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Strategy and Technical Support System for Developing New TCM Drugs
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WORLD SCIENCE AND TECHNOLOGY Volume 10, Issue 3, June 2008 Online English edition of the Chinese language journal Cite this article as: Mode Tradit Chin Med Mater Med, 2008, 10(3): 1–7
REVIEW
Strategy and Technical Support System for Developing New TCM Drugs /,$1*4LRQJOLQ/82*XRDQ=28-LDQTLDQJ*$2;LXPHL/,8-LDQ[XQ<(=XJXDQJ -,$ZHL 0RGHUQ5HVHDUFK&HQWHUIRU7&07VLQJKXD8QLYHUVLW\%HLMLQJ&KLQD 'LYLVLRQRI%LRWHFKQRORJ\DQG0HGLFLQH'HSDUWPHQWRI6RFLDO'HYHORSPHQW0LQLVWU\RI6FLHQFHDQG7HFKQRORJ\RI&KLQD %HLMLQJ&KLQD 7LDQMLQ8QLYHUVLW\RI7UDGLWLRQDO&KLQHVH0HGLFLQH7LDQMLQ &KLQD ;L\XDQ+RVSLWDO&KLQD$FDGHP\RI&KLQHVH0HGLFDO6FLHQFHV%HLMLQJ &KLQD 6WDWH5HVHDUFK&HQWHUIRU5᧢'RI7&00XOWLLQJUHGLHQW'UXJV%HLMLQJ&KLQD 6FKRRORI3KDUPDF\6KDQJKDL-LDR7RQJ8QLYHUVLW\6KDQJKDL&KLQD
Abstract: Along with frequently changed human disease spectrums, multicomponent drugs have attracted increasing attention of the mainstream international medical community. Traditional Chinese Medicine (TCM) has been deemed one of the best choices for treating complex chronic diseases. In this context, people believe that TCM formula and Chinese patented medicine with proven effects are valuable assets for bringing out new drugs and that modernized composite medicine (MCM) can be developed enjoying TCM-specific merits, with rational compatibility, identical pharmaceutical ingredients, clearly defined mechanism, safety assurance, efficacy, and quality control. Such a MCM will become popular in the mainstream international medical market, allowing inventors being at an advantageous position in the international competition for innovative drugs. This paper proposes a technical roadmap for developing composite medicines, with a range of useful suggestions and solutions. It also presents a perspective for developing new composite medicines. Key words: New drug discovery/development; Traditional Chinese Medicine; Composite medicine/Multicomponent drug; Roadmap; Key technology
1 Necessity and importance of developing new TCM drugs A revolutionary breakthrough of drug innovation based on synthetic drugs was made in 20th century, which made an indelible contribution for human health and also promoted the pharmaceutical science and industry. For more than 30 years, pharmaceutical industry has been one of the most rapidly increasing industries with its global gross output value maintaining a high annual growth rate of 11% on average [1]. With the development of society, the human disease spectrums have changed a lot.. Diseases with high incidence and biggest hazards are changing from single-factor infectious diseases to multifactor complex chronic diseases with disordered self-metabolism as their main spectrum group [2]. The Western medicine was successful for the treatment of single-factor infectious diseases, but there is still no satisfying solution for multifactor complex chronic diseases. Therefore, the new drug R&D model guided by the view of Western medicine is also facing a serious challenge. In recent decades, the number of new compounds synthesized, the targets identified, and the
R&D costs have all been increasing, but the success rate of drug R&D has been decreasing for 30 years [3]. The mainstream international medical community has also recognized the limitation of single-constituent and single-target drugs. The success of cocktail therapy, which is the representative of the multicomponent anti-AIDS drugs, has stimulated people’s interests in multicomponent drugs. Through a multicomponent, multipathway and multitarget regulation, multicomponent drugs may have incomparable advantages than single-component drugs in treating multifactor complex chronic diseases. In recent years, the FDA of US has approved a number of multicomponent drugs, such as the double-combination and triple-combination anti-AIDS drugs, the multicomponent tablets for type 2 diabetes (glipizide + metformin hydrochloride), the multicomponent preparation Caduet for hypertension and high blood lipid (amlodipine besylate + atorvastatin calcium), the antiasthma medicine (fluticasone propionate + salmeterol), the antihypertension multicomponent preparation Exforge (angiotensin receptor blocker valsartan + calcium channel blocker amlodipine), and An
Received date: 29 April 2008 * Corresponding author. Tel: +86-10-62781688; E-mail: [email protected] Foundation item: Supported by the Ministry of Science and Technology of the People's Republic of China (No. 2006BAI08B04) Copyright © 2008, World Science and Technology Press. Published by Elsevier BV. All rights reserved.
