Unit 1 Production of Drugs
Depending on their production or origin pharmaceutical agents can be split into three groups:
I .Totally synthetic materials (synthetics)，
Ⅱ.Natural products，and
Ⅲ.Products from partial syntheses (semi-synthetic products).
The emphasis of the present book is on the most important compounds of groups I and Ⅲ一thus Drug synthesis. This does not mean，however，that natural products or other agents are less important. They can serve as valuable lead structures，and they are frequently needed as starting materials or as intermediates for important synthetic products.
Table 1 gives an overview of the different methods for obtaining pharmaceutical agents.
1单元生产的药品
其生产或出身不同药剂可以分为三类：
1。完全（合成纤维）合成材料，
Ⅱ。天然产物，和
Ⅲ。产品从（半合成产品）的部分合成。
本书的重点是团体的最重要的化合物Ⅰ和Ⅲ一所以药物合成。这并不意味着，但是，天然产品或其他代理人并不太重要。它们可以作为有价值的领导结构，他们常常为原料，或作为重要的合成中间体产品的需要。
表1给出了获取药剂的不同方法的概述。
Table 1 Possibilities for the preparation of drugs
Methods Examples
1. Total synthesis -over 75 % of all pharmaceutical agents (synthetics)
2. Isolation from natural sources (natural products):
2.1 Plants -alkaloids;enzymes;heart glycosides;polysaccharides;tocopherol;
steroid precursors (diosgenin, sitosterin);citral (intermediate product for
vitamins A, E，and K)
2.2 Animal organs一enzymes;peptide hormones;cholic acid from gall; insulin) from the
pancreas;sera and vaccines
2. 3 Other sources一cholesterol from wool oils;L-amino acids from keratin and gelatine
hydrolysates
3. Fermentation一antibiotics;L-amino acids;dextran; targeted modifications on steroids，
e.g. 11-hydroxylation; also insulin, interferon, antibodies, peptide
hormones，enzymes，vaccines
4. Partial synthetic modification of natural products (semisynthetic agents):
一alkaloid compounds;semisynthetic /3-lactam antibiotics;steroids;human insulin
Several therapeutically significant natural products which were originally obtained from natural sources are today more effectively -i. e. more economically -prepared.. by total synthesis. Such examples include L-amino acids，Chloramphenicol，Caffeine, Dopamine，Epinephrine，Levodopa, peptide hormones，Prostaglandins，D-Penicillamine，Vincamine，and practically all vitamins.
表1对药物的可能性准备
方法举例
1。全合成，超过75％的药剂（合成纤维）
2。分离（天然产物）天然来源：
2.1植物-生物碱;酶;心甙，多糖，维生素E;
类固醇的前体（薯蓣皂素，sitosterin），柠檬醛（中间产品
维生素A，E和K）
2.2动物器官一酶;肽激素;胆酸从胆;胰岛素）从
胰脏;血清和疫苗
2。从角蛋白和明胶L -氨基酸;三一胆固醇从羊毛油脂的其他来源
水解
3。一抗生素发酵; L -氨基酸，葡聚糖，对类固醇有针对性的修改，
例如11 -羟基化;也胰岛素，干扰素，抗体，肽
激素，酶，疫苗
4。部分合成修改（半合成剂）天然产品：
一生物碱化合物;半合成/ 3-内酰胺类抗生素;类固醇;人胰岛素
其中几个重要的治疗作用最初是从天然产品天然来源获得更有效的今天，我。大肠杆菌更经济的准备..由全合成。这样的例子包括L-氨基酸，氯霉素，咖啡因，多巴胺，肾上腺素，左旋多巴，肽类激素，前列腺素，D -青霉胺，长春胺，以及几乎所有的维生素。
Over the last few years fermentation - i. e. microbiological processes has become extremely important. Through modern technology and results from genetic selection leading to the creation of high performance mutants of microorganisms，fermentation has already become the method of choice for a wide range of substances. Both Eukaryonts (yeasts and moulds)and Prokaryonts(single bacterial cells，and actinomycetes)are used microorganisms. The following product types can be obtained:
1. cell material (single cell protein)，
2. enzymes，
3. primary degradation products (primary metabolites)，
4. secondary degradation products (secondary metabolites).
在过去的几年里发酵-岛大肠杆菌微生物过程变得极其重要。通过现代技术和基因选择的结果导致了突变体的微生物创造高性能，发酵，已成为首选方法各种各样的物质。这两个Eukaryonts（酵母菌和霉菌）和Prokaryonts（单细胞细菌，放线菌和）用于微生物。下列产品类型可以得到：
1。细胞的物质（单细胞蛋白），
2。酶，
3。主要降解产物（主要代谢物），
4。二级降解产物（次生代谢物）。
Disregarding the production of dextran from the mucous membranes of certain microorganisms，e. g. Leuconostoc mesenteroides，classes 2 and 3 are the relevant ones for the preparation of drugs. Dextran itself，with a molecular weight of 50,000 ~ 100,000，is used as a blood plasma substitute. Among the primary metabolites the L-amino acids from mutants of Corynebacterium glutamicum and Brevibacterium flavum are especially interesting. From these organisms some 350，000 tones of monosodium L-glutamate (food additive)and some 70，000 tones of L-lysine(supplement for vegetable proteins)are produced. Further important primary metabolites are the purina nucleotides，organic acids，lactic acid，citric acid，and vitamins，for example vitamin B,2 from Propionibacterium shermanii.
Among the secondary metabolites the antibiotics must be mentioned first. The following five groups represent a yearly worldwide value of US-$17 billion:
不顾来自某些微生物，大肠杆菌粘膜生产的葡聚糖克明串珠mesenteroides，2和3级是毒品有关的准备工作。葡聚糖本身5万?10万分子量，是用作血浆代用品。其中主要来自谷氨酸棒杆菌代谢产物和黄色短杆菌突变体的L -氨基酸特别有趣。从这些味精约35万吨L -谷氨酸（食品添加剂）生物体和L -赖氨酸（用于植物蛋白补充）约70,000吨的生产。此外重要的初级代谢产物的普瑞纳核苷酸，有机酸，乳酸，柠檬酸和维生素，例如维生素B，从丙酸shermanii 2。
其中次生代谢产物的抗生素必须首先提到。以下五组代表了美国每年170亿美元的全球价值：
penicillins ( Penicillium chrysogenum )，
cephalosporins ( Cephalosporium acremonium )，
tetracyclines ( Streptomyces aureofaciens )，
erythromycins ( Streptomyces erythreus )，
aminoglycosides (e. g. streptomycin from Streptomyces griseus).
About 5000 antibiotics have already been isolated from microorganisms，but of these only somewhat fewer than 100 are in therapeutic use. It must be remembered，however，that many derivatives have been modified by partial synthesis for therapeutic use;some 50，000 agents have been semisynthetically obtained from户lactams alone in the last decade. Fermentations are carried out in stainless steel fermentors with volumes up to 400 m3. To avoid contamination of the microorganisms with phages etc. the whole process has to be performed under sterile conditions. Since the more important fermentations occur exclusively under aerobic conditions a good supply of oxygen or air(sterile)is needed. Carbon dioxide sources include carbohydrates，e. g. molasses，saccharides，and glucose. Additionally the microorganisms must be supplied in the growth medium with nitrogen-containing compounds such as ammonium sulfate，ammonia，or urea，as well as with inorganic phosphates. Furthermore，constant optimal pH and temperature are required. In the case of penicillin G，the fermentation is finished after 200 hours，and the cell mass is separated by filtration. The desired active agents are isolated from the filtrate by absorption or extraction processes. The cell mass，if not the desired product，can be further used as an animal feedstuff owing to its high protein content.
青霉素（青霉）
头孢菌素（头孢枝顶）
四环素（金色链霉菌）
erythromycins（链霉菌）
氨基糖苷类（如链霉素从灰色链霉菌）。
关于5000抗生素已经分离出的微生物，但其中只有不到100有些治疗使用。必须记住，但是，许多衍生工具已被用于治疗使用部分合成修改;约50,000剂已被semisynthetically取得户内酰胺在过去十年孤独。发酵都是在不锈钢发酵罐出来的量高达400立方米。为了避免与噬菌体等微生物污染的全过程都必须在无菌条件下进行。由于更重要的发酵只发生在有氧条件下的氧气或空气好电源（无菌）是必要的。二氧化碳的来源包括碳水化合物，大肠杆菌克糖蜜，糖和葡萄糖。另外必须提供的微生物在与含氮如硫酸铵，氨水或尿素化合物生长介质，以及与无机磷酸盐。此外，不断最适pH和温度是必需的。在青霉素G的情况下，发酵完成200小时后，细胞的质量是由过滤分离。所需的活性剂是隔离的滤液吸收或提取工艺。大规模的细胞，如果不理想的产品，可进一步用作动物，由于其蛋白质含量高的饲料。
By modern recombinant techniques microorganisms have been obtained which also allow production of peptides which were not encoded in the original genes. Modified E. coli bacteria make it thus possible to produce A- and B- chains of human insulin or proinsulin analogs. The disulfide bridges are formed selectively after isolation，and the final purification is effected by chromatographic procedures. In this way human insulin is obtained totally independently from any pancreatic material taken from animals.
Other important peptides，hormones，and enzymes，such as human growth hormone (HGH)，neuroactive peptides，somatostatin，interferons，tissue plasminogen activator (TPA)，lymphokines，calcium regulators like calmodulin，protein vaccines，as well as monoclonal antibodies used as diagnostics，are synthesized in this way.
The enzymes or enzymatic systems which are present in a single microorganism can be used for directed stereospecific and regiospecific chemical reactions. This principle is especially useful in steroid chemistry. Here we may refer only to the microbiological 11-a- hydro xylation of progesterone to 11-a-hydroxyprogesterone，a key product used in the synthesis of cortisone. Isolated enzymes are important today not only because of the technical importance of the enzymatic saccharification of starch，and the isomerization of glucose to fructose，They are also significant in the countless test procedures used in diagnosing illness，and in enzymatic analysis which is used in the monitoring of therapy.
A number of enzymes are themselves used as active ingredients. Thus preparations containing proteases (e. g. chymotrypsin，pepsin，and trypsin)，amylases and lipases，mostly in combination with synthetic antacids，promote digestion. Streptokinase and urokinase are important in thrombolytics，and asparaginase is used as a cytostatic agent in the treatment of leukemia.
利用现代微生物重组技术已获得这也让其中不是在原来的基因编码多肽的生产。改性大肠杆菌从而使可能产生A型和B -人胰岛素或胰岛素原类似物链。二硫键形成的选择性分离后，最终由色谱净化工序的影响。通过这种方式获得的人类胰岛素完全独立采取任何从动物胰腺材料。
其他重要肽，激素和酶，如人类生长激素（hGH），神经活性肽，生长抑素，干扰素，组织型纤溶酶原激活物（tPA），淋巴因子，如钙调节钙调蛋白，蛋白疫苗，以及作为诊断用单克隆抗体是合成了这种方式。
这些酶或微生物在一个单一的酶系统，目前可用于立体定向和regiospecific化学反应。这个原则是有用的，尤其是在化学类固醇。在这里，我们只能引用的微生物十一水电黄体酮xylation至11人羟，一个关键的产品在可的松合成。隔离酶是重要的，不仅因为淀粉的酶法糖化技术重要性的今天，和葡萄糖异构果糖，他们也都在无数次试验在诊断疾病所用的程序显着，在酶的分析，在使用监测治疗。
数量的酶本身作为活性成分。因此，含有蛋白酶制剂（如糜蛋白酶，胃蛋白酶和胰蛋白酶），淀粉酶和脂肪酶的合成主要是在与抗酸药相结合，促进消化。链激酶和尿激酶溶栓是重要的，是天冬酰胺酶在治疗白血病细胞生长剂。
Finally mention must be made of the important use of enzymes as `biocatalysts’in chemical reactions where their stereospecificity and selectivity can be used. Known examples are the enzymatic cleavage of racemates of N-acetyl-D，L-amino acids to give L-amino acids，the production of 8-aminopenicillanic acid from benzylpenicillin by means of penicillinamidase and the aspartase-catalysed stereospecific addition of ammonia to fumaric acid in order to produce L-aspartic acid.
In these applications the enzymes can be used in immobilized forms-somehow bound to carriers - and so used as heterogeneous catalysts. This is advantageous because they can then easily be separated from the reaction medium and recycled for further use.
Another important process depending on the specific action of proteases is applied for the production of semisynthetic human insulin. This starts with pig insulin in which the alanine in the 30-position of the B-chain is replaced by a threonine tert-butyl ester by the selective action of trypsin. The insulin ester is separated，hydrolyzed to human insulin and finally purified by chromatographic procedures.
