The Current Situation and Industrialization Direction of Pharmaceutical, Chemical and Biotechnology
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2 The Current Situation of Medical Biotechnology
my country’s Pharmaceutical Consumption Level There is a big gap compared with the international level. In 1997, the national per capita annual consumption was only 116.87 yuan, growing at an annual rate of 16%
; the total pharmaceutical sales were about 140 billion yuan (seven major categories of medicines) , growing at a rate of 21%-22% every year, but the share of imported drugs, joint venture drugs and domestic drugs in the domestic market is basically only one-third of the world. my country will become an export base for raw materials and a sales market for finished drugs, and its risks will become more and more prominent after joining the WTO. Therefore, accelerating the research, development, and production of new drugs is an important national policy of our country.
l Genetically engineered drugs The genetically engineered drugs that have been approved for marketing in China include: recombinant human interferon
Interferon alb (trade name: Interferon, Serogen), recombinant human interferon a2a (trade name: Fukantai, Lefulon, Intefen, Deanan, Bell
fen), recombinant human interferon et2b (trade name: Rifenneng, Anfulong, Endafen, Anfulai, Longhuanuo), recombinant human interferon, recombinant human interleukin
L-2 (trade names: Antruk, Delusheng, Xinluoer, Yinluying, Yuekang Xian, Onite, Intercon), recombinant human granulocyte colony-stimulating factor
(trade names are Jilifen, granulosin, Jiliqiang, Jinleixianqiang, granulocyte, Su Granulin), recombinant human macrophage granulocyte colony-stimulating factor (trade names: Trier, Giliqiang, Genin, Rial, Libado), recombinant streptokinase rSK, Recombinant human erythrocyte growth factor (trade name: Ninghongxin,
Yibio, Yipuding, EPO, Aixuebao, Ibeneng), basic fibroblast growth factor (trade name: Beifuji), recombinant epidermal growth factor. Products currently being studied in China include nerve growth factors
NGF, CNTF, GDNF, BDNF, SOD, leptin (LE), anti-thrombolytic drug design, IGF-1, hGH antagonist, human Insulin C-peptide, hirudin, calcitonin, staphylokinase, human IL-6, Fit3 ligand, human tumor angiogenesis inhibitory factor, bFGF, thrombopoietin, new genetically engineered drug for the treatment of Alzheimer's disease 96718, epidermal growth factor, insulin , growth hormone, streptokinase.
2.2 Hui Biological Fermentation (Dianpeng Medicine)
Genetically engineered medical antibiotics such as propionylspiramycin, medinomycin, and mitomyces were used. Research on various antibiotics such as penicillin and leucomycin. Penicillin and Ve are important fermentation products in my country. Immobilized penicillin acylase and penicillin acylase genetically engineered bacteria are realized in cell membrane reactors. Established a factory to cleave penicillin C on a large scale to produce 6-aminopenicillanic acid (6-APA) through fermentation of self-constructed genetically engineered bacteria to produce cephalosporin C.
The fermentation unit has been increased to more than 2800 units and has been widely used. 7-ACA is the mother core of semi-synthetic cephalosporins. The import volume in 1997 was 400 million yuan. It uses a two-step enzymatic method to convert cephalosporins. C is converted and hydrolyzed into 7-ACA. Genetically engineered bacteria with two enzymes have been successfully cloned. The conversion rate of CPC sodium salt is 73.4%, and the purity of 7-ACA is over 9o%. , several antibiotics have also been developed, such as: tobramycin, rifamycin SV, mitomycin C, tylosmycin, etc.; nicotine X, ningnanmycin, gentamicin, agricultural antibiotics 66oB, etc. The sales of anti-infective drugs ranks second only to cardiovascular drugs in the world, but my country’s anti-infective drugs have always ranked first, especially after the opening of rural markets. Antimicrobial resistance
is increasing, and new antibacterial requirements will become increasingly urgent.