Liang Qionglin et al. / Mode Tradit Chin Med Mater Med, 2008, 10(3), 1-7
Bonuo (angiotensin Ċ receptor blocker irbesartan + diuretics hydrochlorothiazide). This indicates that the multicomponent drugs are accepted by the international mainstream community, and the composite medicine will be more and more important in the 21st century. Of course, the definition and standard of multicomponent drugs of U.S. FDA (which may be named as western composite medicines) are quite different from those of composite medicines of traditional Chinese medicine (TCM). Since TCM has not only profound treatment philosophies but also previous clinical experiences over the current Western composite drugs, we believe that developing composite medicine from TCM guided by the theory of TCM should be more preponderant. Although the complexity of TCM is a great challenge to its research and development, with the progress of modern science and technology available for TCM, it become possible to study and expound its material basis and mechanism so as to get the recognition of mainstream international medical community. For example, in the treatment of acute promyelocytic leukemia (APL) by TCM recipe Huangdai Tablets, Z. Chen’s group had reported a well-designed study in PNAS and given a systematic analysis to the multicomponent and multitarget mechanism [4]. Thus, for many chronic complex multifactor diseases, , it is appealing and technically feasible to develop new composite medicine based on clinical effective TCM, which will become an effective way of developing new drugs with its compatibility with current and future disease spectrum group. In the Major Special Program on ‘New Drugs Innovation’ of the Eleventh Five-Year Plan, Chinese government attaches a great importance to the development of new TCM drugs and will certainly promote it. Considering TCM’s advantage in formulation, the research and development of modernized composite medicine (MCM) based on effective traditional formulas will be the primary option, which can get not only the guidance of theory and clinical experience of TCM but also supports of recent advancement of the science and technology [5-16]. But we have to recognize that the methodology for developing new TCM drugs still need more exploration and study, and there is still no recognized high-throughput screening mode/roadmap for TCM comparing with that for Western medicine. The technical strategy and technological support system will be discussed as reference to the next stage of innovation and development of new TCM drugs.
2 Features and key scientific issues for developing new TCM drugs The fundamental features of TCM and key scientific issues are different from those of Western medicine, including the following items.
2.1
Different R&D pathway with different groundwork
From animal test to clinical trial, it takes long time for drug discovery and development of Western medicine, facing challenges of ‘high cost, low output, and high-risks’. Meanwhile, started usually from recipes with proven efficacy in clinic, the R&D of TCM under the principle of ‘efficacy-preservation and toxicity-reduction’ has a relatively higher success rate and leads to ‘low-input, high-output, and low-risks’ mode. The key issue needed to resolve for developing new TCM drugs is to ensure the proper choice of recipes, the efficacy of which should be evaluated by the investigation of experiments and clinical epidemiology under the principle of ‘a combination of TCM syndrome and diseases’ . 2.2 Different therapeutic philosophy Different from Western medicine focusing on single-target or single pathway corresponding with a disease, the therapeutic philosophy of TCM, particularly the composite medicine, requests an overall comprehensive regulation, so the efficacy of TCM shows not only the treatment of diseases but also the treatment of syndromes including the conditioning for the subhealth and health care. Traditional Chinese medicine therapeutics have unique advantages in clinical practice , but, such an advantage could hardly be demonstrated or even negative results might be obtained if the TCM composite medicine is simply evaluated according to the existing approaches and standards of Western medicine. Therefore, it is necessary to establish an efficacy evaluation system in accordance with the therapeutic philosophy of TCM. 2.3 Different drug formation in chemistry Different drug formation in chemistry requires different strategy for discovery of new drug. Western medicine is generally a single compound with clear specific target, thus a high-throughput screening mode aiming at the target is efficient. Traditional Chinese medicine represents a complex system of chemicals, in which a special combination of components (a group of effective constituents) might be contributed to the efficacy. Therefore, a novel strategy for discovery of new TCM drugs should be established providing approaches to characterize, screen, and understand those effective substances among a complex system of chemicals, to reveal the compatibilities and cooperative relationship of such a special combination of components under the principle of ‘efficacy-preservation and toxicity-reduction’, to control the quality of a complex multicomponent system, to study the pharmacokinetics, and to evaluate the safety of TCM. 2.4 Different patterns of action mechanism Western medicine interacts with human body via a
Liang Qionglin et al. / Mode Tradit Chin Med Mater Med, 2008, 10(3), 1-7
single-compound drug representing a pattern of ‘point vs. system’, while TCM interacts with human body via a group of substances representing a pattern of ‘system vs. system’. In order to reveal the material basis and mechanisms of TCM, an approach corresponding to the action pattern of ‘system vs. system’ is in demand, which requires both the overall characterization of TCM system and the integrative characterization of functional information in biological system, and establishes an appropriate interaction model to impact on the relationship of these two systems.