Sources for enzymes include not only microorganisms but also vegetable and animal materials.
In Table 1 it was already shown that over 75%of all pharmaceutical agents are obtained by total synthesis. Therefore knowledge of the synthetic routes is useful. Understanding also makes it possible to recognize contamination .of the agents by intermediates and by- products. For the reason of effective quality control the registration authorities in many countries demand as essentials for registration a thorough documentation on the production process. Knowledge of drug syntheses provides the R&D chemist with valuable stimulation as well.
There are neither preferred structural classes for all pharmaceutically active compounds nor preferred reaction types. This implies that practically the whole field of organic and in part also organometallic chemistry is covered. Nevertheless，a larger number of starting materials and intermediates are more frequently used，and so it is useful to know the possibilities for their preparation from primary chemicals. For this reason it is appropriate somewhere in this book to illustrate a tree of especially important intermediates. These latter intermediates are the key compounds used in synthetic processes leading to an enormous number of agents. For the most part chemicals are involved which are produced in large amounts. In a similar way this is also true for the intermediates based on the industrial aromatic compounds toluene，phenol and chlorobenzene. Further key compounds may be shown in a table which can be useful in tracing cross-relationships in syntheses.f
In addition to the actual starting materials and intermediates solvents are required both as a reaction medium and ,for purification via recrystallization. Frequently used solvents are methanol，ethanol，isopropanol，butanol，acetone，ethyl acetate，benzene，toluene and xylene. To a lesser extent diethyl ether，tetrahydrofuran，glycol ethers，dimethylformamide (DMF) and dimethyl sulphoxide (DMSO) are used in special reactions.
最后必须提到的，作为他们在那里`biocatalysts'in化学stereospecificity和选择性反应的酶可用于制造重要的用途。著名的例子是对N -乙酰- D，L -氨基酸消旋给予L -氨基酸酶裂解，从青霉素生产8 -氨基青霉烷酸的penicillinamidase手段和天冬氨酸酶，催化氨立体除了富马酸为了酸生产L -天门冬氨酸。
在这些酶可以在固定的形式使用的应用程序，在某种程度上势必运营商- 等为异构催化剂。这是有利的，因为他们可以很容易地分离反应介质和回收再利用。
另一个重要进程的具体行动蛋白酶是根据申请的半合成人胰岛素的生产。与猪胰岛素这将启动，其中在30的B链的位置被替换为丙氨酸苏氨酸叔丁基由胰蛋白酶选择性作用酯。胰岛素酯分离，水解为人体胰岛素和程序，最后由色谱纯化。
对酶的来源不仅包括微生物，而且蔬菜和动物材料。
在表1，已经显示，有超过75％是由药剂全合成获得。因此，合成路线的知识是有用的。认识也使我们能够认识到污染。按中间体和副产品代理。为了有效的质量控制在许多国家的登记要领对生产过程的完整的文档要求登记机关的原因。药物合成知识提供了宝贵的刺激研发化学家以及。
有没有首选的所有药学活性化合物，也反应类型结构类型的首选。这意味着几乎全部领域的有机和有机金属化学中的一部分也被覆盖。不过，也有较大的起始原料和中间体数量较常用，所以它是非常有用的知道他们准备从初级品的可能性。基于这个原因，它是在适当的地方，说明这本书的重要中间体，尤其是树。后面这些中间体领导到数目庞大的代理商合成工艺中的关键化合物。对于大多数的化学品是在涉及大量生产。以类似的方式，这也是对工业芳香族化合物甲苯，苯酚和氯苯中间体为基础的真实。另一个关键的化合物可能会显示在表格可在追踪syntheses.f交叉关系很有用
除了实际的起始原料和中间体溶剂作为反应介质要求和通过再结晶纯化，两者。常用的溶剂是甲醇，乙醇，异丙醇，丁醇，丙酮，醋酸乙酯，苯，甲苯和二甲苯。在较小程度上乙醚，四氢呋喃，乙二醇醚，二甲基甲酰胺（DMF）和二甲基亚砜（DMSO）的使用在特殊的反应。
Reagents used in larger amounts are not only acids (hydrochloric acid，sulfuric acid，nitric acid，acetic acid) but also inorganic and organic bases (sodium hydroxide，potassium hydroxide，potassium carbonate，sodium bicarbonate，ammonia，triethylamine，pyridine). Further auxiliary chemicals include active charcoal and catalysts. All of these supplementary chemicals (like the intermediates) can be a source of impurities in the final product.
In 1969 the WHO published a treatise on `Safeguarding Quality in Drugs'.Appendix 2 is concerned with the `Proper Practice for Reparation and Safeguarding Quality in Drugs' (WHO Technical Report No. 418，1969，Appendix 2;No. 567，1975，Appendix 1A). This has in the meantime become known as `Good Manufacturing Practices' or GMP rules，and these should now be obeyed in drug production. They form the basis for mutual recognition of quality certificates relating to the production of pharmaceuticals and for inspections of the production. facilities.
For a long time the US drug authority，the Food and Drug Administration (FDA)，has issued regulations for the preparation of drugs analogous to the WHO rules，and it applies these strictly. Exports of drugs to the USA，like those of finished products，require regular inspection of the production facilities by the FDA. 5
It may merely be noted here that such careful control applies not only to the products，but also to the raw materials (control of starting Materials)，and also to the intermediates. Clearly. the technical and hygienic equipment of the production and the storage areas have to fulfill set conditions.
Since only a few compounds，such as acetylsalicylic acid，paracetamol and vitamins，are prepared in large amounts，most of the actual production takes place in multi-purpose (multi-product) facilities. .Special care has to be taken to avoid cross-contamination by other products what can be effected by good cleansing of used apparatus. A careful description and definition of all stored intermediates and products is needed.
Selected -from H. J. Roth and A. Kleemann, Pharmaceutical Chemistry, Vol. 1，Drug Synthesis,
Ellis Horwood Limited，England, 1988.
在较大的数额使用的试剂，不仅酸（盐酸，硫酸，硝酸，醋酸），而且无机和有机碱（氢氧化钠，氢氧化钾，碳酸钾，碳酸氢钠，氨，三乙胺，吡啶）。进一步的辅助化学品包括活性炭和催化剂。这些（如中间体）补充品都可以成为最终产品中杂质的来源。
1969年，世界卫生组织发表了`保障药品质量的论文中（WHO技术报告号418,1969，附录二，附录二是有关`适当的做法的赔偿和保障药品质量。';号567,1975，附件1A）。这已成为在此期间为'良好生产规范'或GMP规则众所周知的，现在应在这些药品生产服从。它们构成的质量有关的药品生产证书互认的生产和检验的基础。设施。
长期以来，美国药品管理局，美国食品和药物管理局（FDA）已发出的药品制剂类似于谁的规则规定，而且适用于这些严格。向美国药物如成品者外，出口由FDA要求的生产设施进行定期检查。 5
它可能只是在此指出，这种严格控制不仅适用于产品，而且对原材料（原辅料控制），同时还以中间体。清楚。对生产和储存方面的技术和设备必须符合卫生规定的条件。
由于只有少数的化合物，如乙酰水杨酸，对乙酰氨基酚和维生素，是在大量的准备，在实际生产中最需要的多用途（多产品）设施的地方。。特别小心，注意避免交叉通过什么可以按所使用的仪器良好的清洁影响其他产品的污染。经过仔细的描述和所有储存的中间体和产品的定义是必要的。
选择从黄建忠罗斯和A. Kleemann，药物化学，卷。 1，药物合成，
埃利斯霍伍德有限公司，英国，1988年。
6 Exercises
1. Answer the following questions:
(1)How many groups can pharmaceutical agents be split into depending on their production or origin?
(2)Can you illustrate any significant examples of pharmaceutical agents obtained by total synthesis?
(3) What is the difference between the synthetic drugs and traditional Chinese herbal medicine?
2. Put the following into English:
3. Put the following into Chinese:
Polysaccharide peptide hormone vaccine heterogeneous catalyst
contamination plasma steroid penicillin metabolite
4. Fill in the blanks with the following verb words:
derive term distinguish present compose
Nucleic acids are polyanionic molecules of high molecular weight. These polymers are _____ of a sequence of subunits or nucleotides so that the whole is usually _____ a polynucleotide. The nucleic acids are of two main varieties，ribonucleic(RNA)and deoxyribonucleic (DNA).DNA is found primarily in the chromatin of the cell nucleus，whereas 90%of RNA is _____ in the cell cytoplasm and 10 0 o in the nucleolus. The two classes of nucleic acids are _____ primary on the basis of the five-carbon atom sugar or pentose present. Two general kinds of bases are found in all nucleic acids. One type is a derivative of the parent compound purine. Principle examples are guanine and adenine. The second class of bases found in all nucleic acids is _____ from the parent compound pyrimidine.
6习题
1。回答下列问题：
（1）有多少组可以药剂成其生产或出身而定分裂？
（2）你能说明所取得的全合成药剂任何重大的例子吗？
（3）什么是之间的合成药物和传统中药的区别？
2。把以下内容翻译成英语：
3。把成中文如下：
多糖肽类激素疫苗非均相催化剂
青霉素类固醇代谢物污染血浆
4。填写以下动词的单词填空：
目前构成派生词区别
核酸是超高分子量聚阴离子分子。这些聚合物的一个亚基或核苷酸，使整个通常是一个多核苷酸序列__________。核酸是两个主要品种，核糖核酸（RNA）和脱氧核糖核酸（DNA）的。DNA是主要存在于细胞核内的染色质，而90％是_____的RNA在细胞的细胞质和细胞核中的10 0?。核酸类_____两对五碳糖或戊糖原子现有基础上小学。一般两个种基地发现，在所有核酸。一类是母体化合物嘌呤的衍生物。原理是鸟嘌呤和腺嘌呤的例子。在所有发现核酸碱基第二类是从母体化合物嘧啶_____。
Unit 5 Drug Development (I)
1. Introduction
Drug Development is a very complex process requiring a great deal of
coordination and communication between a wide range of different functional
groups. It is expensive，particularly in the later phases of clinical development，
where studies involve hundreds of patients. It is currently estimated that the
development of a new drug costs about$230 million(1987 dollars)and takes
somewhere between 7 and 10 years from initiation of preclinical development to
first marketing (excluding regulatory delays). Drug development is a high-risk
business;although the rate is increasing，only about ONE out of every TEN new
chemical entities studied in human beings for the first time will ever become a product. As a drug candidate progresses through development the risks of failure decrease as ‘hurdles’are overcome along the way. Typical reasons for failure include unacceptable toxicity，lack of efficacy，or inability to provide advantages over competitive products
(Fig. 1).
Attrition Rate of New Chemical Entities
(NCE's) entering development. On average
only about I in 400^1000 compounds
synthesized enters development.
Reasons for termination of development of NCE's
(excluding anti-infectives)
1:Lack of efficacy
2: Pharmacokinetics
3: Animal toxicity
4: Miscellaneous
5: Adverse effects in man
6: Commercial reasons
Fig. 1 Attrition rates and reasons for terminations
2. Planning for development
Assessment of whether a drug candidate is likely to provide competitive advantages highlights the need first to have in place a set of product `goals' or target product profile. Particular attention should be paid to the differentiation from competitors. This is becoming 55 more and more critical with the increasing emphasis on limited formularies，healthcare costs，and pharmacoeconomics (discussed later in the chapter).
A target profile will define the indication(s) that a drug candidate will be developed for，along with goals such as once a day dosing，faster onset of action，better side effect profile than a major competitor. The target profile can be refined and revised as a drug candidate moves through development and new data on the drug candidate or competitors become available. The logical next steps are to define the development strategy，for example，which indications to develop first，which countries to aim to market the drug in and then to define the core clinical studies necessary to achieve regulatory approval and commercial success.
This chapter will describe the main activities required for successful development of a new drug. All these activities，many of which are interdependent，need to be carefully planned and co-ordinate. Speed to market with collection of high quality data is critical for success. The path of activities which determine the time it will take to get to registration is called，in project management terms，the critical path. It is vital to plan and prepare before studies begin and to monitor and manage problems so as to ensure that the critical path remains on schedule. With increased economic pressures and competitive intensity it is important for companies to explore ways to shorten this critical path. Running activities in parallel，or overlapping studies which would usually run sequentially，often involves an increase in risk but the dividends in time-saving can make such strategies worthwhile.
The critical path for development of a new drug generally runs through the initial synthesis of compound，subacute toxicology studies，and then the clinical program. A chart showing the critical path activities for a typical drug candidate is shown in Fig. 2.
