ArchiveThe product production chain of traditional Chinese medicine suffers from low product quality, low efficiency transformation, and insufficient innovation capability, and there lacks complete innovation process chain to address product-independent R&D innovation. For the process chain of Chinese medicine product development, this paper analyzes and discusses the application of Chinese medicine product innovation methods by combining five methods: quality function development (QFD), inventive problem solving theory Teoriya Resheniya Izobreatatelskikh Zadatch (TRIZ), quality by design (QbD), design of experiments (DOE), and data envelopment analysis (DEA). Firstly, QFD is applied to determine the direction of innovation by comprehensive analysis of user needs and actual situation; secondly, TRIZ is applied to analyze and solve the contradictions to be solved by the product, propose solutions and combine QbD and DOE for experimental design and verification; finally, DEA is applied to allocate resources to optimize the efficiency. Combining innovation methods to develop and design Chinese medicine products can develop core technologies and equipment with independent intellectual property rights, effectively improve the quality and effectiveness of Chinese medicine products transformation, which is meaningful for the development of Chinese medicine products.
Clinical orientation is the expected therapeutic effect of drugs on diseases, and accurate clinical orientation is the key to successful development of new drugs and clinical rational drug use after marketing. The rationality of clinical orientation for traditional Chinese medicine should be evaluated from the aspects of research drugs, targeting diseases, existing therapeutic drugs and review requirements. The methods and basis of clinical orientation include human experience, theory of traditional Chinese medicine, basic researches and clinical trials. By selecting reasonable clinical orientation and taking clinical value as the guidance, the curative effect of traditional Chinese medicine can be truly reflected, and the quality of research and development and success rate of new Chinese medicine will be improved.
The drug R&D of rare diseases in China is still in early stage. Collaborations have become a choice for many companies to enter that field. This article analyzes the collaboration deals involving Chinese companies from year 2011 to April 30th, 2022 on drugs with indication included in the first batch of rare disease list. It is found that as the country has put more emphasis on rare diseases, the number of transactions has increased significantly after the year of 2019. The deal model is mainly licensing deal, and transactions in rare disease indications with a big population is relatively concentrated. A group of biotechnology companies with rare diseases as their strategic focus have emerged. It is suggested to promote the legislation of rare diseases in China and more incentive policies concerning the research and development in rare diseases can be introduced in the future, so as to promote more Chinese companies to join in the research and development of innovative drugs in the rare diseases, and to further accelerate the development of local innovative drugs for rare diseases.
Patents have long been considered as the most important way to protect pharmaceutical innovations, and the drug patent system has exerted a profound impact on the development of the pharmaceutical industry. In the context that domestic effective drug regulations and patent laws and regulations have covered the provisions on drug patent linkage system, this paper, by taking the first case of domestic drug patent linkage litigation as an instance, analyzes the trial effect of the newly launched drug patent linkage system in China, explores its impact on the generic drug industry, and tries to give suggestions to generic drug enterprises on the choice of patent application types and the authenticity of application materials. The research-based pharmaceutical enterprises need to seize the opportunity to safeguard their rights and protect themselves against patent infringement by choosing an appropriate method to resolve patent disputes. Moreover, given the constraints of China's binary separation of procedures of patent infringement and patent invalidation on the early solution of pharmaceutical patent disputes and the problems awaiting to be solved in different types of patent applications, this paper also puts forward related suggestions on patent protection, including the necessity of timely review and analysis of the implementation of the patent linkage system, enhancement of the legal status of administrative adjudication to enable some authorities of administrative confirmation, and the necessity for clearer definition of types of patent applications and further standardization of patent infringement cases under different circumstances.
Elemental impurities in drug products may arise from several sources, and should be controlled within acceptable limits. ICH has published the final version Q3D (R2) Guideline for Element Impurities in 2022, establishing a global harmonized guideline for the control of elemental impurities in new drug products. Based on ICH Q3D (R2), this article summarizes the classification and safety assessment principles of element impurities, proposes the general considerations in the risk assessment and control strategy from the perspective of CMC review, and discusses the key steps and main problems in the evaluation of elemental impurities, providing reference for the establishment of science-based and risk-based control strategy.
