preparation from multiple angles. Wanglulu et al^[18]When studying the compound Polygonum cuspidatum prescription, the fingerprint and principal component analysis were established（PCA）The combined extraction technology research method not only comprehensively inspected the extraction of medicinal materials, but also simplified the data.

In the study of the preparation molding process of traditional Chinese medicine compound, there are few kinds of excipients to choose, and the research on the adaptability of new excipients is limited, which hinders the innovation of the preparation molding process of traditional Chinese medicine compound to a certain extent. We should strengthen the compatibility research between traditional Chinese medicine compound and commonly used excipients, and explore and develop new excipients suitable for traditional Chinese medicine compound on the basis of satisfying the formation and stability of the preparation. Du Pingping^[19]In the preparation of Shaoyao Gancao gastric floating sustained-release tablets, chitosan was selected as the excipient, and the tablets had good formability, which solved the problems of strong viscosity of traditional Chinese medicine extract and difficult formation of the preparation.

For a long time, traditional Chinese medicine preparations have been produced in traditional production methods. Product quality mostly depends on terminal control and ignores process control. The research and development concept also less considers the impact of the process on the final quality of products. It is impossible to predict the problems that may occur in the process, and it is difficult to find the key controllable points that affect the process and product quality. Nowadays, quality comes from design（QbD）The concept of "the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of the formation of^[20]。

3  Issues needing attention in pilot study

Pilot study is the verification and improvement of the rationality of laboratory process, the necessary link to ensure the stability and operability of the process, and is directly related to the safety, effectiveness and quality control of drugs^[21]。

The pilot scale-up study of the preparation process of traditional Chinese medicine compound new drugs should focus on the following2Aspects: ① process parameters: due to the difference between the pilot test equipment and the laboratory, the best process parameters obtained from the laboratory pilot test need to be properly adjusted during the pilot production. For example, the heating efficiency should be considered during the heating reaction or pretreatment. If the heating efficiency of the pilot test is high, the extraction time can be appropriately reduced. ② . Like Sunjin^[22]In the process scale-up study of Shuangshen Tongguan capsule, it was found that the transfer rate of salvianolic acids in the purification and elution process of macroporous resin was significantly different from that in the pilot scale test. After re examining the loading amount according to the parameters of the pilot scale macroporous resin column, the transfer rate of salvianolic acids could be stabilized at85%. 1.34While the concentration equipment in pilot production is a single effect concentrator, when the relative density is greater than1.2The materials will hang on the wall and agglomerate seriously, resulting in great consumption.

It can be seen that in order to carry out the pilot scale research smoothly, it is necessary to understand the production equipment and technical requirements in the pilot scale stage, predict the uncertain factors in production, and make the process route and parameters adapt to the requirements of pilot scale production as much as possible. In addition, strictly implementing the process steps and operating procedures, and doing a good job in the quality control of intermediates are also important guarantees for the smooth development of the pilot study.

4  Issues needing attention in quality standard research

The quality standard is one of the important contents in the pharmaceutical research of traditional Chinese medicine compound new drugs. .

The inspection items of traditional Chinese medicine preparations should include the basic items under the general principles of corresponding preparations in the Pharmacopoeia. In addition, other inspection items should be formulated according to their characteristics, processes, etc. Ruzaishukang capsule^[23]Macroporous resin is used for separation and purification in the preparation method, so the inspection of "residual resin organic matter" is added to the inspection items of the quality standard, and benzene, xylene, n-hexane, etc. are determined by gas chromatography and the limits are specified; Manna disinfection pill^[23]It contains talc, a mineral drug. According to the method of the general principles of the Pharmacopoeia, heavy metals and arsenic salts are checked in the quality standard. It is stipulated that the content of heavy metals and arsenic salts in this product should not exceed10 mg/kgHuoxue Zhuangjin pill^[23]It contains toxic drug flavored aconite, and HPLC（HPLC）According to the law of the people's Republic of China, the limit inspection of the toxic component diester alkaloids was carried out, and the total amount of diester alkaloids contained in each pill of this product should not exceed10 μg。

Content determination is the main index to evaluate the quality of drugs. The limit of content should be determined according to the measured values of multiple batches of samples. At present, the content of most traditional Chinese medicine preparations has only a lower limit,2019year6According to the exposure draft of the "technical guidelines for the research of quality standards of new traditional Chinese medicine" in August, it is proposed that the content range of compound new drugs should be reasonable^[8]. For example, the original standard of Jinguan tabletsHPLCThe content of triptolide was determined by HPLC, and the limit of each tablet was1.0～10.0 μg, Luo Yaling et al^[24]Re production10After batch of samples and determination, it was found that the content of each tablet was1.4～2.1 μg, so its limit is revised to each piece1.0～5.0 μgThe content limit range is more reasonable.