Chemistry chemical Synthesis Route selection Pilot plant,scale up and stability testing Manufacturing plant production
Toxicology Acute&subacute toxicology Long term and repro-toxicology
Clinical Phase I Phase ll Phase lll Analysis data and report Phase lV Review
Regulatory Submission and updating of clinical trial application prepare submit Authority
MAA/NDA Regulatory Approval
Post marketing Surverillance
Pharmaceutics Preclinical,clinical and commercial formulation
Development and stability testing Prepare labelling
Drug metabolism
and pharmacokinetics Animal ADME* Healthy humans Human patients
Activities likely to be on the critical path are shown in bold
* Absorption , Distribution , Metabolism , Excretion
Fig. 2 The major processes in new drug development
The following sections highlight the objectives and activities of drug development work.Activities within each technical discipline are described broadly in chronological order.At any one time，work in all these disciplines may be proceeding in parallel. The timing and outcome of much of the work has direct impact on work in other disciplines. The major phases of drug development are Preclinical ( studies required before the compound can be dosed in humans)，Phase I (clinical studies usually in healthy human volunteers ) Phase Ⅱ( initial efficacy and safety and dose finding studies in patients)，and Phase Ⅲ(studies in several hundred patients). There then follows assembly of a marketing application dossier for subsequent review by country regulatory authorities.
3. Chemical development
Rapid development of a drug candidate is dependent on the availability of sufficient quantity of the compound. The purity of compound needs to reach certain standards in order for it to be used in safety (toxicology)，pharmaceutical，and clinical studies. Initially，chemists will work on a small to medium scale to investigate production of the compound by several different methods so as to identify the optimum route for synthesizing the compound. ‘Optimum’here may mean a combination of several factors，for example，most efficient，cheapest safe，or that producing minimal waste. Analysis of the final product as well as intermediates and impurities plays a key role in identifying the best method of synthesis. Development and validation of analytical methods are necessary to support process development and guarantee the purity of the drug substance.
In some cases levels of impurities may be unacceptably high and either improved purification procedures will need to be developed or the synthetic process may require significant alterations. The main aim is to ensure that the composition of compound is understood and that ultimately the material that is prepared is as pure as possible.
As a drug candidate progresses through development，larger and larger amounts of compound are required. The amount of material required for different tests will often depend on the actual potency and dosage form of the compound.
A pilot plant can be regarded as a mini-manufacturing set-up. Before transferring to a pilot plant，extensive evaluation and testing of the chemical synthesis is undertaken to ensure that any changes and hazards are minimized. Procedures are optimized，particular attention being paid to developing environmentally acceptable ways of disposing of waste products. Commercial production of bulk drug substance for production of a drug，once approved and marketed，will likely take place on a larger scale or at a registered manufacturing plant.
4. Formulation development
The dosage form of a drug is the form by which it is administered to the patient. There are a vast array of possible dosage forms ranging from transdermal patches to inhalers to intranasal medicines. The more common dosage forms include oral tablets or capsules，oral liquids，topical ointments or creams，and injectables. The dosage form or forms chosen for a particular drug candidate will be defined in the target profile.
Sometimes a more simple dosage form，for example an oral solution，is chosen for early 57 clinical studies in human beings. This may save time and upfront costs at an early，high-risk stage of the drug development process. Later clinical studies would use the expected marketed dosage form.
Whatever the dosage form，the combination of drug and other materials which constitute it must fulfil certain criteria. One of the most important is that of adequate stability. That means a predetermined potency level must remain after，for example，two or three years. The stability data generated on a dosage form will determine its shelf-life and recommended storage conditions. Early in development the shelf-life may be limited to several months. This will not be a problem provided it is sufficient to cover use of the drug over the duration of the clinical study or studies.
5. Pharmacology
Before a drug candidate is given to man，its pharmacological effects on major systems are often investigated in a number of species. The body systems studied include cardiovascular，respiratory，and nervous systems;the effects on gross behavior can also be studied.
Experiments are sometimes conducted to see whether the drug candidate interferes with the actions of other medicines which，because of their specific effects or because of their common use，are likely to be taken concurrently with the drug candidate. Any synergism or antagonism of drug effects should be investigated，and any necessary warning issued to clinical investigators.(It may be judged necessary to investigate such effects further in clinical studies，and any potential or proven drug interactions are likely to be noted in the product labeling for the drug.)
It may also be appropriate to identify a substance for possible use in the management of overdosage，particularly if the therapeutic margin of the drug candidate is small.
6. Safety evaluation
The objective of animal toxicology testing，carried out prior to the administration of a drug to man，is to reject compounds of unacceptable toxicity and to identify potential target organs and timings for adverse effects of the drug. This means that in early human studies these organs and tissues can be monitored with particular attention. It is important to establish whether toxic effects are reversible or irreversible，whether they can be prevented and，if possible，the mechanism of the toxicological effects. It is also important to interrelate drug response to blood levels in humans and blood levels in various animal species.
The toxicological studies required for the evaluation of a drug candidate in man will be relevant to its proposed clinical use in terms of route of administration and duration of treatment of the clinical studies. The size and frequency of the doses and the duration of the toxicology studies are major determinants of permissible tests in man. Countries，including UK，USA，Australia，and Nordic countries，have regulatory guidelines which relate the duration of treatment allowed in man to the length of toxicity studies required in two species. Points from the guidelines are referenced in the subsequent sections.
58 Initially，the pharmacological effects of increasing doses of the test substances are established in acute toxicity studies in small numbers of animals，generally using two routes of administration (one being that used in man). Results provide a guide to the maximum tolerated doses in subsequent chronic. toxicity tests，aid selection of dose levels，and identify target organs.
The main aim of the subsequent sub-acute toxicity tests is to determine whether or not the drug candidate is adequately tolerated after administration to animals for a prolonged period as a guide to possible adverse reactions in man. Two to four week (daily dosing) studies are required，using the same route of administration as in man，in two species (one non-rodent)prior to administration of the compound to man. Three dose levels are usually necessary:the low daily dose should be a low multiple of the expected therapeutic dose，and the highest dose should demonstrate some toxicity.
A general guide for the evaluation of new chemical entities would be that toxicology studies of a minimum duration of
14 days are required to support single-dose exposure of a new drug candidate in normal volunteers in Phase 1. Toxicology studies of 30 days duration are required to support clinical studies of 7 to 10 days duration. Clinical studies of greater than 7 to 10 days up to 30 days duration require the support of at least 90 days toxicology studies. These requirements illustrate the need to plan ahead in drug development. The duration and approximate timings for future clinical trials need to be considered well in advance in order to schedule and conduct the appropriate toxicology studies to support the clinical program and avoid any delays.
Two types of safety test are used to detect the ability of the drug candidate to produce tumours in man. The first are short-term in vitro genotoxicity tests，for example bacterial tests. The second are long-term animal carcinogenicity studies which are conducted in mice and rats;their length of often 2 years covers a large part of the lifespan of the animal. Mice and rats are used because of their relatively short life span，small size，and ready availability. Also，knowledge，which has accumulated concerning spontaneous diseases and tumours②in particular strains of these species，helps greatly in the interpretation of‘results.
Long-term toxicology and carcinogenicity studies are conducted in order to obtain approval to test and finally to market a product for chronic administration to man. These studies may need to start during the late preclinical/ early clinical phase in order to `support' the subsequent clinical program. Long-term toxicity studies will normally include toxicity studies of six and twelve months duration in two species (one non-rodent).Any toxicity previously detected may be investigated more closely，for example extra enzymes looked at in blood samples.
Reproductive toxicology is that part of toxicology dealing with the effect of compounds on reproduction-fertility，
foetal abnormalities，post-natal development. Prior to clinical studies in women of child-bearing age，regulatory authorities require teratology data from two species (normally rat and rabbit)as well as clinical data from male volunteers. No reproductive data are required prior to clinical studies in male subjects. The effects of 59 compounds on reproduction differ with the period of the reproductive cycle in which exposure takes place and studies are designed to look at these phases. Teratology`'' studies are designed to detect foetal abnormalities，fertility studies to investigate the compounds' effect on reproductive performance，And peri- and post-natal studies to study the development of pups.
Selected from F. D. King，’Medicinal Chemistry Principles and Practice ’ the Royal Society of
Chemistry Thomas , Graham House G. B. , 1994.
5单元药物研发（I）
1。简介
药品开发是一个非常复杂的过程，需要一个协调和沟通不同功能之间的群体广泛很大。它是昂贵的，特别是在临床开发的后期阶段，在研究涉及的数百名病人。据估计，目前约2.3亿美元（1987美元）的新药开发成本，并采取介于7和10多年的临床前开发阶段开始，首先市场（不包括监管滞后）。药物开发是一项高风险业务，虽然利率不断上升，大约只有每十个新的化学研究在人类首次实体开展会不会成为一个产品。作为候选药物的进步，通过发展'的失败降低风险hurdles'are克服前进的道路上。失败的典型原因包括不可接受的毒性，缺乏有效性，或不能提供比其他竞争产品的优点