2.3 Lanthanum medicines derived from animals and plants'
This is an important field of traditional pharmaceuticals. In addition to medicines, there are also biological products, preventive medicines and nutritional products. Currently, this industry has Problems such as backward separation technology, low yield, and scattered production. There have been some new developments in the introduction of biotechnology for improvement, such as: in the modernization of traditional Chinese medicine, analysis and research on the genes, enzymes, biochemistry, and structure and performance of natural plants, the use of biotechnological methods to extract effective plant ingredients, and the use of plant cell reactors to cultivate factories It chemically produces paclitaxel, ginkgolides, artemisinin, shikonin, ephedrine, etc.; it uses animal cell reactors to culture and produce monoclonal antibodies, interferons, growth hormones, growth factors, enzymes and other biological drugs.
3 The developing fields of biopharmaceuticals
With the intensification of obesity and aging problems, in addition to cardiovascular drugs, weight loss and lipid-lowering drugs, diabetes drugs, and anti-Alzheimer's drugs It became a best-selling drug. With the accelerated pace of life, fierce competition, and changing situations, the incidence of mental illness in major countries in the world has increased rapidly, which has become a new problem that seriously affects people's quality of life. Therefore, the research and development and production of cardiovascular Drugs, anti-cancer drugs, AIDS drugs, diabetes drugs, anti-Alzheimer's drugs and
psychiatric drugs have become the focus. For most cities, there is still a lack of upstream research institutions to establish biopharmaceutical manufacturers. However, from strategic considerations, one or two "five-year plans" are needed to establish leading research institutions, leading development institutions and Leading biopharmaceutical company. The "National Life Science and Technology Talent Training Base" approved by the Ministry of Education and the State Planning Commission to be established by 36 universities proposed the overall idea of ??"four
combinations, four innovations, and two supporting facilities" (i.e.: Combination of upstream and downstream, combination of industry, academia and research, domestic and foreign combination, cross-combination of different disciplines; institutional innovation, mechanism innovation, model innovation; policy matching, investment matching) are worth learning from.
3.1 Genomics and proteomics
Pharmnacogenomics is a field that uses human genetic information to guide the development of new drugs. This field is the study of genetics
The diversity of individual differences affects the specificity of medication. Use known genetic theory to study the personalization of medication and optimize the design of drugs, and discover compounds with potential effector toxicity in the clinic
, improving ineffective and highly toxic drugs on the market through pharmacogenomics.
After the completion of the Human Genome Project, genomics can provide humans with strong evidence of the correlation between gene activity and diseases. xuexicn.com
But in fact, most diseases are not caused by genes. Caused by changes, and the way gene expression is complex
the same gene may play completely different roles under different conditions and at different times, which is something that genomics cannot answer
, thus giving rise to postgenomics and proteomics. The process of completing life functions is: DNA-mRNA_ten protein
protein. In this process, one gene may encode several or dozens of different proteins. Gene transcription produces a protein precursor, which is then processed and modified into an active protein. It can play a normal physiological role through a series of transportation and positioning. Proteomics is the study of "a gene"
p>The complete set of proteins expressed”. Through comparative analysis of the proteomes of normal individuals and diseased individuals, we can find "disease-specific protein molecules" that can become molecular targets for new drug design.
3.2 Drug screening and combinatorial chemistry
Drug screening refers to the process of selecting biologically active compounds from numerous compounds, which is based on specific biological indicators.
The first compound found is the lead compound.
New drug screening is divided into two categories: one is random screening (general screening), which is to find lead compounds from a completely unknown group of compounds; the other is directional screening, which is to design new compounds based on known lead compounds. To screen out compounds with better efficacy
. Experience with natural compounds, animals, plants, and traditional Chinese medicine is an advantage for us in drug screening.
Combinatorial chemistry is a combination of chemical synthesis,
computer design, and computer technology. It can produce many structurally related but orderly changing compounds at the same time, and then use high-speed Sensitive biological methods screen these compounds simultaneously to identify biologically active substances, and then conduct structural determination in order to find new lead compounds. Combinatorial chemistry includes the establishment of molecular diversity compound libraries, cluster screening (separation of solid and solid/liquid phases), and confirmation of active molecular structures.
