(Institute of traditional Chinese medicine, Chinese Academy of traditional Chinese medicine, Beijing   100700)

Traditional Chinese medicine is the treasure of the Chinese nation,For thousands of years,Played an important role in disease prevention and treatment,Traditional Chinese medicine is driven by modern science and technology,Is realizing the leap to modern Chinese Medicine,It has been paid more and more attention all over the world2011The annual Lasker clinical medicine award was awarded to researcher Tu Youyou, the discoverer of artemisinin,It has also caused a great discussion among scholars on the research and development of new Chinese medicine The author puts forward three core and key links in the design of new drugs of traditional Chinese Medicine,That is, prescription discovery, differentiation and prescription optimization This paper describes and discusses the research strategies for the discovery of new prescriptions of traditional Chinese medicine

The foundation of new drug research and development of traditional Chinese medicine is the determination of new drug prescription,The current research status shows that,In order to determine the prescription or object of research and development of new Chinese Medicine,Improve the hit rate of R & D objectives of new Chinese Medicine,Most of them are based on literature and ancient books,Select prescriptions from ethnic and folk medicines, famous clinical prescriptions, old medicines and foreign natural medicines,As the object of further development

1.1Development of ancient prescriptions and empirical prescriptions Ancient prescriptions and tested prescriptions are usually the summary of clinical experience for thousands of years,Many prescriptions are effective,This is our advantage,Is the premise of new drug research,It is an important source of new Chinese medicine prescriptions Select the ancient prescriptions in classical medical books with accurate Chinese certificates, rigorous formulation and reliable curative effect,Use its original formula or add or subtract slightly,Then according to the prescription and syndrome, the appropriate syndrome or disease type shall be determined The characteristic of this screening is that the prescription has classical significance,The formulation is highly theoretical,But it should be combined with modern clinical experience,Further determine its functional indications The basic research of this kind of prescription is extensive and thorough,There are many reports of clinical cases,Doctors and consumers have certain loyalty to them therefore,Relatively short development cycle and quick return,However, there are many manufacturers of such drugs,The market competition of similar products is fierce

Because there are quite a number of doctors engaged in clinical work for a long time in all branches of traditional Chinese Medicine,And has a variety of technical expertise and unique experience,Even a certain academic school has been formed According to their expertise,Select qualified empirical prescriptions as candidate drugs for the development of new Chinese Medicine,It is characterized by good clinical foundation,Functional indications and indications are relatively clear,As a prescription source for new drugs,It often has considerable development prospects Some hospital preparations are aimed at common, frequently occurring or difficult clinical diseases,Prescription drawn up by famous TCM experts,Finalized after repeated modification in clinical use,It is also an important prescription source for the research and development of new Chinese medicine

1.2Secondary development of Chinese patent medicine The secondary development of Chinese patent medicine refers to the process of in-depth research on the problems or influencing factors of the listed Chinese patent medicine around the drug quality and clinical medication and achieving results,It can improve, refine, supplement and revise the contents related to the effectiveness, safety and economy of the instructions for Chinese patent medicines,It can also target diseases(Syndrome)Screening, determination and recombination of population and drugs,Form a combination of products or series of products with more market competitiveness therefore,Secondary development of Chinese patent medicine is an extension of post marketing re evaluation,Systematically study and summarize some immature achievements from past research,Select potential seedlings for secondary development Due to the long-term clinical application of famous and high-quality Chinese patent medicines,Reliable curative effect,Clear role,Solid theoretical and practical foundation,The research results have universal regularity Secondary development of famous and high-quality Chinese patent medicines,It can not only clarify its effective material base and its action mechanism,It is also of great significance for the rediscovery of new Chinese medicine