（图1）。
损耗率的新化学实体
（竞争性考试的）进入发展。平均
只有约400 ^ 1000我在化合物
合成进入发展。
原因的罗富国教育学院的发展终止
（不包括抗感染药）
1：缺乏疗效
2：药代动力学
3：动物毒性
4：杂项
5：在人的不良影响
6：商业上的原因
图。 1磨损率和终止的原因
2。发展规划
候选药物是否有可能提供有竞争力优势的评估首先需要强调的地方有一个产品'的目标，目标产品或配置文件集。应特别注意支付给竞争者形成差异。这已成为55个，并与有限的处方，医疗费用，以及药物经济学（本章稍后讨论）日益重视更为关键。
配置文件将确定一个目标指示（县），将候选药物开发以及诸如每日一次给药的目标，起效更快的行动，更好地侧比主要竞争对手效应特征。目标配置文件可以通过完善和发展为移动和候选药物的候选药物或竞争对手成为可用的新数据修改。合乎逻辑的下一个步骤是确定发展战略，例如，有适应症先发展，哪些国家向市场为目标的药物，然后确定要达到的核心监管机构的批准和商业成功的临床研究。
本章将描述一个成功的新药开发所需的主要活动。所有这些活动，其中许多是相互依存，需要认真规划和协调。速度与高品质的数据收集到的市场是成功的关键。该活动确定的时间会去登记被称为项目管理方面，关键路径，路径。这是非常重要的计划和准备，并在研究开始监控和管理问题，以确保关键路径如期进行。增加经济压力和竞争强度，重要的是企业，探讨如何缩短这一关键路径。并行运行的活动，或重叠研究，这将通常按顺序运行，往往涉及的风险增加，节省时间，但分红可以使这种战略值得的。
用于药物开发的一个新的关键路径通常贯穿初步合成的化合物，亚急性毒性研究，然后临床计划。图表显示了一个典型的候选药物的关键路径上的活动图所示。 2。
化学化学合成路线的选择试验厂，规模和稳定性测试制造工厂生产
急性及亚急性毒理学毒理学长期和再现毒理学
第一阶段会期临床阶段微光分析数据和报告相低压回顾
监管意见书和临床试验申请更新准备提交管理局
甲基丙烯酸/新药审批管理
上市后Surverillance
药物临床前，临床和商业配方
发展和稳定的测试准备标签
药物代谢
动物药代动力学和操作ADME *健康人的人类患者
活动可能是在关键路径上以粗体显示
*吸收，分布，代谢，排泄
图。 2，在新药开发的主要过程
以下各节突出了每个技术学科的目标和药物开发work.Activities活动中介绍了大致按时间顺序order.At任何一个时间，在所有这些领域的工作可能是平行进行。的时间和大量的工作成果对其他学科的工作有直接的影响。药物开发的主要阶段是临床前（前化合物所需的研究，可在人体剂量），第一阶段（通常在健康志愿者的临床研究）的Ⅱ期（初始疗效和安全性和治疗剂量调查研究），及Ⅲ期（在几百病人的研究）。然后讲述了一个有上市申请档案大会由国家监管当局随后的审查。
3。化工发展
候选药物的快速发展是建立在足够数量的化合物可依赖。该化合物的纯度需要达到一定的标准，以便它在安全使用（毒理学），制药和临床研究。最初，化学家将在小到中等规模的调查数，以便确定该化合物合成路线的最佳方法不同，该化合物的生产。'最佳'这里可能意味着多种因素的组合，例如，最有效，最便宜的安全，或产生最少的废物。最终产品以及中间体和杂质分析在确定最佳的合成方法的关键作用。开发和分析方法验证是必要的支持过程的发展，保证原料药的纯度。
在某些情况下，杂质含量高得令人无法接受，要么提高净化程序，将需要开发或合成过程可能需要大量的改变。其主要目的是确保组成的化合物，最终理解和准备的材料是尽可能纯净。
作为候选药物开发的进展，复合数额越来越大的需要。材料的数量不同的测试规定，往往取决于实际效力和剂量的复合形式。一个实验工厂内可被视为一个小型制造业设置。才转一个试验工厂，广泛的评估和测试，进行化学合成，以确保任何改变和危害降至最低。程序的优化，特别注重发展产品的废物处置环境可接受的方式。为一次批准和销售的药品，生产原料药进行商业化生产，将可能采取更大规模的或在地方登记的制造工厂。
4。配方开发
一个是药物剂型，它是由病人的管理，以形成。有可能的剂量从贴剂到吸入到鼻腔药品形式繁多。较常见的剂型包括口服片剂或胶囊，口服液，外用药膏或面霜，和注射剂。剂型或特定候选人所选择的药物形式将目标配置文件中定义。
有时，一个更简单的剂型，例如一个口服液，是选择提前57人类临床研究。这可节省在早期，高风险的药物开发过程的前期阶段，时间和成本。随后的临床研究将使用预期销售剂型。
无论是什么剂型，药物和构成它必须符合一定标准的其他材料的组合。最重要的之一是足够的稳定性。这意味着，必须预先确定的水平后继续效力，例如，两年或三年。稳定剂型上产生的数据将决定其保质期和储存条件的建议。于早期发展的保质期可能仅限于数个月。这不会是一个问题，只要是足以应付使用的药物在临床研究或学习的时间。
5。药理
前候选药物是考虑到人，对大型系统的药理作用研究往往在一个物种的数目。身体系统的研究，包括心血管，呼吸和神经系统;总值行为的影响也有待研究。
有时进行实验，看看是否与这些候选药物，由于其具体效果，或者因为他们的共同使用，有可能采取与其他药物同时候选药物的行为干预。任何协同或拮抗作用的药物作用，应进行调查，并发出警告任何必要的临床调查。（这可能被认为有必要探讨进一步的临床研究这些影响，以及任何潜在的或行之有效的药物相互作用可能在产品上发现在药物标签。）
这也可能是适当的，以确定在管理方面可能的过量使用一种物质，特别是如果该候选药物治疗幅度很小。
6。安全性评价
对动物毒理学测试的目标，开展前的一个男子药品监督管理局，是拒绝不可接受的毒性化合物，并确定为潜在的药物不良反应的靶器官和时序。这意味着，在研究这些早期人类器官和组织，可特别注意监测。重要的是要确定是否有毒或不可逆转的影响是可逆的，他们是否可以预防的，如果可能的话，毒性作用的机制。这也是很重要的相互联系药物的反应水平在人类血液和各种动物的血液水平。
对于在人候选药物评价所需的毒理学研究将有关其建议的管理和治疗的临床研究，临床使用期限途径方面。的大小和剂量频率和持续时间的毒理学研究允许在人测试的主要因素。国家，包括英国，美国，澳大利亚和北欧国家，其中有涉及在男人的毒性研究两个物种所需要的长度允许疗程监管指引。百分点，从准则被引用在随后的章节。
58最初，测试物质增加剂量的药理作用是建立在急性毒性研究在动物小数目，一般采用两种给药途径（一个是在人使用）。结果提供了一个指南，在随后的慢性最大耐受剂量。毒性试验，援助的剂量水平的选择和确定目标器官。
在随后的亚急性毒性试验的主要目的是确定是否有足够的候选药物，给药后为，作为对人类可能产生的不良反应在长期指导动物的耐受性。两到四个星期（每日剂量）的研究是必需的，使用与男子相同的路线的管理，在两个物种（一非啮齿类）之前，该化合物对人的管理。三个剂量水平通常必要的：每天低剂量应是所期望的治疗剂量低倍数，最高剂量应表现出一定的毒性。
一种新的化学实体评价的一般指南将是一个为期14天以上毒理学研究需要支持正常的志愿者在第一阶段的单剂量接触一个新的候选药物。为期30天的毒理学研究是必需的，以支持7至10天时间的临床研究。超过7至10天至30天的时间更多临床研究需要有至少90天的毒理学研究的支持。这些要求说明需要计划在药物向前发展。的时间及今后的临床试验的近似时序需要考虑，以便提前做好安排，并进行相应的毒理学研究，以支持临床程序，并避免任何延误。
两种类型的安全测试是用来检测的候选药物在人的能力产生肿瘤。第一类是短期的体外遗传毒性试验来看，例如细菌试验。第二类是动物长期致癌性是在小鼠和大鼠进行了研究;他们往往二年长度覆盖了动物寿命的很大一部分。小鼠和大鼠的使用，因为他们的寿命相对较短，体积小，随时可用性。此外，知识，积累了自发的疾病及有关这些物种的特定菌株②肿瘤，大大有助于在'结果的解释。
长期毒理学和致癌性研究是为了获得批准，试验，终于向市场推出了人类对慢性管理的产品。这些研究可能需要后期临床前/早期临床阶段的开始，以'支持'随后的临床计划。长期毒性试验通常包括毒性研究的6到12个月，两个物种的持续时间（一个非啮齿类）。任何毒性，可调查发现以前更加紧密，例如额外的酶在血液样本看。
生殖毒理学则是一对繁殖的化合物，生育，胎儿畸形，产后处理毒理学发展的影响的一部分。之前，在生育年龄的妇女的临床研究，监管部门需要从两个物种（通常大鼠和家兔）以及从男性志愿者的临床资料畸形的数据。没有生育的数据之前，必须在男性受试者临床研究。 59个化合物对生殖的影响不同的生殖周期中，暴露发生和研究的目的是看看这些阶段的时期。畸形`''研究的目的是检测胎儿畸形，生殖研究，以探讨该化合物对繁殖性能的影响，城郊和产后的研究，研究幼崽的发展。
从fd选定国王的，药物化学原理与实践'皇家学会
化学托马斯，格雷厄姆府湾湾，1994年。
Exercises
1 .Answer the following questions:
(1)Why do people consider the discovery of the novel drug is a long，expensive and tortuous process with no guarantee of success?
(2) How many major processes are there in new drug development?
(3) What has been achieved in the novel drug development in the past century?
(4) Please list the disadvantages or barriers in Chinese novel drug development.
2. Put the following into English:
3. Put the following into Chinese:
pharmacokinetics assessment optimum highlight regulatory approval
preclinical pharmacology side effect excretion safety evaluation
4. Fill the blanks with the following words:
Pharmacodynamics toxicology pharmacognosy
Pharmacotherapeutics pharmacokinetics pharmacy
____ is a descriptive science concerned with the physical characteristics of natural drugs，primarily those derived from plants and animals. ____ is the art and science of preparing，compounding，and dispensing medicines. ____ is the study of the way drugs are absorbed into the body，their metabolism by the body，and the way they are excreted. ____ is the study of the actions of drugs on living organisms and can itself be further subdivided. It borrows freely from the experimental techniques of physiology，biochemistry，microbiology，pathology，genetics，immunology and cellular and molecular biology. Research in this area of pharmacology is at the very frontier of medical knowledge. It studies the ways in which drugs interact with the molecular structures(such as enzymes，cell receptors，and genetic material) that make up the machinery of living tissue. As knowledge has expanded，several of these subareas have developed specialized journals，such as the Journal of Molecular Pharmacology and the Journal of Biochemical pharmacology. Knowledge of precisely how drugs affect the chemistry of the cell has permitted the deliberate design of new drugs to treat formerly untreatable diseases. ____ deals with the use drugs in the prevention and treatment of disease，while ____ deals with the adverse effects of drugs.
练习
1。回答下列问题：
（1）为什么人们考虑新药物的发现是一个没有成功的保证长期的，昂贵的和曲折的过程？
（2）有多少主要过程是在新药开发呢？
（3）什么一直在新药开发取得了过去一个世纪？
（4）请列出的缺点或中国新药开发的障碍。
2。把以下内容翻译成英语：
3。把成中文如下：
药代动力学评价优化突出监管部门的批准
临床前药理副作用排泄安全性评价
4。填写以下单词填空：
药效毒理学药学
Pharmacotherapeutics药药房
____是一种描述性科学与主要是来自植物和动物的天然药物，物理特性有关。____是艺术和准备，复合，并配发药物科学。 ____是这些药物进入体内，被人体的新陈代谢，以及它们排出的方式吸收方式的研究。 ____是药物对生物体的行动本身，可以进一步细分研究。它借用自由地从生理学，生物化学，微生物学，病理学，遗传学，免疫学，细胞和分子生物学实验技术。在这方面的研究药理学是在非常前沿的医学知识。它研究的方法，使药物相互作用的分子结构（如酶，受体细胞和遗传物质）构成的活组织机制。由于知识不断扩大，其中有几个子区域发展，如分子药理学杂志和杂志生化药理专业刊物。，正是药物如何影响细胞的化学知识已批准新的药物来治疗前精心设计无法治愈的疾病。 ____在预防和治疗疾病使用的药物处理，而与药物的
PART 3 INDUSTRIAL PHARMACY
Unit 11 Tablets (The Pharmaceutical
Tablets Dosage Form)
Role in Therapy
The oral route of drug administration is the most important method of administering drugs for systemic effects. Except in cases of Insulin therapy，the parenteral route is not routinely used for self-administration of medications. The topical route of administration has only recently been employed to deliver drugs to the body for systemic effects，with two classes of marketed products: Nitroglycerin for the treatment of angina and scopolamine for the treatment of motion sickness'. Other drugs are certain to follow，but the topical route of administration is limited in its ability to allow effective drug absorption for systemic drug action. The parenteral roue of administration is important in treating medical emergencies in which a subject is comatose or cannot swallow，and in providing various types of maintenance therapy for hospitalized patients. Nevertheless，it is probable that at least 90 0 o of all drugs used to produce systemic effects are administered by the oral rote. When a new drug is discovered，one of the first questions a pharmaceutical company asks is whether or not drug can be effectively administered for its intended effect by the oral route. If it cannot，the drug is primarily relegated to administration in a hospital setting or physician's office. If patient self- administration cannot be achieved，the sales of the drug constitute only a small fraction of what the market would be otherwise. Of drugs that are administered orally，solid
oral dosage forms represent the preferred class of product. The reasons for this preference are as follows. Tablets and capsules represent unit dosage forms in which one usual dose of the drug has been accurately placed. By comparison，liquid oral dosage forms，such as syrups，suspensions，emulsions，solutions，and elixirs，are usually designed to contain one dose of medication in 5 to 30 ml. The patient is then asked to measure his or her own medication using a teaspoon，tablespoon，or other measuring device. Such dosage measurements are typically in error by a factor ranging from 20 0 o to 50% o when the drug is self-administered by the patient.
Liquid oral dosage forms have other disadvantages and limitations when compared with tablets. They are much more expensive to ship (one liquid dosage weighs 5 g or more versus 0. 25 to 0. 4 g for the average tablet)，and breakage or leakage during shipment is a more serious problem with liquids than with tablets. Taste masking of the drug is often a problem (if the drug is in solution even partially). In addition，liquids are less portable and require much more space per number of doses on the pharmacist's shelf. Drugs are in general less 118 stable (both chemically and physically) in liquid form than in a dry state and expiration dates tend to be shorter. Careful attention is required to assure that the product will not allow a heavy microbiologic burden to develop on standing or under normal conditions of use once opened(preservation requirements).There are basically three reasons for having liquid dosage forms of a drug:(1)The liquid form is what the public has come to expect fox certain types of products (e. g. cough medicines).(2) The product is more effective in a liquid form (e. g.，many adsorbents and antacids). (3) The drug(s) are used fairly commonly by young children or the elderly，who have trouble swallowing the solid oral dosage forms.
Properties
The objective of the design and manufacture of the compressed tablet is to de liver orally the correct amount of drug in the proper form at or over the proper time and in the desired location，and to have its chemical integrity protected to that point. Aside from the physical and chemical properties of the medicinal agent (s)to be formulated into a tablet，the actual physical design，manufacturing process，and complete chemical makeup of the tablet can have a profound effect on the efficacy of the drug(s)being administered.
A tablet(1)should be an elegant product having its own identity while being free of defects such as chips，cracks，discoloration，contamination，and the like;(2) should have the strength to withstand the rigors of mechanical shocks(5) encountered in its production，packaging，shipping，and dispensing; and (3) should have the chemical and physical stability to maintain its physical attribute over time. Pharmaceutical scientists now understand that various physical properties of tablets can undergo change under environmental or stress conditions，and that physical stability，through its effect on bioavailability in particular，can be of more significance and concern in some tablet systems than chemical stability.