3 Mode and roadmap for developing new TCM drugs Considering these differences between Western medicine and Chinese medicine, a modern R&D system in accordance with characteristics of TCM should be established, which requires not only the guidelines of TCM theory system but also all of the modern advanced civilizations including Western medicine so as to maintain the efficacy and develop the advantage of TCM. In recent years, the progress of TCM modernization has benefited greatly from the progress of science and technology. Thus, the efforts in introducing modern science and technology will not blemish TCM but rather promote the modernization of TCM to be more widely recognized and prosperous. But we should realize that current scientific and technological means could not be expected to provide a perfect solution to such a complex system as TCM at this stage. Therefore, practical and realistic criterions should be applied at different stages upgrading with the progress of science and technology. In order to develop new TCM drugs, some key points should be considered, including the current situation and future development trends of the pharmaceutical industry, the practical demand of the community, the feasibility of existing technologies and the input-output efficiency. Under the premise of ‘safety, effectiveness, stability, and homogeneousness’, several kinds of TCM products with different R&D routines all should be acceptable. Of course, the modernization and internationalization become increasingly important in developing new TCM drugs. It is the easiest and direct way of internationalization to discover potential drug candidates by searching in compound library of TCM, according to conventional mode for high-throughput lead compound screening. The enormous compounds of TCM may become an important resource for drug discovery in the future. Besides the advantages in medicinal resources and even more valuable treasures may lie in clinical experiences and theories of TCM, especially its genius and success in the manner of composite medicine. Therefore, in the competition with powerful Western medicine countries, China may get the dominance if
seeking to develop new modernized TCM products with independent intellectual property rights and admission of the main international medicine market while maintaining characteristics of TCM. On the other hand, there are many historic classic and proved recipes that are practically tested to be effective and safe with long history of clinical use. It is also necessary to inherit and develop the custom and traditional form of TCM since the current science and technology is unable to completely solve all the problems of TCM modernization. Consequently, the roadmap of developing new TCM drugs is proposed as shown in Fig. 1. The key to a high success rate in developing new TCM drugs is the proper choice of TCM recipes with proven effects in clinic, which are suggested in priority to be historic, classic, and well-known recipes or well-marketing Chinese Patent Medicine. Some of effective recipes come from the TCM specialists’ innovation in formulation for therapy of some specific syndrome and diseases based on their long-term accumulated clinical experience and the guidelines of TCM therapeutics, which have been continually optimized during their application in clinic; others come from historic, classic, and well-known recipes, which could be modified on the basis of specific syndrome or diseases. Due to the importance of basal recipe with certain efficacy in clinic, the clinical epidemiology methods should be adopted to evaluate its clinical efficacy. For the selected TCM recipe passing the primary assessment, further research and development will be conducted following the roadmap as shown in Fig. 1. As a result, either of three options is possible according to the expected outcome and undertaking routine. Option 1: The product of ‘traditional composite medicine formulated with herbs After the identification of main indications and customization of pharmaceutical dosage form, a homemade preparation based on the selected TCM recipe can be approved as a within-hospital pharmaceutical for temporary use. And some of the within-hospital pharmaceuticals will have the privilege of developing a new drug product via a short cut, which means few pharmacological and chemical studies other than the nonclinical safety data and basic quality standards are required before admittance of clinical trial. Option 2: The product of ‘modernized composite medicine formulated with fractions’ For clinically effective TCM recipes, various types of extracts, components, and ingredients are obtained by using modern technologies such as extraction, isolation, purification, and building a material library of TCM. Based on the research of Components-Activities Relationship [6, 12, 15], effective components responsible
Liang Qionglin et al. / Mode Tradit Chin Med Mater Med, 2008, 10(3), 1-7
Fig.1 Roadmap of developing new TCM drugs
for the clinical efficacy will be screened out, while dispensable components will be removed. Then, guided by the theory of TCM and supported by the optimized compatibility design methods, some compatible combination patterns of effective components can be achieved and these combinations are further evaluated via an integrative assessment mode. The integrative assessment mode requires an efficacy evaluation system, which is accorded with the comprehensive characteristics of TCM, including the traditional diagnostic approaches upon TCM therapeutics (such as the quantificational score of syndrome, functional index, etc.), the classic pharmacological tests (including multiple levels such as the animal, organ, cell, and molecular biology), and
System Biology studies (including genomics, proteomics, and metabonomics). The optimized compatible combination of effective components can be developed into a preparation via modern pharmaceutical technology, establishing its quality standards and completing the pharmacological (including pharmacokinetics) and safety evaluation before clinical trial. If passing the clinical trials with the control, random and double-blind design, it will eventually be approved as a new drug product, which represents a MCM enjoying TCM-specific merits, with confirmed clinical efficacy, rational compatibility, identical pharmaceutical ingredients, clearly defined mechanism, modernized dosage form, and stable controllable quality.
Liang Qionglin et al. / Mode Tradit Chin Med Mater Med, 2008, 10(3), 1-7
Option 3: The product of ‘natural medicine or chemical drug’ By employing modern technologies of extraction, isolation, and purification, various components and pure compounds are able to be acquired from clinically effective TCM. These compounds isolated from TCM are possible to be used for the screening of new drug products according to the conventional research and development roadmap of natural medicines or chemical drugs.
system. Based on combination of the traditional diagnostic approaches upon TCM therapeutics (such as the quantificational score of syndrome, functional index, etc..), the classic pharmacological tests (including multiple levels such as the animal, organ, cell, and molecular biology), and the System Biology studies (including genomics, proteomics, and metabonomics), an integrative efficacy evaluation system in accordance with the comprehensive characteristics of TCM can be established.