2.1Blindness of literature prescription screening Transmission of traditional Chinese medicine from generation to generation,Accumulated a large number of ancient books and documents,Plus the current research reports related to traditional Chinese Medicine,Forming a huge literature knowledge base,It records or collects a large number of prescriptions, traditional Chinese medicine and other information,It is an important source of candidate prescriptions for research and development of new Chinese medicines However, due to the extensive nature of the records,It needs a test process to eliminate the false and retain the true,If we blindly select the research and development objects of new Chinese Medicine,Not only the hit rate is low,And the inspection process is expensive,The R & D cycle is too long In the development of new Chinese Medicine,Screening and obtaining new drug prescriptions with reasonable formulation, clear treatment of disease and syndrome, and obvious characteristics and advantages,Need to introduce mining and analysis methods for massive data,Can retain valid information,And quickly obtain candidate prescriptions,To reduce the blindness of screening

2.2Limitations of experienced parties Many clinical front-line TCM workers,Through long-term dedicated research and Practice,An empirical prescription with unique effect on a certain disease or a certain type of disease has been formed Some of these empirical formulas are added and subtracted on the basis of classical famous formulas,Most of them carry the traditional theories of traditional Chinese Medicine,Meet the theoretical guidance requirements of traditional Chinese medicine according to the provisions of new drug application;Some of them are family heirlooms or folk experience,The composition of these prescriptions often contains less applied varieties of traditional Chinese Medicine,The nature, taste, meridian tropism and other records are not very clear,Some prescriptions are difficult to explain with traditional Chinese medicine theory,Encountered a dilemma in the declaration process Most of these prescriptions are based on the experience of one person, one place,For large-scale population, it may not be completely consistent,In order to prove the wider clinical possible value,Clinical observations should be systematically sorted out and summarized,Analyze its function characteristics and applicable population,Overall evaluation of clinical efficacy,And compare with similar drugs already on the market,Explain the advantages and characteristics of its development as a patent medicine

2.3Risk of active ingredient preparations Learn from the process of Western medicine development,Guided by bioactivity screening,Separation, purification and structure identification of effective components of traditional Chinese Medicine,The number of preparations made according to the research results of pharmacological activities of active ingredients is increasing gradually By comparison,The characteristics and advantages of these preparations are as follows,Comprehensive and targeted quality control,More clear clinical positioning,The purpose of clinical research is clearer,Pre clinical research is easy to carry out however,Because clinical diseases are often not caused by a single factor,Especially for complex diseases such as tumors, heart and brain diseases,Various pathogenic factors,Complex pathological mechanism,in addition,The pathological basis of human diseases is different from that of animal models,After entering the clinical research according to the non clinical research results,The pharmacological action of the test substance in human body is often not consistent with the results of non clinical trials therefore,Develop new drugs according to the pharmacological activity research results of active ingredients,Its development risk is very large

2.4The lag of the creation of new Chinese Medicine To increase support for new drug research,In recent years,Relevant state departments have set up a major scientific and technological special project of "major new drug creation",Conducted special research on new drug candidates,To speed up the pace of new drug creation,However, the number of new Chinese medicines approved for marketing in China in recent years is still small Relevant data show that,2011~2013New Chinese medicine approved for marketing in(1~6class)The quantities of are21,21and15individual,It shows that the creation of new Chinese medicine lags behind,The development level needs to be improved Some scholars put forward "guided by clinical needs,R & D concept of "clinical efficacy as the feature",Clinical needs for the treatment of a disease,Targeted screening,Developing new drugs according to the idea of "from disease to drug",So as to speed up the development of new Chinese medicine

The creation of new drugs of traditional Chinese medicine must attach importance to traditional Chinese medicine knowledge and clinical practice,Using computer information processing technology to build a database of traditional Chinese medicine knowledge and clinical practice on this basis ,Introduce data mining technology suitable for the characteristics of traditional Chinese medicine data to mine and analyze the data of traditional Chinese medicine cases, prescriptions, ethnic medicines, etc. in the database,Finding rules from data,Judgment based on professional knowledge,Then conduct targeted screening and confirmation of candidate prescriptions,Repeatedly verified by clinical practice,Determine the candidate prescription of new Chinese medicine and conduct in-depth pre clinical research,The specific process is shown in the figure1This research strategy,Breaking through the limitation of relying only on experimental evaluation and personal experience,It provides references for accelerating the creation of new Chinese medicine