On the other hand，the tablet(1)must be able to release the medicinal agent(s) in the body in a predictable and reproducible manner and (2) must have a suitable chemical stability over time so as not to allow alteration of the medicinal agent(s). In many instances，these sets of objectives are competing. The design a of tablet that emphasizes only the desired medicine effects may produce a physically inadequate product. The design of a tablet emphasizing only the physical aspects may produce tablets of limited and varying therapeutic effects. As one example of this point，Meyer and associates present information on 14 Nitrofurantoin products，all of which passed the compendia physical requirements，but showed statistically，significant bioavailability differences.
Selected from Lachman Leon et al. The Theory and Practice可Industrial Pharmacy,
3 rd ed., Lea and Febiger, Philadelphia, 1986.
第3部分工业药物
11单元
片（该药片剂型）的治疗作用
在口服给药途径是全身作用的药物管理最重要的方法。除胰岛素治疗的情况下，常规肠外路由不用于自药物管理。行政专题路线只是最近被用来传送药物的系统性影响的机构，两个上市产品类：用于心绞痛和东莨菪碱用于运动病的治疗硝酸甘油治疗。其他药物一定会跟进，但政府外用途径在于，它能够让全身药物作用的有效药物的吸收有限。行政肠外roue在处理医疗紧急情况，其中一个主题是昏迷或不能吞咽，住院，并为维持治疗患者的各类重要。不过，很可能至少有90 0用于生产系统影响O的所有药物通过口服死记硬背管理。当一个新的药物被发现，在一家制药公司要求的第一个问题是，是否得到有效的药物可以用于其预定的口服效果管理。如果不能，该药物主要是降级到政府在医院设
置或医生的办公室。如果病人自我管理，就不可能实现，该药物的销售只占一个什么样的市场，否则将是一小部分。那是口服药物，口服固体制剂产品的首选代表类。这种偏好的原因如下。片剂和胶囊代表哪一个单位剂量的药物常用剂量已准确地放置形式。相比之下，口服液等剂型，糖浆，混悬剂，乳剂，解决方案和药酒，通常设计为包含一个药物剂量5至30毫升。然后问病人是衡量他或她自己的药物使用一茶匙，汤匙，或其他测量设备。在这种剂量测量误差通常由20?0度至50％O当药物自我管理因素的病人。
口服液剂型有其他的缺点和局限性，当与药片。他们更昂贵的船舶（一液用量重5克与0或更多。
25 0 4。对于普通片剂G）和运输过程中破损或渗漏是一个比片液体更严重的问题。品味的药往往是掩盖问题（如在溶液中的药物，即使是部分）。此外，液体移植性较差，需要更多的每对药剂师的货架剂量数空间。毒品在一般不太稳定，118液态形式（包括化学和物理），比在干燥状态和过期日期往往较短。需要认真注意，以确保该产品将不会允许一个沉重的负担，发展微生物站立或根据一旦打开（保存要求）正常使用条件基本上有三种具有液体剂型药物的原因：。（1）液体形式是公众所期望的产品（如咳嗽药）某些类型的狐狸。（2）该产品是在液体中更多的形式（例如，许多吸附剂和制酸剂）有效。（3）药物（s）是用于儿童或老人，谁吞咽困难的固体口服剂型相当普遍。
属性
在设计和制造的压缩片的目的是去肝口服药物在达到或超过适当的时间和所需的位置适当的形式正确的金额，并有完整的保护，其化学这一点。除了从药用剂的物理和化学性质（县）制定成片，实际的物理设计制造过程，以及完整的片剂的化学成分可能对药物（s）的有效性产生深远的影响被管理。
甲片（1）应该是一个高雅的产品有它自己的身份而被如薯片，裂缝，变色，污染的缺陷，等等;（2）应该有实力能够承受机械冲击的严峻考验（5）中遇到的生产，包装，运输和分配，以及（3）应具有的化学和物理稳定性随着时间的推移，以维持它的物理属性。医药科学家们现在明白，片剂各种物理性能进行生物利用度的变化，特别是在环境或压力的条件，并通过其物理稳定性的影响，可以为更多的意义和化学稳定性比一些片剂系统的关注。
另一方面，片剂（1）必须能够在体内释放的药物剂（s）在可预测和可重复性的方式和（2）必须有一个合适的化学稳定性随着时间的推移，以便不容许改变药用剂（s）。在许多情况下，这些目标的集竞争。片剂的设计，强调只有所需的药物的效果可能会产生身体不足的产物。一个只注重物质方面片剂设计可能会产生不同的治疗效果有限，而且片。作为其中的一个点，迈耶和联营公司14呋喃妥因的产品，所有这些都通过汇编物理要求，但统计表明，生物利用度差异显着目前的信息的例子。
选自拉克曼莱昂等。理论与实践可工业药剂，
第三编。，Lea和Febiger，费城，1986年。
Exercise
1. Answer the following questions.
(1)How many kinds of the route of drug administration are there?
(2) Can you present these usual dosage forms of the drug that are administered orally?
(3) How is an evaluation of a tablet's properties made?
2. Complete the passage below.
Solid ____ dosage forms are delivery systems presented as solid dose units readily administered by mouth. The group includes ____，____ ，____ ，and ____ , as well as bulk or unit-dose powder and granules. The group constitutes the most popular form of presentation，and tablets and capsules account for the greatest number of preparations in this category. The prime reasons for this popularity includes:easy of accurate (yet versatile) ____ ，good ____ and ____ stability，competitive unit production costs，and an elegant distinctive appearance resulting in a high level of patient acceptability. Among the potential disadvantages are irritant effects on the gastrointestinal mucosa by some solids and the possibility of bioavailability problems caused by the fact that both ____ (in most causes)and ____ must take place before the drug is a available for absorption.
3. Put the following into Chinese.
absorption action treat medication
medicine pharmaceutical compress quality
quantity uniformity measure composite
4. Put the following into English.
练习
1。回答下列问题。
（1）如何对药物给药途径有多少种？
（2）你认为目前这些药物通常是口服剂型？
（3）如何评价是一个片的属性呢？
2。完成以下的段落。
____固体剂型为口服固体剂量容易管理的单位提交的运载系统。该集团包括____,____,____和____，以及大量或单位剂量粉末和颗粒。本集团构成了最流行的表现形式，片剂和胶囊的筹备工作最大的此类账户。这个大受欢迎的首要原因包括：精确的（但灵活）____，____和____稳定性好，有竞争力的单位生产成本，独特的外观和优雅的病人在接受高层次造成容易。在可能的缺点是对一些固体胃肠黏膜和的事实，这两个____（多数原因）和____前必须进行药物的吸收是一个可导致生物利用度问题的可能性有刺激性作用。
3。把成中文以下。
治疗药物的吸收作用
医药制药压缩质量
量均匀性测量复合材料
4。把以下内容翻译成英语。
Unit 13 Sterile Products
Sterile Products
Sterile products are dosage forms of therapeutic agents that are free of viable microorganisms. Principally，these include parenteral，ophthalmic，and irrigating preparations. Of these，parenteral products are unique among dosage forms of drugs because they are injected through the skin or mucous membranes into internal body compartment. Thus，because they have circumvented the highly efficient first line of body defense，the skin and mucous membranes，they must be free from microbial contamination and from toxic components as well as possess an exceptionally high level of purity. All components and processes involved in the preparation of these products must be selected and designed to eliminate，as much as possible，contamination of all types，whether of physical，chemical，or microbiologic origin.
Preparations) for the eye，though not introduced into internal body cavities，are placed in contact with tissues that are very sensitive to contamination. Therefore，similar standards are required for ophthalmic preparations).
Irrigating solutions(M are now also required to meet the same standards as parenteral solutions because during an irrigation procedure，substantial amounts of these solutions can enter the bloodstream directly through open blood vessels of wounds or abraded mucous membranes. Therefore，the characteristics and standards presented in this chapter for the production of large-volume parenteral solutions apply equally to irrigating solutions.
Sterile products are most frequently solutions or suspensions，but may even be solid pellets for tissue implantation. The control of a process to minimize contamination for a small quantity of such a product can be achieved with relative ease. As the quantity of product increases，the problems of controlling the process to prevent contamination multiply. Therefore，the preparation of sterile products has become a highly specialized area in pharmaceutical processing. The standards established，the attitude of personnel，and the process control must be of a superior level.
vehicles
By far the most frequently employed vehicle for sterile products is water，since it is the vehicle for all natural body fluids. The superior quality required for such use is described in the monograph on Water for Injection in the USP. Requirements may be even more stringent for some products，however.
One of the most inclusive tests for the quality of water is the total solids content，a gravimetric evaluation of the dissociated and undissociated organic and inorganic substances present in the water. However，a less time-consuming
test，the elevtrolytic measurement of conductivity of the water，is the one most frequently used. Instantaneous measurements can 132 be obtained by immersing electrodes in the water and measuring the specific conductance , a measurement that depends on the ionic content of the water. The conductance may be expressed by the meter scale as conductivity in micromhos ，resistance in megohms , or ionic content as parts per million (ppm)C" of sodium chloride. The validity of this measurement as an indication of the purity of the water is inferential in that methods of producing high-purity water，.such as distillation and reverse osmosis，can be expected to remove undissociated substances along with those that are dissociated. Undissociated substances such as pyrogens，however，could be present in the absence of ions and not be disclosed by the test. Therefore，for contaminants other than ions，additional tests should be performed.
Additional tests for quality of Water for Injection with permitted limits are described in the USP monographs. When comparing the total solids permitted for Water for Injection with that for Sterile Water for Injection，one will note that considerably higher values are permitted for Sterile Water for Injection. This is necessary because the latter product has been sterilized，usually by a thermal method，in a container that has dissolved to some extent in the water. Therefore，the solids content will be greater than for the nonsterilized product. On the other hand，the 10 ppm total solids officially permitted for Water for Injection may be much too high when used as the vehicle for many products. In practice. water for Injection normally should not have a conductivity of more han 1 micromho(I megohm，approximately 0. 1 ppm NaCI ).
Added Substances.
Substances added to a product to enhance its stability are essential for almost every product. Such substances include solubilizers，antioxidants，chelating agents，buffers，tonicity contributors，antibacterial agents，antifungal agents，hydrolysis inhibitors，antifoaming agents，and numerous other substances for specialized purposes. At the same time，these agents must be prevented from adversely affecting the product. .In general，added substances must be nontoxic in the quantity administered to the patient. They should not interfere with the therapeutic efficacy nor with the assay of the active therapeutic compound. They must also be present and active when needed throughout the useful life of the product. Therefore，these agents must be selected with greatcare，and they must be evaluated as to their effect upon the entire formulation.- An extensive review of excipients used in parenteral products and the means for adjusting pH of these products has recently been published and should be referred to for more detailed information.
Formulation
The formulation of a parente.ral product involves the combination of one or more ingredients with a medicinal agent to enhance the convenience，acceptability，or effectieness of the product. Rarely is it preferabl6 to dispense a drug singly as a sterile dry powder unless the formulation of a stable liquid preparation is not possible.
On the other hand，a therapeutic agent is a chemical compound subject to the physical and chemical reactions characteristic of the class of compounds to which it belongs. Therefore，a careful evaluation must be made of every combination of two or more 133 ingredients to ascertain whether or not adverse interactions occur，and if they do，of ways to modify the formulation so that the reactions are eliminated or minimized. The formulation of sterile products is challenging，therefore，to the knowledge and ingenuity of the persons responsible.
The amount of information available to the formulator concerning the physical and chemical properties of a therapeutic agent，particularly if it is a new compound，is often quite meager. Information concerning basic properties muse be obtained，including molecular weight，solubility，purity，colligative properties，and chemical reactivity，before an intelligent approach to formulation can begin. Improvements in formulation are a continuing‘ process，since important properties of a drug or of the total formulation may not become evident until the product has been stored or used for a prolonged time: However，because of the extensive test documentation required by the U. S. Food and Drug Administration (FDA)，only outstanding formulations can be justified for continuance to the state of a maketed product.
Production
The production process includes all of the steps from the accumulation and combining of the ingredients of the formula to the enclosing of the product in the individual container for distribution. Intimately associated with these processes are the personnel who carry them out and the facilities in which they are performed. The most ideally planned processes can be rendered ineffective by personnel who do not have the right attitude or training，or by facilities that do not provide an
efficiently controlled environment.
To enhance the assurance of successful manufacturing operation，all process steps must be carefully reduced to writing after being shown to be effective. These written process steps are often called standard. operating procedures (SOPs)⑥.No extemporaneous changes are permitted to be made in these procedures;any change must go through the same approval steps as the original written SOP. Further，extensive records must be kept to give assurance at the end of the production process that all steps have been performed as prescribed，an aspect emphasized in the FDA's Good Manufacturing Practices. Such in-process control is essential to assuring the quality of the product，since these assurances are even more significant than those from product release testing. The production of .a quality product is a result of the continuous，dedicated effort of the quality assurance，一production，and quality control personnel within the plant in developing，performing，and confirming effective sops.