4 Construction of technical support system for developing new TCM drugs
4.3 Quality standards and quality evaluation platform of TCM The platform should form a quality expression mode, which could reflect the characteristics of TCM of integrative effect upon a group of compounds. The quality standards should reflect the relationship between physical/chemical parameters and the efficacy. The parameters systems should combine the overall characterization (fingerprinting) and characteristic components (effective components and maker components), and also combine the quality control of final products with that of the herbs and intermediate. To establish the platforms and new mode in accordance with the characteristics of TCM for developing new TCM drugs, it is necessary to develop some key technologies, for example: 4.3.1 Systematic separation technology and the omics study of TCM Innovation of key technologies including extraction, isolation, separation, and analytical technologies are required for the systematic preparation of TCM components guided by activities screening, and for the study of Chemomics of TCM [12] and system biology [15]. 4.3.2 Theory and technology of design and optimization of TCM components combination According to the therapeutic principles and theory of TCM, new patterns of compatible combination should be developed including the combination of crude extracts, combination of fractions/components, as well as combination of specific constituents. And the approach to optimizing components combinations should be established to achieve the screening of TCM with low cost and high outcome by integrating the optimization algorithms for combination design, integrative assessment technologies, and informatics technologies. 4.3.3 Pharmacokinetics technology of TCM The pharmacokinetics study of TCM should reflect the integrity and cooperativity of a multicomponent drug and reveal the interaction relationship of herbs to herbs, components to components, or constituents to constituents among a composite medicine upon the dynamic characterization of chemical or biological
The roadmap makes the outlets and targets clear, and it also points out some key scientific issues and key technologies to be solved, which will help us in the construction. We should follow the government’s support, rely on some research institutes, universities, and high-tech parks with strong technology, integrate advantaged resources and build a strong union, construct some platforms of the innovation system, strengthen the common and key technology studies, and eventually establish and improve the technical support system for developing new TCM drugs through the demonstration research. In order to meet the urgent need for developing new TCM drugs, it is particularly necessary to build the following research platforms: 4.1 Efficacy evaluation platform of TCM The efficacy evaluation platform should show the ‘system vs. system’ feature of TCM and follow the principle of ‘disease-syndrome integration’. The quantitative syndrome parameters of Chinese medicine, the clinical pathology and biochemistry parameters of Western medicine, and the system biology evaluation parameters should be integrated, and so are the overall efficacy parameters and specific pathology parameters. 4.2 New drug discovery and assessment platform (integrative screening) of TCM As mentioned before, the innovation of TCM should has its own unique roadmap, thus, the new drug discovery and evaluation platform should be also different with other medicine systems, and the establishment of an integrative screening mode of TCM is significant. The platform should have the ability of systematic preparation of TCM components, design of components combination, integrative assessment, and screening of TCM components and their combinations. It should also integrate the compatibility theory of TCM, separation technologies of TCM components, approaches for analysis of Components-Activities Relationship, and information processing technologies to characterize and reveal the interaction between TCM system and human
Liang Qionglin et al. / Mode Tradit Chin Med Mater Med, 2008, 10(3), 1-7
changes. It is important to conduct the integrative study of drug metabolism and biological efficacy evaluation, and the integrative study of multicomponent pharmacokinetics and pharmacodynamics based on the overall effect of TCM. 4.3.4 Safety evaluation technology of TCM The acute toxicity and long-term toxicity should be evaluated under the regulation of GLP. Keystones should be put on the influence of the toxicity and efficacy after the compatible combination of different herbs or different components to demonstrate the scientificity and rationality of the principle ‘efficacy-preservation and toxicity-reduction for a TCM recipe’ through comparative study of different compatible combinations on systems characterization of species, profile, content, conformation, and metabolism of the toxic component and biological effects. 4.3.5 Quality control technology of TCM The integrative technology should be developed with the combination of chemical fingerprint, the biological response fingerprint and DNA fingerprint, combination of the chemistry of pharmaceutical components, metabolites in vivo, and activity information. The multiresidue testing and industrial removal technology of toxic and harmful substances (pesticide residues, heavy metals, etc.) are also appealing. For major products which demand most rigorous standards in quality control such as injection product of TCM, the development of on-line quality control should be encouraged so as to establish an overall process-included, comprehensive, and automated quality control system of TCM. 4.3.6 Pharmaceutical technology of TCM New pharmaceutical technologies in accordance with TCM should be developed, including nano-carrier, sustained and controlled release, and immediate release, etc...For the new modernized composite medicine (MCM) with identical pharmaceutical ingredients, clearly defined mechanism, stable and controllable quality, modern advanced dosage form can be applicable. Even the injection and large infusion are also acceptable if being used as ‘First-aid Medicine’ with confirmed clinical efficacy. 4.3.7 Technology of TCM informatics and bioinformatics The TCM informatics and bioinformatics are useful throughout the research and development process of new drugs, in particular, the informatics technologies concerning the identification of Components-Activities Relationship, quantitative analysis of the interaction among the multicomponents of TCM, and the modeling technology on biological regulation network are urgently desired.
5
Conclusions and prospects Compared with Western medicine, the research and
development of TCM has different goals, strategies, methods, and key technologies. The innovation of TCM should follow its own characteristics and discipline and call for an independent innovation with Chinese Characteristics. Our goal is not only simply in line with the international practice but also to establish an independent new drug innovation system in accordance with TCM and also to be accepted internationally. Thus, it will provide a platform to develop new MCM with characteristics of TCM, rational compatibility, basically clear composition and mechanism, and controllable quality and good safety. It is believed that innovative MCMs with advantaged therapeutics philosophy, scientific evidence-based study, and modernized form will be gradually recognized by the mainstream international medicine market and will be in an advantageous position in the future competition. At this stage, the innovation of new TCM drugs will be advantageous in two aspects, one is development from effective TCM recipes, the other is redevelopment of famous and well-marketing products of Chinese Patent Medicine. Since many companies own their products of Chinese Patent Medicine, which have been famous and popular in the market, it will be an efficient way with low risk and high output for these companies to cooperate with universities and research institutes in the redevelopment of well-marketing products of Chinese Patent Medicine. Even though, these products of Chinese Patent Medicine have a good reputation in their efficacy,, they are still deficient in the specification of their material basis and mechanism, establishment of effective quality control, and supports of scientific evidence-based study. Thus, further research and development is necessary to maintain their competitiveness in future market. According to the innovation roadmap, redevelopment of famous Chinese Patent Medicine is essential to basically clarify its material basis and mechanism and to improve the quality control. Based on the clarity of effective components among the TCM recipe, it is also possible to further optimize the compatible combination of effective components and develop a refined new prescription with equal or even better efficacy than the original. Pharmaceutical study will then be conducted to determine the proper dosage form. Then a new product of MCM will be obtained enjoying TCM-specific merits, with confirmed clinical efficacy, rational compatibility, identical pharmaceutical ingredients, clearly defined mechanism, modernized dosage form, and stable controllable quality. Since most of famous products of Chinese Patent Medicines have a solid foundation of theory and practice with reliable efficacy and relatively specific functions and indications based on long-term clinical application, their
Liang Qionglin et al. / Mode Tradit Chin Med Mater Med, 2008, 10(3), 1-7
redevelopment will yield a high output rate and bring important economic and social benefits.
