In recent decades, with the continuous emergence of drug targets and the continuous innovation of drug screening and optimization technologies, the global small molecule and macromolecular drug market has maintained stable and rapid growth. At the same time, the continuous increase in the cost of new drug research and development has gradually become the norm in the industry, the difficulty of new drug research and development continues to increase, and the success rate of new drug research and development continues to decrease. Therefore, preclinical research, as the core link of new drug discovery, is becoming more and more important. As for the domestic market, driven by policies in recent years, the pharmaceutical industry is in the process of profound changes, and “encouraging innovation and integrating with the world” will be the general trend in the future. In this environment, me-too-type innovative drugs will gradually lose their living soil, transition to Me-better/Best-in-class, and ultimately develop First-in-class drugs, which will be a must in my country’s innovative drug market. By the way. Based on this, the preclinical development of new drugs will be crucial.
Chemical drugs refer to APIs and their preparations prepared by synthetic or semi-synthetic methods; new effective monomers and their preparations extracted from natural substances or by fermentation; known methods prepared by resolution or synthesis Optical isomers in medicines and their preparations.
Chemical drugs are mostly small molecule drugs, and their structures are relatively easy to identify. At the same time, they are mainly taken orally, which can directly enter cells to produce drug effects. As biological drugs are increasingly used in clinical treatments, the proportion of chemical drugs in the pharmaceutical market is gradually decreasing, but they are still the main source of current drug candidates. The value chain of the chemical pharmaceutical industry includes basic chemical raw materials, pharmaceutical intermediates, chemical raw materials and chemical preparations.
1. New Registration Classification of Chemical Drugs
Innovative drugs that have not been marketed at home or abroad
Drugs containing new compounds with clear structures, pharmacological effects, and clinical value.
Improved new drugs that have not been marketed at home or abroad
Based on the known active ingredients, the structure, dosage form, prescription technology, route of administration, indications, etc. are optimized, and the drug has obvious clinical advantages.
Category 3 :
Domestic applicants imitate drugs that are marketed overseas but not domestically marketed original research drugs
Such drugs should be consistent with the quality and efficacy of the original drug
The original research drug refers to the first drug approved for marketing at home and abroad, and has complete and sufficient safety and effectiveness data as the basis for marketing.
The domestic applicant imitates the drug of the original research drug that has been marketed in China
Such drugs should be consistent with the quality and efficacy of the original drugs.
Drugs listed overseas apply for domestic listing
2. Discovery of Leading Compounds of Chemical Drugs
A seed compound refers to a compound that is active on a specific target, which may be a natural ligand or a molecule selected from the literature. Change the “hits” found in the screening into “Hit to Lead”. The lead compound may be a selected compound or a series of homologues, or it may be a compound derived from the literature. For high-throughput screening, discrete, multiple series of emerging compounds may be generated, which requires selecting one of the series to continue research.
3. Optimization of lead compounds for chemical drugs
The optimization of a lead compound is the process of selecting a lead compound for preclinical evaluation and converting it into a candidate drug:
When modifying the lead compound, pay attention to the change of its physical and chemical properties
For compounds with no selectivity, consider off-target effects/toxicity
Pay close attention to pre-clinical research requirements
4. Chemical drug production-CMC
CMC (Chemical, Manufacturing and Control) mainly refers to pharmaceutical research materials such as production process, impurity research, quality research, stability research, etc. It is an important aspect of drug research and development, and CMC application is also a very important part of drug application materials.
Determination of the nature of the compound
A comprehensive understanding of the properties of compounds can provide an important basis for choosing dosage forms and prescriptions. Such as solubility, powder properties, pH value (isoelectric point, etc.), moisture absorption, stability research, etc.
Clarifying the structure of the compound can ensure the stability of the compound and ensure the consistency of subsequent research drugs.
Determination of dosage form, prescription and specifications
Since this stage is the initial stage of drug development, dosage forms and prescriptions may change as the research progresses.
The specification of the compound is not clear, so the design of the dosage form and prescription needs to ensure the consistency of the preparation quality and the controllable impurities under the premise of ensuring safety.
At this stage, since the development value of the compound is not yet clear, the focus of research and development is to prepare sufficient raw materials and preparations to meet the pharmacology, toxicology and phase I clinical research, as well as to meet the research needs of CMC.
Process research is basically carried out in the laboratory. Under normal circumstances, there is no need to optimize the process, but the impurities generated in the process, such as reaction by-products, organic solvents, heavy metals, etc., must be effectively controlled, and the prescription process must be initially determined.
5. Chemical drug production process-raw material drug production
The production process of chemically synthesized raw materials: Chemically synthesized raw materials refer to products with certain medicinal effects obtained through chemical reactions of various chemical raw materials in industrial production under certain conditions, and then undergo crystallization and drying processes to achieve various indicators of drugs. The production method of the raw material medicine.
Fermentation API production process: Fermentation is one of the important methods of API production process. In particular, antibiotic APIs such as penicillium and cephalosporins are usually obtained through a semi-synthetic method combining fermentation and chemical synthesis. First, the main structure of the target compound is obtained through biological fermentation, such as the specific 3-lactam structure of penicillin, and then the structure is modified to obtain the final target compound; finally, the final API product is obtained through refining and recrystallization. The fermentation process generally needs to go through the process of culture medium preparation, canning treatment, inoculation, fermentation, wall breaking, filtration, precipitation, centrifugation, drying and other processes.
Animal and plant extraction API production process: Nature is a treasure house of natural compounds. Through their own metabolism, animals or plants produce many compounds that cannot be synthesized but are of great significance to the treatment of diseases. Therefore, animal and plant extraction is a way to obtain target raw materials.