3.1Traditional Chinese medicine knowledge and clinical practice are the source of new Chinese Medicine The traditional knowledge of traditional Chinese medicine includes the theory of traditional Chinese medicine and the medical theory, Materia Medica, prescriptions, disease knowledge, etc. discussed in the literature of previous dynasties,Most of these records are valuable experiences that have been tested by clinical practice,Therefore, the thinking concept and medication experience formed by the long-term clinical practice of traditional Chinese medicine are important sources of new drug prescriptions of traditional Chinese medicine,It has a solid clinical foundation and safe and effective guarantee For example, the discovery of artemisinin is the most typical example,The records of Artemisia annua intercepting malaria have been recorded in medical books of past dynasties,Researcher Tu youyou said in the ancient document "emergency prescription for elbow reserve" that "a grasp of Artemisia annua,One liter of water stains,Wring juice,Under the Enlightenment of "serving it all",Artemisinin was found in the sample prepared by cold dipping Artemisia annua leaves with low boiling point solvent Due to the use of artemisinin in the field of anti malaria,Worldwide,Especially in developing countries,Saved the lives of millions of malaria patients,Researcher Tu youyou won2011American Lasker clinical medicine award of the year This event once again enlightens us,The research and development of new Chinese medicine must pay attention to the record of traditional Chinese medicine knowledge,Find clues and inspiration for new drug research and development

The research and development process of new Chinese medicine is different from that of chemical innovative drugs,The prescription of new Chinese medicine includes single drug and compound drug,Relatively speaking, compound prescription is the characteristic and advantage of traditional Chinese Medicine,Supported by TCM theory and clinical practice,To provide a strong basis for explaining the rationality of the selected prescription for the treatment of diseases and syndromes Many new Chinese medicine compounds come from the summary of clinical experience,It has been used in clinic for a long time Characteristics of fixed medication of famous and old traditional Chinese Medicine,Even a fixed special prescription for specific diseases,Provide a good prescription source for the creation of new Chinese Medicine,Lay a foundation for the development of new drugs Therefore, the inheritance of traditional Chinese medicine knowledge is the premise for the creation of new Chinese medicine,The creation of new drugs of traditional Chinese medicine is one of the important contents of the inheritance of traditional Chinese Medicine,It is also an important embodiment of the dissemination of academic ideas of traditional Chinese medicine

3.2The construction of TCM prescriptions and clinical databases is a rapid platform for the discovery of new Chinese medicines Through long-term clinical practice of traditional Chinese Medicine,Accumulated a large number of effective prescriptions and medication experience,It can be preserved with books, documents and living famous doctors as carriers How to make effective use of ancient and modern literature,It can inherit the essence of famous doctors, masters and prescriptions,It can also ensure the accuracy of clinical efficacy,It is a problem that the traditional Chinese medicine industry is generally concerned about and looking forward to solving With the development of modern information technology,The wide application of computer in medical field,Database construction technology is becoming more and more mature,Various famous medical record databases, prescription databases and traditional Chinese medicine databases have been established successively,It has built a platform for the in-depth analysis of its formula rules