Compound Chinese Medicines. World Science and
Acknowledgment
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The authors acknowledge the Ministry of Science and Technology of China for the support of National Key Technology R&D Program (2006BAI08B04).
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WORLD SCIENCE AND TECHNOLOGY Volume 10, Issue 3, June 2008 Online English edition of the Chinese language journal Cite this article as: Mode Tradit Chin Med Mater Med, 2008, 10(3): 1–7
REVIEW
Strategy and Technical Support System for Developing New TCM Drugs /,$1*4LRQJOLQ/82*XRDQ=28-LDQTLDQJ*$2;LXPHL/,8-LDQ[XQ<(=XJXDQJ -,$ZHL 0RGHUQ5HVHDUFK&HQWHUIRU7&07VLQJKXD8QLYHUVLW\%HLMLQJ&KLQD 'LYLVLRQRI%LRWHFKQRORJ\DQG0HGLFLQH'HSDUWPHQWRI6RFLDO'HYHORSPHQW0LQLVWU\RI6FLHQFHDQG7HFKQRORJ\RI&KLQD %HLMLQJ&KLQD 7LDQMLQ8QLYHUVLW\RI7UDGLWLRQDO&KLQHVH0HGLFLQH7LDQMLQ &KLQD ;L\XDQ+RVSLWDO&KLQD$FDGHP\RI&KLQHVH0HGLFDO6FLHQFHV%HLMLQJ &KLQD 6WDWH5HVHDUFK&HQWHUIRU5᧢'RI7&00XOWLLQJUHGLHQW'UXJV%HLMLQJ&KLQD 6FKRRORI3KDUPDF\6KDQJKDL-LDR7RQJ8QLYHUVLW\6KDQJKDL&KLQD
Abstract: Along with frequently changed human disease spectrums, multicomponent drugs have attracted increasing attention of the mainstream international medical community. Traditional Chinese Medicine (TCM) has been deemed one of the best choices for treating complex chronic diseases. In this context, people believe that TCM formula and Chinese patented medicine with proven effects are valuable assets for bringing out new drugs and that modernized composite medicine (MCM) can be developed enjoying TCM-specific merits, with rational compatibility, identical pharmaceutical ingredients, clearly defined mechanism, safety assurance, efficacy, and quality control. Such a MCM will become popular in the mainstream international medical market, allowing inventors being at an advantageous position in the international competition for innovative drugs. This paper proposes a technical roadmap for developing composite medicines, with a range of useful suggestions and solutions. It also presents a perspective for developing new composite medicines. Key words: New drug discovery/development; Traditional Chinese Medicine; Composite medicine/Multicomponent drug; Roadmap; Key technology
1 Necessity and importance of developing new TCM drugs A revolutionary breakthrough of drug innovation based on synthetic drugs was made in 20th century, which made an indelible contribution for human health and also promoted the pharmaceutical science and industry. For more than 30 years, pharmaceutical industry has been one of the most rapidly increasing industries with its global gross output value maintaining a high annual growth rate of 11% on average [1]. With the development of society, the human disease spectrums have changed a lot.. Diseases with high incidence and biggest hazards are changing from single-factor infectious diseases to multifactor complex chronic diseases with disordered self-metabolism as their main spectrum group [2]. The Western medicine was successful for the treatment of single-factor infectious diseases, but there is still no satisfying solution for multifactor complex chronic diseases. Therefore, the new drug R&D model guided by the view of Western medicine is also facing a serious challenge. In recent decades, the number of new compounds synthesized, the targets identified, and the
R&D costs have all been increasing, but the success rate of drug R&D has been decreasing for 30 years [3]. The mainstream international medical community has also recognized the limitation of single-constituent and single-target drugs. The success of cocktail therapy, which is the representative of the multicomponent anti-AIDS drugs, has stimulated people’s interests in multicomponent drugs. Through a multicomponent, multipathway and multitarget regulation, multicomponent drugs may have incomparable advantages than single-component drugs in treating multifactor complex chronic diseases. In recent years, the FDA of US has approved a number of multicomponent drugs, such as the double-combination and triple-combination anti-AIDS drugs, the multicomponent tablets for type 2 diabetes (glipizide + metformin hydrochloride), the multicomponent preparation Caduet for hypertension and high blood lipid (amlodipine besylate + atorvastatin calcium), the antiasthma medicine (fluticasone propionate + salmeterol), the antihypertension multicomponent preparation Exforge (angiotensin receptor blocker valsartan + calcium channel blocker amlodipine), and An
Received date: 29 April 2008 * Corresponding author. Tel: +86-10-62781688; E-mail: [email protected] Foundation item: Supported by the Ministry of Science and Technology of the People's Republic of China (No. 2006BAI08B04) Copyright © 2008, World Science and Technology Press. Published by Elsevier BV. All rights reserved.