33 Gene diagnosis and gene therapy
Gene diagnosis is mainly for genetic testing of pathogens, tumors and genetic diseases, eugenics and difficult diseases in modern cities (related to genes and heredity
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The control of (off) is one of the signs of advancement. There is basically no relevant prenatal diagnosis. From this, we started to establish genetic diagnosis and accumulate data while serving the society
To prepare for gene therapy . Gene therapy is the introduction of functional genes into the patient's body for expression, and the expression product, a protein, functions to treat the disease. Gene variations or defects can cause various diseases and may be passed on to future generations. Gene therapy is an operation on genes
, also known as "molecular surgery." Somatic cell gene therapy is the current mainstream of research.
3.4 Gene knockout, transgenic animals and bioreactors
Gene knockout refers to the molecular design of a gene whose structure is known but whose function is unknown. In experiments, the gene is removed (including introducing site-directed mutations), and then the animal is observed as a whole to speculate on the corresponding function. The technology mainly includes the construction of recombinant gene vectors, and
transformation In the nuclei of human recipient cells, the cells that have been screened are transferred to human embryos to grow into genetically deleted animals.
Transgenic animals are a type of animal that uses experimental introduction methods to stably integrate foreign genes into the chromosomal genome and can also be passed on to future generations
In 1974, American scholars used microinjection to obtain transgenic mice for the first time. Transgenic animals have been widely used in basic research, establishment of disease animal models, production of medicinal proteins, agriculture (production of transgenic livestock) , such as featherless chicken) and other fields.
3.5 Biochips and biosensors
Biochips use microelectronics, micromechanics, chemistry, physics technology, computer technology, sample detection, and analysis processes to be continuous and integrated. ,
miniaturization. Including Lab-on-a-chip, DNA chip, protein chip, cell chip, tissue chip, etc. Biochip technology includes the structure of chip arrays, sample preparation, biomolecule reactions, and signal detection and analysis. It is mainly used for disease diagnosis, drug screening, gene sequencing, and in agriculture, food supervision, and environmental protection. , forensic identification and other aspects will make significant contributions
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Biosensors have the characteristics of specific detection, sensitivity, and fast response. They can be used to measure the metabolism and intermediate products of many biological products and can measure
non-biological chemicals. Biosensors use enzymes and cells that can be used over and over again. Biosensors use enzymes, immune systems, tissues, organelles
or complete cells as catalysts to make immobilized membranes and connect them to physical and chemical instruments (chemistry, heat, light, sound waves) to convert physiological signals into physical and chemical signals
The output can be prepared into micro sensors and multi-parameter sensors.
The United States invests approximately US$1.3 billion in biosensor technology and product development research every year. The combined development of bioengineering and computer engineering has great industrial prospects.
3.6 Tissue engineering and organ transplantation
Tissue engineering is the application of biological and engineering principles to the research and development of artificial tissues that can repair and improve tissue damage or missing functions
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Or an emerging discipline of organs. Tissues such as cartilage, bone, tendon, and skin have been successfully reconstructed. Composite tissues such as blood vessels and trachea have been regenerated. Research on tissue regeneration such as pancreas and liver has made varying degrees of progress. Other tissues such as ureters, urethra, esophagus, small intestine, kidneys, blood vessels, and blood cells have been successfully regenerated. The project has also made some progress.
3.7 New Types of Drugs
Drugs for treatment, prevention and diagnosis all serve humans in certain dosage forms. The authoritative view is that "providing new drug delivery methods
Almost as important as providing new medicines.” Drugs must be made into a certain dosage form and used in the form of preparations for treatment, prevention or diagnosis, and the preparations xuexicn.com
4 Medical 1l5 Dagger
effectiveness and safety , rationality and precision all reflect the level of medicine and determine the effect of medicine. Improving the efficacy of drugs, reducing the toxic and side effects of drugs
and reducing drug-induced diseases have continuously put forward higher requirements for pharmaceutical preparations, and new dosage forms and new preparation technologies of drugs are also coming into play
Growing influence.