Selected from Lachman Leon et al. The Theory and Practice of Industrial Pharmacy,
3rd ed.，Lea and Febiger, Philadelphia，1986.
无菌产品的单位13
无菌产品
无菌产品是可行的微生物属于免费治疗药物剂型。主要是，这些包括胃肠，眼科以及灌溉准备。其中，肠外产品深受毒品剂型独一无二的，因为他们是通过皮肤或粘膜进入人体内部隔间膜注入。因此，因为他们有规避的体魄，对皮肤和粘膜高效的第一线，他们必须从微生物污染和有毒成份，以及拥有的纯度极高的水平。所有组件及这些产品的筹备工作进程，必须选择和设计，以消除，尽可能，所有类型的污染，无论是物理，化学或微生物的起源。
虽然不是筹备工作进入体腔内部引入了眼睛，，）被放置在与组织的联系是非常敏感的污染。因此，类似的标准都需要眼科制剂）。
冲洗液（男，现在也需要，因为在灌溉过程肠外解决方案以满足相同的标准，这些解决方案可以大量通过伤口进入血管或磨损开放粘膜的血液直接。因此，呈现的特点和标准在这个大批量生产章肠外解决方案同样适用于灌溉的解决方案。
无菌产品是最常见的解决方案或暂停，但甚至可能用于组织植入固体颗粒。一个过程的控制，尽量减少对此类产品少量可相对容易地实现了污染。由于产品的增加，过程控制，以防止污染的问题，乘以数量。因此，无菌产品的制备已成为一个高度专业化的制药加工区。该标准建立，人员的态度，和过程控制必须是一个高水准。
车辆
到目前为止，最常用的无菌产品汽车是水，因为它是所有自然体液车辆。优质的使用需要的是这样描述的水专着在美国药典注射。要求可能更严格的一些产品，但是。
在对水的质量最具包容性的测试之一是总固形物含量，是游离的和未解离有机和无机物质在水中的重量评价。然而，耗时少试验，水的电导率elevtrolytic测量，是一个最常用的。瞬时测量可以得到132浸泡在水中的电极和电导率测量，测量，关于水的离子含量而定。电导可表示，作为每百万（百万分之一）的C氯化钠“部分，至于在micromhos电导率，电阻兆欧，或离子含量米的规模。作为水的纯净度适应症这种测量的有效性推理在生产高纯度水的方法。如蒸馏和反渗透，可以预料，随着除去那些游离未解离的物质。未解离如热原物质，然而，可存在于离子的情况下，不被披露的考验。因此比其他离子污染物，应进行更多的测试。
在水质允许的限度与注射额外的测试中描述了美国药典专着。当允许使用比较水与注射用无菌水注射液总固体，人会注意到，相当值越高，无菌注射用水许可。这是必要的，因为后者的产品已消毒，通常由热法在一个完全溶解在水中的一些程度的容器。因此，固形物含量会比在nonsterilized产品更大。另一方面，10 ppm的总固形物正式允许使用注射用水可能过于高时，作为车用许多产品。在实践中。注射用的水通常应该不会有更多的韩一micromho（我兆欧，约0。1 ppm的氯化钠）导电。
新增物质。
物质添加到产品，以提高其稳定性是几乎每一个产品的关键。这些物质包括增溶剂，抗氧剂，螯合剂，缓冲器，强壮贡献者，抗菌剂，抗菌剂，水解剂，消泡剂，以及许多其他专门用途的物质。与此同时，这些药物必须防止产生不利影响的产品。。一般而言，增加物质，必须在管理，以病人的数量无毒。他们不应该干预治疗效果，也不符合化合物的积极治疗法。他们也必须存在和活跃的时候整个产品的
使用寿命需要。因此，这些药物必须选择与greatcare，他们必须就其对整个制定.-一种产品所使用的赋形剂肠外广泛的审查和调整这些产品的pH值影响评价手段已出版，并应转介到更详细的信息。
配方
一个parente.ral产品配方涉及到一个或多个代理药用成分的组合，以提高便利性，可接受性，或产品effectieness。很少是preferabl6免除无菌干粉作为单独的药物，除非在一个稳定的液体制剂配方是不可能的。
另一方面，一个治疗剂是一种化学化合物受到物理和化学反应的化合物类的特性在它所属。因此，仔细评估必须由两个或两个以上的每133成分的组合，以确定是否发生不良的相互作用，如果他们做，如何修改，以便消除或尽量减少的反应是制定。无菌产品的配方是具有挑战性，因此，对知识和责任人的聪明才智。
的信息提供给有关的配方治疗剂的物理和化学性能，尤其是当它是一种新的化合物，金额往往是相当贫乏。有关信息的基本属性得到灵感，包括分子量，溶解度，纯度，依数性质，化学反应，在一个聪明的办法，就可以开始制定。在配方改进是一种持续'的过程，因为一种药物或总配方可能不会明显重要的属性，直到该产品已被储存或使用时间过久：然而，由于广泛的测试文件要求由美国食品和药物管理局（FDA），只有优秀的配方可以说得过去持续到一个maketed产品的状态。
生产
生产过程包括所有从积累的步骤公式的成分，结合到产品的封闭在分配个别货柜。与这些进程密切相关的人员是谁的贯彻落实和执行中，他们的设施。最完美的计划过程可以失效的人员谁不有正确的态度或培训，或设施，没有提供一个有效的控制环境。
为了提高成功的制造运作的保证，所有工艺步骤必须小心以书面记录后，证明是有效的。这些书面处理步骤通常称为标准。。作业程序（SOP）⑥没有即席更改允许在这些程序的，任何改变必须经过书面正本为SOP的批准步骤相同。此外，广泛的记录必须保存给在生产过程结束时保证，所有的步骤已经按照规定，这方面强调，在FDA的良好生产规范。这就是必须保证产品的质量，因为这些保证是从产品甚至比那些显着的发行测试过程控制。生产各种。高质量的产品是一个连续的，质量保证，一生产，并在植物的质量控制人员在开发，实施和确认有效的SOP专用努力的结果。
选自拉克曼莱昂等。的理论与实践工业制药，
第三版。，Lea和Febiger，费城，1986年。
Exercise
1. Answer the following questions:
(1)Can you tell the difference in quality control between the, oral tablet and sterile products injected. 135
(2) How is the quality of sterile products assured in-process?
(3) What is the standard operating procedure (SOPs)?
(4) How is the water for injection usually prepared?
2. Complete the passage below:
Sterile product are dosage forms of therapeutic agent that are free of viable ____ , these include ____ ____ and ____ ，because they are injected through the ____ or ____ membranes into internal body，parenteral products must be free from ____ and from ____ .
Sterile products are most frequently ____ or ____，the most frequently employed ____ for sterile product is ____ the quality of water for injection (WFI) is required by pharmacopeia，which is superior quality required，the natural water contain generally dissociated and undissciated ____ and ____ substances which they must be essentially removed and set a permitted limits，____ are products of matabolism of microorganisms，the removal of ____ is very important for water for injection.
Water for injection is prepared by ____ or ____.
3. Put the following into Chinese:
parenteral ophthalmic irrigating microoganisms
contamination specialize conductivity pycogens
4. Put the following into English
5. Why the removal of pycogens is very important for WFI?
练习
1。回答下列问题：
（1）你能告诉之间，口服片剂和无菌产品质量控制的不同注射。 135
（2）如何是无菌产品的质量保证在进程？
（3）什么是标准作业程序（SOP）的？
（4）如何准备通常是注射用水？
2。通过完成如下：
无菌产品是治疗药物剂型是可行的____自由，其中包括________和____的，因为他们是通过将人体内部的____或____膜注射，注射产品必须是自由和从________。
无菌产品是最常见的____或____,为无菌产品，是最常用的________的注射用水（WFI的）质量是由药典的要求，这是优越的质量要求，一般的天然水含有游离和____和____ undissciated他们基本上必须拆除，并设置许可限制,____物质是微生物matabolism产品，____搬迁是非常重要的注射用水。
注射用水制备了____或____。
3。把成中文如下：
肠外眼科灌溉microoganisms
污染专门导电pycogens
4。把以下内容翻译成英语
5。为什么pycogens注射用水去除是非常重要的？
PART 4 PHARMACEUTICAL ENGINEERING第4部分制药工程
Unit 16 Reactor Technology
Reactor technology comprises(D the underlying principles of chemical reaction engineering (CRE)and the practices used in their application. The focuses of reactor technology are reactor configurations，operating conditions，external operating environments，developmental history，industrial application，and evolutionary change. Reactor designs evolve from the pursuit of new products and uses，higher conversion，more favorable reaction selectivity，reduced fixed and operating costs，intrinsically safe operation，and environmentally acceptable processing.
Besides stoichiometry and kinetics，reactor technology includes requirements for introducing and removing reactants and products，efficiently supplying and withdrawing heat，accommodating phase changes and material transfers，assuring efficient contacting of reactants，and providing for catalyst replenishment or regeneration. Consideration must be given to physical properties of feed and products (vapor，liquid，solid，or combinations)，characteristics of chemical reactions (reactant concentrations，paths and rates，operating conditions，and heat addition or removal)，the nature of any catalyst used (activity，life，and physical form)，and requirements for contacting reactants and removing products(flow characteristics，transport phenomena，mixing requirements，and separating mechanisms).
All the factors are interdependent and be considered together. Requirements for contacting reactants and removing products are a central focus in applying reactor technology;other factors usually are set by the original selection of the reacting system，intended levels of reactant conversion and product selectivity，and economic and environmental considerations.
Reactor Types and Characteristics
Specific reactor characteristics depend on the particular use of the reactor as a laboratory，pilot plant，or industrial unit. All reactors have in common selected characteristics of four basic reactor types : the well-stirred batch reactor，the semibatch reactor，the continuous- flow stirred-tank reactor，and the tubular reactor (Fig. 1).