Liang Qionglin et al. / Mode Tradit Chin Med Mater Med, 2008, 10(3), 1-7
Bonuo (angiotensin Ċ receptor blocker irbesartan + diuretics hydrochlorothiazide). This indicates that the multicomponent drugs are accepted by the international mainstream community, and the composite medicine will be more and more important in the 21st century. Of course, the definition and standard of multicomponent drugs of U.S. FDA (which may be named as western composite medicines) are quite different from those of composite medicines of traditional Chinese medicine (TCM). Since TCM has not only profound treatment philosophies but also previous clinical experiences over the current Western composite drugs, we believe that developing composite medicine from TCM guided by the theory of TCM should be more preponderant. Although the complexity of TCM is a great challenge to its research and development, with the progress of modern science and technology available for TCM, it become possible to study and expound its material basis and mechanism so as to get the recognition of mainstream international medical community. For example, in the treatment of acute promyelocytic leukemia (APL) by TCM recipe Huangdai Tablets, Z. Chen’s group had reported a well-designed study in PNAS and given a systematic analysis to the multicomponent and multitarget mechanism [4]. Thus, for many chronic complex multifactor diseases, , it is appealing and technically feasible to develop new composite medicine based on clinical effective TCM, which will become an effective way of developing new drugs with its compatibility with current and future disease spectrum group. In the Major Special Program on ‘New Drugs Innovation’ of the Eleventh Five-Year Plan, Chinese government attaches a great importance to the development of new TCM drugs and will certainly promote it. Considering TCM’s advantage in formulation, the research and development of modernized composite medicine (MCM) based on effective traditional formulas will be the primary option, which can get not only the guidance of theory and clinical experience of TCM but also supports of recent advancement of the science and technology [5-16]. But we have to recognize that the methodology for developing new TCM drugs still need more exploration and study, and there is still no recognized high-throughput screening mode/roadmap for TCM comparing with that for Western medicine. The technical strategy and technological support system will be discussed as reference to the next stage of innovation and development of new TCM drugs.
2 Features and key scientific issues for developing new TCM drugs The fundamental features of TCM and key scientific issues are different from those of Western medicine, including the following items.
2.1
Different R&D pathway with different groundwork
From animal test to clinical trial, it takes long time for drug discovery and development of Western medicine, facing challenges of ‘high cost, low output, and high-risks’. Meanwhile, started usually from recipes with proven efficacy in clinic, the R&D of TCM under the principle of ‘efficacy-preservation and toxicity-reduction’ has a relatively higher success rate and leads to ‘low-input, high-output, and low-risks’ mode. The key issue needed to resolve for developing new TCM drugs is to ensure the proper choice of recipes, the efficacy of which should be evaluated by the investigation of experiments and clinical epidemiology under the principle of ‘a combination of TCM syndrome and diseases’ . 2.2 Different therapeutic philosophy Different from Western medicine focusing on single-target or single pathway corresponding with a disease, the therapeutic philosophy of TCM, particularly the composite medicine, requests an overall comprehensive regulation, so the efficacy of TCM shows not only the treatment of diseases but also the treatment of syndromes including the conditioning for the subhealth and health care. Traditional Chinese medicine therapeutics have unique advantages in clinical practice , but, such an advantage could hardly be demonstrated or even negative results might be obtained if the TCM composite medicine is simply evaluated according to the existing approaches and standards of Western medicine. Therefore, it is necessary to establish an efficacy evaluation system in accordance with the therapeutic philosophy of TCM. 2.3 Different drug formation in chemistry Different drug formation in chemistry requires different strategy for discovery of new drug. Western medicine is generally a single compound with clear specific target, thus a high-throughput screening mode aiming at the target is efficient. Traditional Chinese medicine represents a complex system of chemicals, in which a special combination of components (a group of effective constituents) might be contributed to the efficacy. Therefore, a novel strategy for discovery of new TCM drugs should be established providing approaches to characterize, screen, and understand those effective substances among a complex system of chemicals, to reveal the compatibilities and cooperative relationship of such a special combination of components under the principle of ‘efficacy-preservation and toxicity-reduction’, to control the quality of a complex multicomponent system, to study the pharmacokinetics, and to evaluate the safety of TCM. 2.4 Different patterns of action mechanism Western medicine interacts with human body via a
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single-compound drug representing a pattern of ‘point vs. system’, while TCM interacts with human body via a group of substances representing a pattern of ‘system vs. system’. In order to reveal the material basis and mechanisms of TCM, an approach corresponding to the action pattern of ‘system vs. system’ is in demand, which requires both the overall characterization of TCM system and the integrative characterization of functional information in biological system, and establishes an appropriate interaction model to impact on the relationship of these two systems.