4 Industrialization Issues of Biopharmaceuticals
Due to the gradual saturation of the drug market in developed countries such as Europe and the United States, and the upcoming patent expiration of some best-selling drugs protected by patents, as well as new patents Due to the slow speed of drug development and other reasons, the structure of the international drug market has undergone ten major changes: the sudden emergence of biotech drugs; the sales proportion of generic drugs
(drugs that have expired) in prescription drugs has surged. Much higher than the average annual growth rate of the entire pharmaceutical industry in the world; the growth rate of over-the-counter drugs (OTC) is also accelerating; in terms of drug development, cholesterol control, congestive heart failure, schizophrenia, elderly
In the treatment fields of memory loss, Alzheimer's disease, diabetes, AIDS, and various cancers, research and development are accelerating, and the market prospects are broad; in terms of pharmaceutical preparations and dosage forms, transdermal absorption, controlled and sustained-release drugs Preparations have broad prospects; in order to reduce the number of inpatients, ease the burden on inpatient beds, and save medical expenses, new drugs that change inpatient treatment to outpatient treatment are constantly on the market; the market for drugs for geriatric diseases and women and children is developing rapidly; preventive drugs, health care, and nutritional tonic drugs The development of medicine will continue to heat up; the development potential of natural medicines is huge; the research and development of new medicines is becoming more and more difficult.
Biopharmaceuticals are characterized by high investment, high benefits, high risks, and long cycles. The early development of a biopharmaceutical requires a large investment of capital, technology, manpower, and experience. several years. Drug approval and clinical trials also take several years, so the success rate of biological drugs is only 5%-10%. However, compared with traditional pharmaceuticals, they have the advantages of easy mass production, high profits, simple production process, low labor investment, no pollution, and short production cycle. Once new drugs are successfully developed, the profits will be huge. According to the analysis of Ernst-yong Company, there are 00 new biotechnology drugs in the late clinical trial stage, and 240 new drugs will be on the market by 2007.
The following issues require special attention in the development and industrialization of genetic engineering drugs:
(1) Choose good projects
The commercialization of new biotechnology is highly competitive. , so except for some results in the Human Genome Project that are not patented, all new discoveries have been patented. How to obtain the right to use patents is the first thing to study in the development of new drugs; the second is market assessment, which Some genetic drugs are suitable for the whole world, and some are only suitable for certain regions. For enterprises, only the market they can control is meaningful; the third is the feasibility of the project, including the maturity level (
The existence of a drug certificate does not necessarily mean maturity), whether it can be industrialized, whether the process cost is low, and environmental issues, etc. We must also consider the redevelopment investment after acceptance.
The development direction of genetic engineering drugs:
①Develop new peptides, proteins and nucleic acids for major diseases such as the nervous system, tumors, cardiovascular system, AIDS and immune deficiency
p>Physical technology products. The development focus in this area will mainly be interferon, growth hormone and T-PA.
② Select a batch of biotechnology products with good market prospects, as well as vaccines and diagnostic monoclonal antibodies for development. my country has a certain foundation in this regard.
The development focus is on hepatitis B genes Vaccines and monoclonal antibody diagnostic reagents.
③The development of targeted drugs mainly involves the development of anti-tumor drugs. Current cancer treatment drugs have a problem of "no distinction between friend and foe". While killing cancer cells, they also kill normal cells. Targeted therapy was proposed to address this problem. The so-called targeted therapy uses antibodies to find targets, like missile navigators, to accurately introduce drugs to the focus without damaging
and other Tissues and cells.
④Research and development of humanized monoclonal antibodies. Antibodies can fight against various pathogens and can also be used as guides. However, most of the current monoclonal antibodies are mouse-derived antibodies. When injected into the human body, they will produce antibodies (anti-antibodies) or stimulate an immune response. At present, phage antibody technology, chimeric antibody technology, and genetic engineering antibody technology have been studied abroad to solve the problem of humanized antibodies.
⑤The research and development of blood substitutes still plays an important role. Blood products are made from large amounts of mixed human plasma. Since human blood is inevitably contaminated by various pathogens, such as HIV and hepatitis B virus, patients can be infected with AIDS or hepatitis B through blood transfusions. Cases
happen from time to time, so the use of genetic engineering to develop blood substitutes is compelling.