The Great Dictionary of traditional Chinese medicine prescriptions is the master of prescriptions of all ages,Loading prescription10More than ten thousand heads,It is a good material for analyzing the law of prescription composition,It is also an important source of new Chinese medicine research and development;The pharmaceutical standard of the Ministry of health of the people's Republic of China - traditional Chinese medicine formulated preparations is the national standard for traditional Chinese medicine formulated preparations,Collection of Chinese patent medicine4000More than species,It is widely used in clinic nowadays,It is an important reference for the research and development of new Chinese medicine Based on this,Applying computer technology to build its structured database,It will lay a foundation for further data mining The medical records recorded by traditional Chinese medicine doctors in the past dynasties are the concrete embodiment of their clinical practice,Nowadays, the clinical practice of traditional Chinese Medicine,Case data has been basically electronic,Hospitals all over the country generate a large amount of prescription information every day,The effective use of this information is also an urgent problem to be solved,Structured processing of these clinical data,Construction of TCM clinical prescription database,It can not only be stored as data and Archives,The corresponding data mining methods can also be used for mining analysis,Search for the drug laws contained therein,Provide basis and reference for the discovery of new Chinese medicine prescriptions

3.3The introduction of data mining method is a powerful tool for the discovery of new drugs in traditional Chinese Medicine Data mining is also called database knowledge discovery,It refers to the extraordinary process of revealing hidden, unknown and potentially valuable information from a large amount of data in the database,It is an interdisciplinary research field of database technology, statistics, machine learning, knowledge engineering, information retrieval, artificial intelligence, data visualization and high-performance computers Using data mining technology,Data mining of famous old TCM medical records, tested prescriptions, ancient prescriptions, ethnic medicines and other data in the database,Searching for the rule of group prescription from data,Based on the group formula determined by data mining and analysis and calculation,Combined with expert experience,Further targeted prescription screening will improve the hit rate Using data mining technology to study effective prescriptions,Can comprehensively analyze the laws,Breaking through the previous limitations of completely relying on experimental evaluation and personal experience,It provides a good reference for further research on new drugs of traditional Chinese Medicine,It has important guiding value

however,The object of traditional Chinese medicine data mining is the massive data accumulated in the field of traditional Chinese Medicine,The attributes of these data are both discrete,It also has the characteristics of continuous type and mixed type Guided by the professional background knowledge of traditional Chinese Medicine,Link of prescription discovery of new Chinese Medicine,The entropy method of complex system is proposed,And the corresponding research and practice are carried out How to integrate relevant mining methods and form corresponding software,It is an important direction for the application of data mining methods in the field of traditional Chinese medicine The Institute of traditional Chinese medicine of the Chinese Academy of Sciences of traditional Chinese medicine has developed an auxiliary system for the inheritance of traditional Chinese medicine(Traditional Chinese Medicine Inheritance Support System,TCMISS),The software integrates the existing general statistical method, text mining, association rules, complex system entropy method and other mining and analysis methods,The software has been widely used in data mining of famous medical records, analysis of drug use rules of disease prescriptions, screening of new drug formulations, etc,It is a powerful tool for the discovery and research of new Chinese medicine prescriptions

3.4Professional judgment of traditional knowledge and clinical practice verification are the guarantee for the creation of new drugs of traditional Chinese Medicine On the basis of database construction,Adopt appropriate data mining methods to conduct in-depth analysis of the data,Reveal the relevant laws of diseases, prescriptions, drugs, etc,Provide basis and reference for the screening and formulation of new Chinese medicine prescriptions on this basis ,According to TCM theory and personal experience,Can preliminarily determine the prescription of candidate new drugs,After that, the preliminarily determined candidate prescriptions can be revised in the form of written consultation by experts, holding consultation meetings on prescription screening, etc,Gradually elevate personal experience to group consensus,Make it conform to the traditional theory of traditional Chinese Medicine,It also reflects the wisdom of the group,Provide a more powerful guarantee for the drug likeness of new Chinese medicine

Through personal judgment of TCM professional knowledge,Combined with the advice of TCM experts,Identified candidate prescriptions for new Chinese medicines,It is necessary to further solidify the prescription for clinical practice and experimental verification Clinical indications according to candidate prescriptions,Select eligible included cases,Verify the effectiveness or superiority of candidate prescriptions Pre clinical study of new Chinese medicine shall be conducted for the candidate prescriptions with superior efficacy or R & D prospect after verification