3 Mode and roadmap for developing new TCM drugs Considering these differences between Western medicine and Chinese medicine, a modern R&D system in accordance with characteristics of TCM should be established, which requires not only the guidelines of TCM theory system but also all of the modern advanced civilizations including Western medicine so as to maintain the efficacy and develop the advantage of TCM. In recent years, the progress of TCM modernization has benefited greatly from the progress of science and technology. Thus, the efforts in introducing modern science and technology will not blemish TCM but rather promote the modernization of TCM to be more widely recognized and prosperous. But we should realize that current scientific and technological means could not be expected to provide a perfect solution to such a complex system as TCM at this stage. Therefore, practical and realistic criterions should be applied at different stages upgrading with the progress of science and technology. In order to develop new TCM drugs, some key points should be considered, including the current situation and future development trends of the pharmaceutical industry, the practical demand of the community, the feasibility of existing technologies and the input-output efficiency. Under the premise of ‘safety, effectiveness, stability, and homogeneousness’, several kinds of TCM products with different R&D routines all should be acceptable. Of course, the modernization and internationalization become increasingly important in developing new TCM drugs. It is the easiest and direct way of internationalization to discover potential drug candidates by searching in compound library of TCM, according to conventional mode for high-throughput lead compound screening. The enormous compounds of TCM may become an important resource for drug discovery in the future. Besides the advantages in medicinal resources and even more valuable treasures may lie in clinical experiences and theories of TCM, especially its genius and success in the manner of composite medicine. Therefore, in the competition with powerful Western medicine countries, China may get the dominance if
seeking to develop new modernized TCM products with independent intellectual property rights and admission of the main international medicine market while maintaining characteristics of TCM. On the other hand, there are many historic classic and proved recipes that are practically tested to be effective and safe with long history of clinical use. It is also necessary to inherit and develop the custom and traditional form of TCM since the current science and technology is unable to completely solve all the problems of TCM modernization. Consequently, the roadmap of developing new TCM drugs is proposed as shown in Fig. 1. The key to a high success rate in developing new TCM drugs is the proper choice of TCM recipes with proven effects in clinic, which are suggested in priority to be historic, classic, and well-known recipes or well-marketing Chinese Patent Medicine. Some of effective recipes come from the TCM specialists’ innovation in formulation for therapy of some specific syndrome and diseases based on their long-term accumulated clinical experience and the guidelines of TCM therapeutics, which have been continually optimized during their application in clinic; others come from historic, classic, and well-known recipes, which could be modified on the basis of specific syndrome or diseases. Due to the importance of basal recipe with certain efficacy in clinic, the clinical epidemiology methods should be adopted to evaluate its clinical efficacy. For the selected TCM recipe passing the primary assessment, further research and development will be conducted following the roadmap as shown in Fig. 1. As a result, either of three options is possible according to the expected outcome and undertaking routine. Option 1: The product of ‘traditional composite medicine formulated with herbs After the identification of main indications and customization of pharmaceutical dosage form, a homemade preparation based on the selected TCM recipe can be approved as a within-hospital pharmaceutical for temporary use. And some of the within-hospital pharmaceuticals will have the privilege of developing a new drug product via a short cut, which means few pharmacological and chemical studies other than the nonclinical safety data and basic quality standards are required before admittance of clinical trial. Option 2: The product of ‘modernized composite medicine formulated with fractions’ For clinically effective TCM recipes, various types of extracts, components, and ingredients are obtained by using modern technologies such as extraction, isolation, purification, and building a material library of TCM. Based on the research of Components-Activities Relationship [6, 12, 15], effective components responsible
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Fig.1 Roadmap of developing new TCM drugs
for the clinical efficacy will be screened out, while dispensable components will be removed. Then, guided by the theory of TCM and supported by the optimized compatibility design methods, some compatible combination patterns of effective components can be achieved and these combinations are further evaluated via an integrative assessment mode. The integrative assessment mode requires an efficacy evaluation system, which is accorded with the comprehensive characteristics of TCM, including the traditional diagnostic approaches upon TCM therapeutics (such as the quantificational score of syndrome, functional index, etc.), the classic pharmacological tests (including multiple levels such as the animal, organ, cell, and molecular biology), and
System Biology studies (including genomics, proteomics, and metabonomics). The optimized compatible combination of effective components can be developed into a preparation via modern pharmaceutical technology, establishing its quality standards and completing the pharmacological (including pharmacokinetics) and safety evaluation before clinical trial. If passing the clinical trials with the control, random and double-blind design, it will eventually be approved as a new drug product, which represents a MCM enjoying TCM-specific merits, with confirmed clinical efficacy, rational compatibility, identical pharmaceutical ingredients, clearly defined mechanism, modernized dosage form, and stable controllable quality.
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Option 3: The product of ‘natural medicine or chemical drug’ By employing modern technologies of extraction, isolation, and purification, various components and pure compounds are able to be acquired from clinically effective TCM. These compounds isolated from TCM are possible to be used for the screening of new drug products according to the conventional research and development roadmap of natural medicines or chemical drugs.
system. Based on combination of the traditional diagnostic approaches upon TCM therapeutics (such as the quantificational score of syndrome, functional index, etc..), the classic pharmacological tests (including multiple levels such as the animal, organ, cell, and molecular biology), and the System Biology studies (including genomics, proteomics, and metabonomics), an integrative efficacy evaluation system in accordance with the comprehensive characteristics of TCM can be established.