Batch reactor
A batch reactor is one in which a feed material is treated as a whole for a fixed period of time . Batch reactors may be preferred for small-scale production of high priced products，particularly if many sequential operations are employed to
Chapter 1 Passage 1 Human Body In this passage you will learn: 1. Classification of organ systems 2. Structure and function of each organ system 3. Associated medical terms To understand the human body it is necessary to understand how its parts are put together and how they function. The study of the body's structure is called anatomy; the study of the body's function is known as physiology. Other studies of human body include biology, cytology, embryology, histology, endocrinology, hematology, immunology, psychology etc. 了解人体各部分的组成及其功能，对于认识人体是必需的。研究人体结构的科学叫解剖学；研究人体功能的科学叫生理学。其他研究人体的科学包括生物学、细胞学、胚胎学、组织学、内分泌学、血液学、遗传学、免疫学、心理学等等。 Anatomists find it useful to divide the human body into ten systems, that is, the skeletal system, the muscular system, the circulatory system, the respiratory system, the digestive system, the urinary system, the endocrine system, the nervous system, the reproductive system and the skin. The principal parts of each of these systems are described in this article. 解剖学家发现把整个人体分成骨骼、肌肉、循环、呼吸、消化、泌尿、内分泌、神经、生殖系统以及感觉器官的做法是很有帮助的。本文描绘并阐述了各系统的主要部分。 The skeletal system is made of bones, joints between bones, and cartilage. Its function is to provide support and protection for the soft tissues and the organs of the body and to provide points of attachment for the muscles that move the body. There are 206 bones in the human skeleton. They have various shapes - long, short, cube - shaped, flat, and irregular. Many of the long bones have an interior space that is filled with bone marrow, where blood cells are made. 骨骼系统由骨、关节以及软骨组成。它对软组织及人体器官起到支持和保护作用，并牵动骨胳肌，引起各种运动。人体有206根骨头。骨形态不一，有长的、短、立方的、扁的及不规则的。许多长骨里有一个内层间隙，里面充填着骨髓，这即是血细胞的制造场所。 A joint is where bones are joined together. The connection can be so close that no movement is possible, as is the case in the skull. Other kinds of joints permit movement: either back and forth in one plane - as with the hinge joint of the elbow - or movement around a single axis - as with the pivot joint that permits the head to rotate. A wide range of movement is possible when the ball - shaped end of one bone fits into a socket at the end of another bone, as they do in the shoulder and hip joints. 关节把骨与骨连接起来。颅骨不能运动，是由于骨与骨之间的连接太紧密。但其它的关节可允许活动，如一个平面上的前后屈伸运动，如肘关节；或是绕轴心旋转运动，如枢轴点允许头部转动。如果一根骨的球形末端插入另一根骨的臼槽里，大辐度的运动（如肩关节、髋关节）即成为可能。 Cartilage is a more flexible material than bone. It serves as a protective, cushioning layer where bones come together. It also connects the ribs to the breastbone and provides a structural base for the nose and the external ear. An infant's skeleton is made of cartilage that is gradually replaced by bone as the infant grows into an adult. 软骨是一种比一般骨更具韧性的物质。它是骨连结的保护、缓冲层。它把肋骨与胸骨连结起来，也是鼻腔与内耳的结构基础。一个婴儿的骨骼就是由软骨组成，然后不断生长、
Unit 1 Production of Drugs About 5000 antibiotics have already been isolated from microorganisms，but of these only somewhat fewer than 100 are in therapeutic use. It must be remembered，however，that many derivatives have been modified by partial synthesis for therapeutic use;some 50，000 agents have been semisynthetically obtained from户lactams alone in the last decade. Fermentations are carried out in stainless steel fermentors with volumes up to 400 m3. To avoid contamination of the microorganisms with phages etc. the whole process has to be performed under sterile conditions. Since the more important fermentations occur exclusively under aerobic conditions a good supply of oxygen or air(sterile)is needed. Carbon dioxide sources include carbohydrates，e. g. molasses，saccharides，and glucose. Additionally the microorganisms must be supplied in the growth medium with nitrogen-containing compounds such as ammonium sulfate，ammonia，or urea，as well as with inorganic phosphates. Furthermore，constant optimal pH and temperature are required. In the case of penicillin G，the fermentation is finished after 200 hours，and the cell mass is separated by filtration. The desired active agents are isolated from the filtrate by absorption or extraction processes. The cell mass，if not the desired product，can be further used as an animal feedstuff owing to its high protein content. 关于5000抗生素已经分离出的微生物，但其中只有不到100有些治疗使用。必须记住，但是，许多衍生工具已被用于治疗使用部分合成修改;约50,000剂已被semisynthetically取得户内酰胺在过去十年孤独。发酵都是在不锈钢发酵罐出来的量高达400立方米。为了避免与噬菌体等微生物污染的全过程都必须在无菌条件下进行。由于更重要的发酵只发生在有氧条件下的氧气或空气好电源（无菌）是必要的。二氧化碳的来源包括碳水化合物，大肠杆菌克糖蜜，糖和葡萄糖。另外必须提供的微生物在与含氮如硫酸铵，氨水或尿素化合物生长介质，以及与无机磷酸盐。此外，不断最适pH和温度是必需的。在青霉素G的情况下，发酵完成200小时后，细胞的质量是由过滤分离。所需的活性剂是隔离的滤液吸收或提取工艺。大规模的细胞，如果不理想的产品，可进一步用作动物，由于其蛋白质含量高的饲料。 By modern recombinant techniques microorganisms have been obtained which also allow production of peptides which were not encoded in the original genes. Modified E. coli bacteria make it thus possible to produce A- and B- chains of human insulin or proinsulin analogs. The disulfide bridges are formed selectively after isolation，and the final purification is effected by chromatographic procedures. In this way human insulin is obtained totally independently from any pancreatic material taken from animals. Other important peptides，hormones，and enzymes，such as human growth hormone (HGH)，neuroactive peptides，somatostatin，interferons，tissue plasminogen activator (TPA)，lymphokines，calcium regulators like calmodulin，protein vaccines，as well as monoclonal antibodies used as diagnostics，are synthesized in this way. 利用现代微生物重组技术已获得这也让其中不是在原来的基因编码多肽的生产。改性大肠杆菌从而使可能产生A型和B -人胰岛素或胰岛素原类似物链。二硫键形成的选择性分离后，最终由色谱净化工序的影响。通过这种方式获得的人类胰岛素完全独立采取任何从动物胰腺材料。 其他重要肽，激素和酶，如人类生长激素（hGH），神经活性肽，生长抑素，干扰素，组织型纤溶酶原激活物（tPA），淋巴因子，如钙调节钙调蛋白，蛋白疫苗，以及作为诊断用单克隆抗体是合成了这种方式。 The enzymes or enzymatic systems which are present in a single microorganism can be used for directed stereospecific and regiospecific chemical reactions. This principle is especially useful in steroid chemistry. Here we may refer only to the microbiological 11-a- hydro xylation of progesterone to 11-a-hydroxyprogesterone，a key product used in the synthesis of cortisone. Isolated enzymes are important today not only because of the technical importance of the enzymatic saccharification of starch，and the isomerization of glucose to fructose，They are also significant in the countless test procedures used in diagnosing illness，and in enzymatic analysis which is used in the monitoring of therapy. A number of enzymes are themselves used as active ingredients. Thus preparations containing proteases (e. g. chymotrypsin，pepsin，and trypsin)，amylases and lipases，mostly in combination with synthetic antacids，promote digestion. Streptokinase and urokinase are important in thrombolytics，and asparaginase is used as a cytostatic agent in the treatment of leukemia. 这些酶或微生物在一个单一的酶系统，目前可用于立体定向和regiospecific化学反应。这个原则是有用的，尤其是在化学类固醇。在这里，我们只能引用的微生物十一水电黄体酮xylation至11人羟，一个关键的产品在可的松合成。隔离酶是重要的，不仅因为淀粉的酶法糖化技术重要性的今天，和葡萄糖异构果糖，他们也都在无数次试验在诊断疾病所用的程序显着，在酶的分析，在使用监测治疗。 数量的酶本身作为活性成分。因此，含有蛋白酶制剂（如糜蛋白酶，胃蛋白酶和胰蛋白酶），淀粉酶和脂肪酶的合成主要是在与抗酸药相结合，促进消化。链激酶和尿激酶溶栓是重要的，是天冬酰胺酶在治疗白血病细胞生长剂。 Finally mention must be made of the important use of enzymes as `biocatalysts’in chemical reactions where their
第二部分 控制理论 第1章 1.1控制系统的引入 人类控制自然力量的设计促进人类历史的发展,我们已经广泛的能利用这种量进行在人类本身力量之外的物理进程?在充满活力的20世纪中,控制系统工程的发展已经使得很多梦想成为了现实?控制系统工程队我们取得的成就贡献巨大?回首过去,控制系统工程主要的贡献在机器人,航天驾驶系统包括成功的实现航天器的软着陆,航空飞机自动驾驶与自动控制,船舶与潜水艇控制系统,水翼船?气垫船?高速铁路自动控制系统,现代铁路控制系统? 以上这些类型的控制控制系统和日常生活联系紧密,控制系统是一系列相关的原件在系统运行的基础上相互关联的构成的,此外控制系统存在无人状态下的运行,如飞机自控驾驶,汽车的巡航控制系统?对于控制系统,特别是工业控制系统,我们通常面对的是一系列的器件,自动控制是一个复合型的学科?控制工程师的工作需要具有力学,电子学,机械电子,流体力学,结构学,无料的各方面的知识?计算机在控制策略的执行中具有广泛的应用,并且控制工程的需求带动了信息技术的与软件工程的发展? 通常控制系统的范畴包括开环控制系统与闭环控制系统,两种系统的区别在于是否在系统中加入了闭环反馈装置? 开环控制系统 开环控制系统控制硬件形式很简单,图2.1描述了一个单容液位控制系统, 图2.1单容液位控制系统 我们的控制目标是保持容器的液位h 在水流出流量V 1变化的情况下保持在一定 可接受的范围内,可以通过调节入口流量V 2实现?这个系统不是精确的系统,本系 统无法精确地检测输出流量V 2,输入流量V 1以及容器液位高度?图2.2描述了这 个系统存在的输入(期望的液位)与输出(实际液位)之间的简单关系, 图2.2液位控制系统框图 这种信号流之间的物理关系的描述称为框图?箭头用来描述输入进入系统,以及
PART 3 INDUSTRIAL PHARMACY Unit 11 Tablets (The Pharmaceutical Tablets Dosage Form) Role in Therapy The oral route of drug administration is the most important method of administering drugs for systemic effects. Except in cases of Insulin therapy，the parenteral route is not routinely used for self-administration of medications. The topical route of administration has only recently been employed to deliver drugs to the body for systemic effects，with two classes of marketed products: Nitroglycerin硝酸甘油酯for the treatment of angina心绞痛and scopolamine莨菪胺for the treatment of motion sickness晕动病，指晕车、晕船等. Other drugs are certain to follow，but the topical route of administration is limited in its ability to allow effective drug absorption for systemic drug action. The parenteral route of administration is important in treating medical emergencies in which a subject is comatose昏迷的or cannot swallow，and in providing various types of maintenance therapy for hospitalized patients. Nevertheless，it is probable that at least 90 % of all drugs used to produce systemic effects are administered投药，给药by the oral route. When a new drug is discovered，one of the first questions a pharmaceutical company asks is whether or not drug can be effectively administered for its intended effect by the oral route. If it cannot，the drug is primarily relegated to被降级到administration in a hospital setting or physician's office. If patient self- administration cannot be achieved，the sales of the drug constitute only a small fraction of what the market would be otherwise. Of drugs that are administered orally，solid oral dosage forms represent the preferred class of product. The reasons for this preference are as follows. Tablets and capsules represent unit dosage forms in which one usual dose of the drug has been accurately placed. By comparison相比之下，liquid oral dosage forms，such as syrups，suspensions，emulsions，solutions，and elixirs，are usually designed to contain one dose of medication in 5 to 30 ml. The patient is then asked to measure his or her own medication using a teaspoon， 第三部分工业药剂学 第11单元药片(医药的片剂剂型) 在治疗中的作用 口服给药途径是通过给药获得全身作用效果中最重要的方法。除了胰岛素疗法之外，肠外给药途径通常不用于（病人的）自主性用药。而局部给药途径则是在最近才被用来把药物送到体内从而产生全身作用。这种途径有两种上市产品：用于治疗心绞痛的硝酸甘油酯和用于治疗晕动病的莨菪胺。今后肯定还会有其他的药物相继出现，但是局部给药的途径在有效的药物吸收从而获得全身性药物作用方面仍有其局限性。在病人处于昏迷状态或病人不能吞咽的医疗急救处理中，肠外给药途径是很重要的，同时它也给住院的病人提供了各种不同类型的维持疗法。然而，可能至少有90%的被用于产生全身作用的药物是通过口服的途径给药的。当一种新的药物被研发出来的时候，制药公司问的第一个问题就是这种药物能否有效地通过口服给药途径来达到预期的效果。如果不能，那么这种药物就要被降级到医院或者医生的办公室里。如果病人的自主用药不能实现，那么（这种）药物的销量就会是能实现病人的自主用药的药物销量的很少一部分。在所有通过口服来给药的药物当中，固体口服制剂是（人们）偏爱的产品种类。其原因如下：药片和胶囊代表着单元剂量的形式，其中通常已经放置好了一个剂量的药物。相应地，液体口服制剂，比如说糖浆、悬浮液、乳剂、溶液和酏剂，则通常被设计成在5-30 ml （液体中）包含一个剂量的药物。病人会被要求用茶匙、调羹或其他测量装置来衡量他自己的用药量。病人自己用药时这种剂量测量方法，其误差范围通常