Since the first Chimeric Antigen Receptor T Cell (CAR-T) therapeutic drug was approved in 2017, cellular immunotherapy drugs have continued to develop and become a hot spot in the field of biopharmaceuticals. In recent years, with the development of biotechnology, new CAR-T designs have emerged, and their indications have also expanded from hematological tumors to solid tumors, autoimmune diseases, and viral infections. Through optimized design, the activity of novel CAR-T cells has been continuously enhanced, while the toxicity reduced. Meanwhile, in order to further explore the safety and efficacy of CAR-T cells, its non-clinical evaluation models and methods have constantly been improving. In order to provide new ideas and considerations for the safety evaluation of immune cell therapy products, the latest research progress of CAR-T cell therapy and related new non-clinical evaluation methods are reviewed.
A small GTPase encoded by Kirsten rat sarcoma viral proto oncogene (RAS) is a key regulatory protein in multiple cellular signaling pathways. The mutation of glycine to cysteine (G12C) at position 12 often leads to abnormal activation of cellular pathways, which plays an important role in the occurrence and development of tumors. Small molecule covalent inhibitors targeting KRASG12C protein can directly inhibit the abnormal activation of cellular pathways caused by KRASG12C mutation. In this paper, the structure and function of KRAS protein, as well as the research and development progress, challenges and possible solutions of covalent inhibitors of its G12C mutant are reviewed. The development direction of (K) RAS inhibitors in the future is prospected in order to provide a useful reference for the research and development of such inhibitors.
The scale of pediatric drug use in China exceeds 60 billion, but the quantity of pediatric drugs is limited and the variety is few, making the R&D and drug innovation is particularly necessary. Since children's esophagus is narrow, the respiratory tracts prematurely develop and the medication compliance is low, traditional drug dosage forms such as capsule, tablet, and decoction are easy to cause throat blockage, choking and even suffocation. According to the characteristics of children when taking medicine, the concept of oral gels has been put forward in foreign countries to improve the compliance of pediatric patients to take medicine and reduce the risk of aspiration. Based on the review of related literature in China and abroad, we conclude the common matrix and preparation methods of children's oral gels, summarize the characteristics and quality control methods of the dosage forms. Examples are given to show the general research situation of application both in China and abroad, as well as the situation of registration and listing, in order to promote the development of domestic pediatric oral gels, broaden the space of pediatric drugs' research and development, promote the exploitation of new pediatric drugs to protect children's health.
To compare the efficacy and safety of iguratimod or methotrexate combined with leflunomide in patients with active elderly-onset rheumatoid arthritis.
A single-center, randomized, double-blinded, controlled clinical trial was conducted in elderly-onset patients. The patients were randomly assigned to two groups of iguratimod combined with leflunomide (Group Iguratimod) or methotrexate combined with leflunomide (Group Methotrexate) treatments at a ratio of 1∶1. The efficacy and safety of both groups were evaluated at weeks 4, 12, 24 and 52, respectively. The primary endpoint was the American Colleague of Rheumatology 20 (ACR20) response rates at week 52 and disease activity score (DAS28) (CRP) at 52 weeks after treatment.
A total of 104 patients with elderly-onset rheumatoid arthritis were enrolled in the study. The comparison of the two groups on the baseline demographic data and RA activity showed that the iguratimod group was older (67.0 and 64.0, Z=-2.874, P=0.004), and the methotrexate group had a higher DAS28 (CRP) score (4.7 and 6.0, Z=-3.163, P=0.002). There was no statistically significant difference between the remaining results of the two groups. After 52 weeks of treatment, the ACR20 compliance rates in the iguratimod group and the methotrexate group were 90.0% and 93.9%, respectively (χ2=0.115, P=0.735). There was no statistically significant difference in compliance rates of ACR20, ACR50 and ACR70 between the groups at other time points compared to the baseline. There was no statistically significant difference in the DAS28 (CRP) score between the two groups at the end point of 52 weeks. Fewer adverse events were observed in the iguratimod group compared to the methotrexate group (26.0% and 46.9%, χ2=4.689, P=0.030). No serious adverse events were found in Group Iguratimod, but 3 cases of pneumonia were hospitalized in Group Methotrexate.