4 Construction of technical support system for developing new TCM drugs
4.3 Quality standards and quality evaluation platform of TCM The platform should form a quality expression mode, which could reflect the characteristics of TCM of integrative effect upon a group of compounds. The quality standards should reflect the relationship between physical/chemical parameters and the efficacy. The parameters systems should combine the overall characterization (fingerprinting) and characteristic components (effective components and maker components), and also combine the quality control of final products with that of the herbs and intermediate. To establish the platforms and new mode in accordance with the characteristics of TCM for developing new TCM drugs, it is necessary to develop some key technologies, for example: 4.3.1 Systematic separation technology and the omics study of TCM Innovation of key technologies including extraction, isolation, separation, and analytical technologies are required for the systematic preparation of TCM components guided by activities screening, and for the study of Chemomics of TCM [12] and system biology [15]. 4.3.2 Theory and technology of design and optimization of TCM components combination According to the therapeutic principles and theory of TCM, new patterns of compatible combination should be developed including the combination of crude extracts, combination of fractions/components, as well as combination of specific constituents. And the approach to optimizing components combinations should be established to achieve the screening of TCM with low cost and high outcome by integrating the optimization algorithms for combination design, integrative assessment technologies, and informatics technologies. 4.3.3 Pharmacokinetics technology of TCM The pharmacokinetics study of TCM should reflect the integrity and cooperativity of a multicomponent drug and reveal the interaction relationship of herbs to herbs, components to components, or constituents to constituents among a composite medicine upon the dynamic characterization of chemical or biological
The roadmap makes the outlets and targets clear, and it also points out some key scientific issues and key technologies to be solved, which will help us in the construction. We should follow the government’s support, rely on some research institutes, universities, and high-tech parks with strong technology, integrate advantaged resources and build a strong union, construct some platforms of the innovation system, strengthen the common and key technology studies, and eventually establish and improve the technical support system for developing new TCM drugs through the demonstration research. In order to meet the urgent need for developing new TCM drugs, it is particularly necessary to build the following research platforms: 4.1 Efficacy evaluation platform of TCM The efficacy evaluation platform should show the ‘system vs. system’ feature of TCM and follow the principle of ‘disease-syndrome integration’. The quantitative syndrome parameters of Chinese medicine, the clinical pathology and biochemistry parameters of Western medicine, and the system biology evaluation parameters should be integrated, and so are the overall efficacy parameters and specific pathology parameters. 4.2 New drug discovery and assessment platform (integrative screening) of TCM As mentioned before, the innovation of TCM should has its own unique roadmap, thus, the new drug discovery and evaluation platform should be also different with other medicine systems, and the establishment of an integrative screening mode of TCM is significant. The platform should have the ability of systematic preparation of TCM components, design of components combination, integrative assessment, and screening of TCM components and their combinations. It should also integrate the compatibility theory of TCM, separation technologies of TCM components, approaches for analysis of Components-Activities Relationship, and information processing technologies to characterize and reveal the interaction between TCM system and human
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changes. It is important to conduct the integrative study of drug metabolism and biological efficacy evaluation, and the integrative study of multicomponent pharmacokinetics and pharmacodynamics based on the overall effect of TCM. 4.3.4 Safety evaluation technology of TCM The acute toxicity and long-term toxicity should be evaluated under the regulation of GLP. Keystones should be put on the influence of the toxicity and efficacy after the compatible combination of different herbs or different components to demonstrate the scientificity and rationality of the principle ‘efficacy-preservation and toxicity-reduction for a TCM recipe’ through comparative study of different compatible combinations on systems characterization of species, profile, content, conformation, and metabolism of the toxic component and biological effects. 4.3.5 Quality control technology of TCM The integrative technology should be developed with the combination of chemical fingerprint, the biological response fingerprint and DNA fingerprint, combination of the chemistry of pharmaceutical components, metabolites in vivo, and activity information. The multiresidue testing and industrial removal technology of toxic and harmful substances (pesticide residues, heavy metals, etc.) are also appealing. For major products which demand most rigorous standards in quality control such as injection product of TCM, the development of on-line quality control should be encouraged so as to establish an overall process-included, comprehensive, and automated quality control system of TCM. 4.3.6 Pharmaceutical technology of TCM New pharmaceutical technologies in accordance with TCM should be developed, including nano-carrier, sustained and controlled release, and immediate release, etc...For the new modernized composite medicine (MCM) with identical pharmaceutical ingredients, clearly defined mechanism, stable and controllable quality, modern advanced dosage form can be applicable. Even the injection and large infusion are also acceptable if being used as ‘First-aid Medicine’ with confirmed clinical efficacy. 4.3.7 Technology of TCM informatics and bioinformatics The TCM informatics and bioinformatics are useful throughout the research and development process of new drugs, in particular, the informatics technologies concerning the identification of Components-Activities Relationship, quantitative analysis of the interaction among the multicomponents of TCM, and the modeling technology on biological regulation network are urgently desired.
5
Conclusions and prospects Compared with Western medicine, the research and
development of TCM has different goals, strategies, methods, and key technologies. The innovation of TCM should follow its own characteristics and discipline and call for an independent innovation with Chinese Characteristics. Our goal is not only simply in line with the international practice but also to establish an independent new drug innovation system in accordance with TCM and also to be accepted internationally. Thus, it will provide a platform to develop new MCM with characteristics of TCM, rational compatibility, basically clear composition and mechanism, and controllable quality and good safety. It is believed that innovative MCMs with advantaged therapeutics philosophy, scientific evidence-based study, and modernized form will be gradually recognized by the mainstream international medicine market and will be in an advantageous position in the future competition. At this stage, the innovation of new TCM drugs will be advantageous in two aspects, one is development from effective TCM recipes, the other is redevelopment of famous and well-marketing products of Chinese Patent Medicine. Since many companies own their products of Chinese Patent Medicine, which have been famous and popular in the market, it will be an efficient way with low risk and high output for these companies to cooperate with universities and research institutes in the redevelopment of well-marketing products of Chinese Patent Medicine. Even though, these products of Chinese Patent Medicine have a good reputation in their efficacy,, they are still deficient in the specification of their material basis and mechanism, establishment of effective quality control, and supports of scientific evidence-based study. Thus, further research and development is necessary to maintain their competitiveness in future market. According to the innovation roadmap, redevelopment of famous Chinese Patent Medicine is essential to basically clarify its material basis and mechanism and to improve the quality control. Based on the clarity of effective components among the TCM recipe, it is also possible to further optimize the compatible combination of effective components and develop a refined new prescription with equal or even better efficacy than the original. Pharmaceutical study will then be conducted to determine the proper dosage form. Then a new product of MCM will be obtained enjoying TCM-specific merits, with confirmed clinical efficacy, rational compatibility, identical pharmaceutical ingredients, clearly defined mechanism, modernized dosage form, and stable controllable quality. Since most of famous products of Chinese Patent Medicines have a solid foundation of theory and practice with reliable efficacy and relatively specific functions and indications based on long-term clinical application, their
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redevelopment will yield a high output rate and bring important economic and social benefits.
Compound Chinese Medicines. World Science and
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