In short, the chemical composition of traditional Chinese medicine is complex, and its quality control is a systematic and complex process, but also a dynamic and constantly improving process. .

5  Issues needing attention in stability research

Stability research is to find out the unstable factors of drugs, find out the reasons affecting the stability of drugs and control them by investigating the trend of drug characteristics changing with time under different environmental conditions^[25]To improve the quality of drugs, and provide a basis for the determination of production, packaging, transportation, storage conditions and the establishment of validity.

According to the factors of drug prescription, preparation process and dosage form, scientific and reasonable design of test content is the key of stability research. For example, multi dose packaged drugs such as mixtures have a certain service life after the initial use. Corresponding stability experiments should be added to the samples after the package is opened, which are easy to be ignored in new drug research. In addition, according to the guiding principles for stability test of raw materials and preparations, the long-term stability test adopts25 ℃/Relative humidity（RH）60%Chinese Pharmacopoeia2015Annual edition exceptionsSpecifically, normal temperature refers to10～30 ℃, if only the drug in25 ℃/ RH 60%For long-term stability, storage conditions can only be determined as "cool place", not "normal temperature". 30 The investigation time of intermediate conditions within ℃ provides a basis for the determination of storage condition temperature within the validity period. For example, in the stability study of a granule, the design30 ℃/RH 65%Intermediate experimental conditions, after the accelerated experiment, continue to carry out long-term experimental investigation until24Months, and the results showed that the drug was effective in25 ℃/RH 60%and30 ℃/RH 65% 2Under the following conditions, the investigation items are24（30 ℃）。

At present, the experimental research level of the stability of traditional Chinese medicine compound new drugs has been greatly improved, but there are still some problems to be further explored and improved, such as how to define the "significant difference" in the stability result evaluation, and how to inspect the compatibility experiment of drugs and packaging materials^[26]. in addition,2015year1In September, the "technical guidelines for stability research of chemical drugs (APIs and preparations)" has been revised and implemented, while the current effective version of the "technical guidelines for stability research of traditional Chinese medicine and natural drugs" for traditional Chinese medicine varieties is still2006Released in, the research and development ideas and methods of new Chinese medicine have undergone earth shaking changes in China over the past decade. In order to better adapt to the pace of the times, integrate with international standards, and meet the needs of the reform and innovation of traditional Chinese medicine modernization, it is urgent to update the existing guiding principles to standardize and guide the research and development of new Chinese medicine.

6  Conclusion and Prospect

The research of traditional Chinese medicine compound new drugs is a challenging work, which still needs to adhere to the fundamental principle of safety and effectiveness, constantly strengthen the source control of traditional Chinese medicine, reasonably determine the process parameters, establish scientific detection methods, and standardize the research and development of traditional Chinese medicine compound new drugs. So far, the measures for the administration of drug registration has been solicited for comments for many times and is currently being revised. In the future, the process and scope of drug registration management will be more clear, and the technical evaluation system will be further improved, which will promote the transformation of R & D concepts and the improvement of research level. This paper only makes a superficial analysis of some problems in the pharmaceutical research of traditional Chinese medicine compound new drugs. Many of these problems need further research and discussion, hoping to attract the attention and thinking of peers, and jointly develop safe, effective and quality controllable modern traditional Chinese medicine compound new drugs, so that traditional Chinese Medicine can better benefit human health.

References (omitted)  

Come   Source: Guo   Jing, Xuan Zhenyu, Xie   Yan Problems and thoughts in the pharmaceutical research of traditional Chinese medicine compound drugs [j]. Chinese herbal medicine, 2020, 51 (8): 2267-2272