Iguratimod combined with leflunomide is an effective regimen with good safety for the treatment of active elderly-onset rheumatoid arthritis, with comparable efficacy and better safety compared to methotrexate combined with leflunomide.
Research wards are an important carrier for clinical trial research. In order to achieve high-quality and efficient development, it is necessary to comprehensively improve the level of informatization and digital application.
This paper takes application innovation as the guidance and quality and efficiency improvement as the goal. By sorting out the clinical trial business management needs, an information platform is built to open up the whole chain of clinical trial research business processes, and an interconnection mechanism with the hospital information system (HIS) is established to achieve the integrated management of clinical trial projects, trial subjects, trial drugs, trial doctor's orders, trial costs, trial quality, etc..
The digital intelligence-driven clinical trial research business has been transformed from traditional manual management to automated and intelligent management, effectively improving the efficiency of the whole process of management, reducing the burden on researchers, achieving precise and efficient supervision, and promoting the integration of clinical research, etc.
Provide support and guarantee for high-quality construction of research wards from the perspective of information construction, and add new momentum for the transformation and development of hospitals into research hospitals.
To provide reference for the compliance management of sponsors and research institutions in drug clinical trial cooperation.
Based on the typical cases of drug clinical trials in Chinese Judgment Documents Online, this paper studies the legal risks, causes and countermeasures in the process of drug clinical trial cooperation from both macro and micro perspectives.
Overall, violations of drug clinical trial cooperation are probably subject to civil liability, administrative penalties, and criminal sanctions. At the micro level, both sponsors and research institutions generally neglect to review the clinical trial contracts, improperly manage clinical trial quality, and neglect subject protection. At the macro level, the legal policies of drug clinical trials are non-systematic, and the supervision of drug clinical trials is becoming stricter.
The sponsors and research institutions should adapt to the new requirements under the new policy, improve the main responsibility, and pursue higher standards of compliance requirements, in order to ensure the safety of subjects in clinical trials, while maximizing their legitimate rights and interests, thus preventing legal risks.
To synthesize resveratrol analogues and investigate their anti-diabetic activity and related mechanism.
Using different substituted anilines and different substituted benzaldehydes as raw materials, resveratrol analogs were synthesized under ethanol reflux, and their protective effects on pancreatic β cells were tested under the stimulation of palmitic acid (PA). The anti-diabetic mechanism of the dominant compounds was explored.
Most of the compounds have protective effects on pancreatic β cells, and the compounds JA10 and JA12 have significant cytoprotective effects. Molecular mechanism studies showed that the compounds JA10 and JA12 reduced the generation of reactive oxygen, and inhibited the gene expression of inflammatory factors IL-1β and IL-6.
The resveratrol analogs JA10 and JA12 are potential antidiabetic new chemical entities.
To investigate the therapeutic effect and safety of the extract of Qingxin Lianzi Decoction (QLD) on nephritis in rats.
The antibacterial activity of QLD extract against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa in vitro was determined by disk diffusion and double dilution methods. Pyelonephritis model induced by bacterial, adriamycin-induced glomerulonephritis model and IgA nephropathy model in rats were used to evaluate the therapeutic effect on nephritis in rats. The safety of QLD extract was preliminarily evaluated using the acute toxicity test in mice.