(2) Correct the relationship between t, middle and downstream
The Human Genome Project is of great significance and has far-reaching influence. As the "Human Genome Project" begins to take shape, an even more exciting An exciting post-genomic era of protein engineering research is coming. The first thing to benefit are preventive and therapeutic drugs and services that serve human health. Genetically engineered drugs
will flourish, but the relationship between upstream, midstream and downstream must be properly handled.
(3) Establish an advanced engineering technology platform
① Drug screening platform ~ discovery of new drugs; ② Drug pilot transformation platform; ③ Animal experiment platform.
(4) Strengthen biochemical engineering technology in the development of biological drugs to ensure the discovery and preparation of new drugs for diagnosis and treatment of human health
This is the study of the interaction and recognition of biological macromolecules , through the interaction of exogenous drugs with external fields and the transmission and regulation of biological information, effective synthesis and biotransformation are carried out, and the discovered useful active substances are prepared, extracted, separated and purified to obtain products beneficial to human health.
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(5) Intelligent biochemical process engineering
The research of biochemical engineering includes the simulation of basic biological reactions, biological surfaces and interfaces, transmission Mass, heat transfer, momentum transfer, signal molecule transmission and reaction, engineering analysis of complex biological systems, etc.
Biochemical industry strives towards intelligent chemical industry and should actively absorb the latest achievements in modern physics, mathematics, biology, computers, informatics, etc. Intelligent chemical industry is to carefully design new products and their reactions, separations to improve selectivity and process tuning control for the generalized chemical process, using new technologies such as modern computers, intelligent instruments, and system engineering to closely combine computer control , related models and expert systems, local detection points and actuators, enabling traditional chemical industry to achieve miniaturization, modularization and decentralization. That is, through multi-scale research integration and intelligent operation of chemical engineering processes, we can solve scientific problems in macro-level engineering and technology in the process of material transformation.
(6) Give full play to the role of the National Biochemical Engineering Center as a bridge and incubator
The State Planning Commission and the Ministry of Science and Technology allocate part of the funds to establish a mid-stream ( Pilot scale-up and engineering) R&D institution - a national engineering technology center
. In 1996, the Ministry of Science and Technology established biotechnology industry incubators and national biochemical engineering technology research centers in Beijing, Shanghai, Nanjing and Shenzhen respectively. The Shenzhen National Biochemical Center uses the center's equipment and talent conditions in view of factors such as fierce competition and extremely high prices for mature laboratory results of genetically engineered drugs at home and abroad, and the heavy workload of improving pilot scale-up tests.
The software was used to establish the source project research work of the genetic engineering laboratory, which not only saved a lot of money, but also fully utilized the potential of the existing equipment
, and accelerated the speed of project development, which was conducive to catching up. It is also conducive to the development of the center to meet the international advanced level and market demand.
(7) Develop CliO service industry
For biotechnology and pharmaceutical companies, it is not easy to bring new drugs to the market. A typical new drug application requires at least 4,000 clinical trials, sometimes as many as 50 different trials. As the number of drug candidates increases, the burden on companies continues to increase. In order to reduce the pressure on each drug's time to market, many biotechnology and pharmaceutical companies have begun to integrate external resources for drug development. Contract Research Organization (CRO) has the special expertise required by biotechnology and pharmaceutical companies, and has global, high-quality clinical trial management capabilities that can meet these needs. The company's requirements for the time to market of new drugs. CRO mainly targets pharmaceutical and biotechnology companies, providing various professional services related to drug development. It has now been extended to the discovery of early drug lead compounds and a series of services after the launch of new drugs.
Such as drug discovery, preclinical research, pharmacogenomics, phase I to III clinical trials, informatics, clinical documents, policy and regulatory consultation, production and packaging, promotion, marketing, product launch and sales support, pharmacoeconomics and business
Business consulting, etc. Main references
1. Hebei Chemical Industry. 2004(4): 1-5
2. Modern Chemicals, 2004(6): 1
3. Fine and Specialty Chemicals, 2004, 12(2): 1-3