QLD extract had no obvious antibacterial activity against the three pathogenic bacteria in vitro, but it significantly reduced the contents of creatinine and urea nitrogen in serum, decreased the levels of urinary occult blood and urine protein in pyelonephritis rats. At the same time, the 8 g·kg-1 dose of QLD significantly reduced the contents of creatinine and urea nitrogen in serum, but had no significant effect on the kidney index and urine protein in glomerulonephritis rats. Moreover, the 8 g·kg-1 dose of QLD significantly reduced the level of urine protein in IgA nephropathy rats, but had no significant effect on creatinine, urea nitrogen and kidney index. The results of acute toxicity showed that the maximum dose of QLD extract is 48 g·kg-1, and no obvious toxicity and death were observed.
QLD extract has therapeutic effects on three experimental nephritis in rats.
The present study explored the active ingredients and potential mechanism of Wuwei Ganlu yaoyu decoction powder in the treatment of gouty arthritis(GA).
The main chemical components of Wuwei Ganlu yaoyu decoction powder were identified by UPLC-Q-Exactive-Orbitrap-MS. The target compounds were screened from the identified compounds by Swiss Target database. The databases genecards, OMIM and others were used to screen disease targets, STRING to build PPI network and select key targets, DAVID to enrich GO and KEGG pathways of common targets of drug diseases. Based on these, we discussed the mechanism of Wuwei Ganlu yaoyu decoction powder in the treatment of GA. In addition, the "drug-component-target-disease" network was constructed by using Cytoscape 3.9.1 software, and Maestro software was used to conduct molecular docking between components and core targets to screen effective components.
A total of 52 compounds were identified, including 24 flavonoids, 5 alkaloids, 10 organic acids, 5 phenols, 5 phenylpropanoids, 2 terpenoids and 1 alkane. According to the analysis of network pharmacology, there were 520 component targets and 141 intersection targets of Wuwei Ganlu yaoyu decoction powder, and 5 core targets were screened (SRC, STST3, PIK3CA, MAPK1, HSP90AA1). Molecular docking showed that six components such as Luteolin had good binding ability with five core targets.
The active components of Wuwei Ganlu yaoyu decoction powder in the treatment of GA are luteolin, hyperoxin-7-O-β-D-glucopyranoside, Hyprolatine-7-O-β-D-xylopyranoside, quercetin, naringin and luteolin, which may be related to the action on targets like SRC, STAT3, PIK3CA and others to regulate the signal pathways of PI3K Akt, Ras, MAPK, etc.
To evaluate the impact of budget on the total health care costs of using ferric carboxymaltose to correct iron deficiency anaemia compared with usual care in perioperative anaemia management in general surgery, and to provide a decision-making basis to promote the implementation of patient blood management (PBM) in China, particularly anaemia management focused on rapid and adequate iron supplementation in the perioperative period.
Based on Chinese epidemiological data, the differences in the reduction of allogeneic blood transfusion rate and length of stay in the perioperative period between the PBM group and the conventional treatment group were compared, and an analysis model of impact on budget was constructed combined with domestic cost data. Clinical outcomes were from data of foreign randomized clinical trials, and cost data were from public prices in the domestic market, including iron drug (oral iron, ferric carboxymaltose), injection, EPO use, blood transfusion, and hospitalization.
Based on 3.758 million elective general surgery patients nationwide, the use of ferric carboxymaltose for anaemia management in the perioperative period as a complete substitute for routine care would have prevented 704,690 blood transfusions and saved a total of ￥139 million in treatment costs, with an average saving of ￥42 per patient. A sensitivity analysis showed total treatment cost savings of ￥1.086 billion, ￥2.033 billion, ￥2.981 billion and ￥3.928 billion assuming a 10%, 20%, 30% and 40% reduction in the price of ferric carboxymaltose, with average cost savings per patient being ￥289, ￥541, ￥793 and ￥1 045, respectively.
It is recommended that the patients with clinical perioperative iron deficiency anaemia undergo implementation of patient blood management and that ferric carboxymaltose be used for anaemia management.
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