医学专业英语翻译 医学专业英语翻译如下： portable electric dental engine 轻便电动钻牙机，轻便牙钻portable hearing aid 袖珍助听器 portable microtome 手提式切片机 portable monitor 手提式监护仪 portable obstetric table 轻便产床 portable operating table 轻便手术台 portable photoelectric colorimeter 便携式光电比色计 portable suction unit 便携式吸引器 portable testing set 便携式测试仪器 portable typewriter 手提式打字机 portable X-ray machine 手提式X 光机 portacid 移酸滴管，滴酸器 portal 门，入门 portal venography 门静脉造影术 port B/L 港口提单 portcaustic 腐蚀药把持器 porte 柄 porte-acid 移酸滴管，滴酸器
porte-aiguille 持针器 porte-caustique 腐蚀药把持器 porte-ligature 深部结扎器，缚线把持器porte-meche 填塞条器 porte-noeud 瘤蒂结扎器 porte-polisher 握柄磨光器 porterage 搬运费 portial impression trays 局部牙托portion 部分，段，份 portligature 深部结扎器，缚线把线器port of arrival 到达港 port of delivery 交货港 port of departure 出发港 port of destination 到达港目的港 port of discharge 卸货港 portogram 门静脉造影片 portoraphy 门静脉造影术portovenogram 门静脉造影片 posion 阴离子，阳向离子 position 位置，状态 positioner 定位器（牙），位置控制器
Table of Contents Uuit 1 What is Geomatics? （什么是测绘学） (2) Unit 2 Geodetic Surveying and Plane Surveying（大地测量与平面测量） (6) Unit 3 Distance Measurement（距离测量） (10) Unit 4 Angle and Direction Measurement（角度和方向测量） (14) Unit 5 Traversing （导线测量） (17) Unit 6 Methods of Elevation Determination（高程测量方法） (21) Unit 7 Robotic Total Station （智能型全站仪） (25) Unit 8 Errors in Measurement（测量工作中的误差） (29) Unit 9 Basic Statistical Analysis of Random Errors (32) Unit 10 Accuracy and Precision （准确度和精度） (35) Unit 11 Least-Squares Adjustment (38) Unit 12 Geodesy Concepts (40) Unit 13 Geoid and Reference Ellipsoid (42) Unit 14 Datums, Coordinates and Conversions (44) Unit 15 Map Projection (46) Unit 16 Gravity Measurment (48) Unit 17 Optimal Design of Geomatics Network (50) Unit 18 Construction Layout （施工放样） (53) Unit 19 Deformation Monitoring of Engineering Struvture (56) Unit 20 Understan ding the GPS（认识GPS） (59) Uuit 21 Understanding the GPS (II) 认识GPS(II) (62) Unit 22 Competition in Space Orbit（太空轨道上的竞争） (64) Unit 23 GIS Basics（GIS 的基础） (69) Unit 24 Data Types and Models in GIS GIS中的数据类型和模型 (75) Unit 25 Digital Terrain Modeling（数字地面模型） (79) Unit 26 Applications of GIS (83) Unit 27 Developments of photogrammetry (87) Unit 28 Fundamentals of Remote Sensing （遥感的基础） (90) Unit 29 Digital Image Processing and Its Applications in RS (94) Unit 30 Airborne Laser Mapping Technology（机载激光测图技术） (99) Unit 31 Interferometric SAR(InSAR) (102) Unit 32 Brief Introduction toApplied Geophysics (104) Unit 33 Origon of Induced Polarization (105) Unit 34 International Geoscience Organization (108) Unit 35 Prestigious Journals in Geomatics (110) Unit 36 Relevant Surveying Instrument Companies (115) Unit 37 Expression of Simple Equations and Scientific Formulsa (116) Unit 38 Professional English Paper Writing (119) Unit 39 Translation Techniques for EST (127)
cardiovascular diseases; 脑垂体的功能the function of pituitary; 泌尿道urinary tract; 分子molecule; 动脉artery; 内分泌学endocrinology; 呼吸困难dyspnea; 唾液saliva; 组织学histology; 血液循环blood circulation; 血液学hematology; 生理学physiology; 解剖学anatomy; 女性生殖系统femal reproductive system; 神经细胞nerve cell; 免疫学immunology; 消化不良dyspepsia; 随意肌voluntary muscle; 胚胎学embryology; 心理学psychology; 细胞学cytology; 原生质protoplasm; 细胞膜cell membrane; 细胞核nucleus; 细胞质(浆)cytoplasm; 脱氧核糖核酸deoxyribonucleic acid; 能半渗透的semipermeable; 分子生物学molecular biology; 碳水化合物carbohydrate; 有区别性的differentially; 使…完整intact; 根据according to; 遗传特性hereditary trait; 渗滤diffusion; 转换transaction; 蓝图blueprint; 染色体chromosome; 色素pigment; 排出废液excrete waste fluid; 散开disperse; 脉冲信号impulse; 核糖核酸ribonucleic acid; 损害正常功能impair the normal function; 污染环境pollute environment; 功能失调malfunction; 致病因子causative agents; 易受侵害的人群vulnerable groups; 局部化的感染localized infection; 花柳病venereal disease; 抗原与抗体antigen&antibody; 肌电图electromyogram; 多发性硬化multiple sclerosis; 心电图electrocardiograph; 疾病的后遗症sequelea of disease; 光纤技术fiber optic technology; 造血系统hematopoietic system; 致命的疾病fatal disease; 体液body fluid; 无副作用的治疗hazard-free treatment; 无侵犯的实验检查non-invasive laboratory test; 核磁共振nuclear magnetic resonance; 葡萄糖耐糖实验the glucose-tolerance test; 乐观的预后optimistic prognosis; 超声波检测法ultrasonography; 病史medical history; 随访活动follow-up visit; 营养不良nutritional deficiency; 使细节显著highlight detail; 脑电图electroencephalogram; 缺血的组织blood-starved tissue; 肌纤维muscle fiber; 随意肌voluntary muscle; 消化道alimentary canal; 肌腹fleshy belly of muscle; 横纹肌striated muscle; 肌肉痉挛cramps of muscle; 肌肉收缩muscle contraction; 肌肉附着点attachment of the muscle; 肌肉放松relaxation of muscle; 动脉出血arterial hemorrhage; 止端insertion;起端origion;供血blood supply; 屈肌flexor; 蛋白分子protein molecule; 纤维结缔组织fibrous connective tissue; 伸肌extensor; 意志力willpower; 横切面transverse section; 起搏器pacemaker; 肌萎缩muscle atrophy; 重症肌无力myasthenia gravis; 弥散性局部缺血diffuse ischemia; 常染色体隐性autosomal recessive; 全身性感染systemic infection; 受累的肌肉muscle involved; 显著相关性significant correlation; 神经末梢nerve terminal; 自体免疫反应autoimmune reaction; 神经支配innervation; 肌营养不良muscular dystrophy; 慢性营养不良chronic mulnutrition; 先天性肌病congenital myopathy; 预期寿命life expectancy; 免疫紊乱immunologic derangemant; 发病高峰年龄the peak age of onset; 胸腺肿瘤thymoma; 呼吸肌受累the involvement of respiratory muscle; 感染性肌炎inflammatory myositic; 去神经支配denervation; 矿物质吸收mineral absorption; 机械应力mechanical stress; 骨基质有机部分the organic parts of bone matrix; 青春期早熟premature puberty; 蛋白溶解酶protein-digesting enzyme; 破骨细胞osteoclast; 松质骨spongy bone; 骨折fracture; 不规则骨irregular bone; 骨骼系统skeletal system; 维生素吸收vitamin absorption; 骨钙丧失the loss of calcium from bone; 生长激素growth hormone;
1、应力和应变 应力和应变的概念可以通过考虑一个棱柱形杆的拉伸这样一个简单的方式来说明。一个棱柱形的杆是一个遍及它的长度方向和直轴都是恒定的横截面。在这个实例中，假设在杆的两端施加有轴向力F，并且在杆上产生了均匀的伸长或者拉紧。 通过在杆上人工分割出一个垂直于其轴的截面mm，我们可以分离出杆的部分作为自由体【如图1(b)】。在左端施加有拉力P，在另一个端有一个代表杆上被移除部分作用在仍然保存的那部分的力。这些力是连续分布在横截面的，类似于静水压力在被淹没表面的连续分布。 力的集度，也就是单位面积上的力，叫做应力，通常是用希腊字母，来表示。假设应力在横截面上是均匀分布的【如图1(b)】，我们可以很容易的看出它的合力等于集度，乘以杆的横截面积A。而且，从图1所示的物体的平衡，我们可以看出它的合力与力P必须的大小相等，方向相反。因此，我们可以得出 等式(1)可以作为棱柱形杆上均匀应力的方程。这个等式表明应力的单位是，力除以面积。当杆被力P拉伸时，如图所示，产生的应力是拉应力，如果力在方向是相反，使杆被压缩，它们就叫做压应力。 使等式(1)成立的一个必要条件是，应力，必须是均匀分布在杆的横截面上。如果轴向力P作用在横截面的形心处，那么这个条件就实现了。当力P没有通过形心时，杆会发生弯曲，这就需要更复杂的分析。目前，我们假设所有的轴向力都是作用在横截面的形心处，除非有相反情况特别说明。同样，除非另有说明，一般也假设物体的质量是忽略的，如我们讨论图1的杆
一样。 轴向力使杆产生的全部伸长量，用希腊字母δ表示【如图1(a)】，单位长度的伸长量，或者应变，可以用等式来决定。 L是杆的总长。注意应变ε是一个无量纲的量。只要应变是在杆的长度方向均匀的，应变就可以从等式(2)中准确获得。如果杆处于拉伸状态，应变就是拉应变，代表材料的伸长或者延长如果杆处于受压状态，那么应变就是压应变，这也就意味着杆上临近的横截面是互相靠近的。 当材料的应力和应变显示的是线性关系时，也就是线弹性。这对多数固体材料来说是极其重要的性质，包括多数金属，塑料，木材，混凝土和陶瓷。处于拉伸状态下，杆的应力和应变间的线性关系可以用简单的等式来表示。E是比例常数，叫做材料的弹性模量。 注意E和应力有同样的单位。在英国科学家托马斯·杨(1773 ~ 1829)研究杆的弹性行为之后，弹性模量有时也叫做杨氏模量。对大多数材料来说，压缩状态下的弹性模量与处于拉伸时的弹性模量的一样的。 2、拉伸应力应变行为 一个特殊材料中应力和应变的关系是通过拉伸测试来决定的。材料的试样通常是圆棒的形式，被安置在测试机上，承受拉力。当载荷增加时，测量棒上的力和棒的伸长量。力除以横截面积可以得出棒的应力，伸长量除以伸长发生方向的长度可以得出应变。通过这种方式，材料的完整应力应变图就可以得到。 图1所示的是结构钢的应力应变图的典型形状，轴向应变显示在水平轴，对应的应力以纵坐标表示为曲线OABCDE。从O点到A点，应力和应变之间是
这里汇聚了中西医学行业的大部分英语词汇和详细解说，如果要查询相关词汇，你可以点此word 文档工具栏的“编辑”，找到“查找”，然后点开输入你要查询的词汇就可以查询了。 西医篇： 1、医院部门及科室名称 2、医务人员名称 3、诊断和治疗常用词汇 4、常见疾病名称 5、常见手术名称 6、常用药物名称 7、常用护理术语 8、常用临床医学术语 9、医疗器材 10、医学英语快速记忆－后缀 11、主要人体系统名称 12、医院类型名称 13、医学词汇 14、医学常用字首与字根 1.医院部门及科室名称 out-patient department 门诊部 In-patient department 住院部 Nursing department 护理部 Admission office 住院处 Discharge office 出院处 Registration office 挂号处 Reception room, waiting room 侯诊室 Consultation room 诊察室 Isolation room 隔离室 Delivery room 分娩室 Emergency room 急诊室 Ward 病房室 Department of internal medicine 内科 Department of surgery 外科 Department of pediatrics 儿科 Department of obstetrics and gynecology 妇科 Department of neurology 神经科 Department of ophtalmology 眼科 E.N.T.department 耳鼻喉科 Department of stomatology 口腔科 Department of urology 泌尿科 Department of orthopedic 骨科 Department of traumatology 创伤科 Department of endocrinology 内分泌科
医学英语课后翻译答案完 整版 Revised by Jack on December 14,2020
Translation： Unit one 1 医院，在现代意义上，就是由专业人员和专业的设备为病人提供医疗服务的机构，通常但也不总是提供长期的住院治疗。它的历史意义，直至最近，是给退伍战士提供服务的地方。 2 在现代社会，从广义上说，医院或者由它所处的国家的政府提供资助，或者在私营部门通过竞争在经济上生存下来。目前，为医院提供赞助的通常有公共部门，医疗机构，赢利或者非赢利的，医疗保险公司或者教会，包括直接由教会提供捐赠。在历史上，医院通常由宗教机构或者教会的成员或领导来建立和资助。与此不同的是，现代医院主要由专业的内科医生、外科医生和护士组成，在过去这些工作主要由成立医院的宗教机构或者志愿者来完成。 3 一些病人去医院只是去接受诊断和治疗，然后离开，不在医院过夜（门诊病人）；也有一些病人被收入院，在医院过夜，甚至长达几个星期或几个月（住院病人）。医院的等级划分通常由它们所提供的医疗设施的类型和为住院病人提供的医疗服务，以及其他的在门诊所提供的医疗服务水平所决定。（医院与其他医疗机构的区别在于它具有将病人收住院并为住院病人提供医疗服务的能力，而其他一类通常称为诊所。） Unit two 1它们平均是每两位医生为一千位病人提供预防性和初级医疗服务。下一级别的为城镇医疗中心，这些中心通常主要为一万到三万位病人
提供门诊医疗服务。每一个中心有十到三十个床位，中心的专业医生为医士(助理医师）。这两个较低级别的医疗机构构成了乡村合作医疗系统，为大多数的乡村病人提供医疗服务。 2强调公共卫生和预防性治疗为主的医疗政策始于50年代早期，在那个时候，共产党开始有大批的人口流动，（动员群众）参与大规模的“爱国卫生运动”，目的在于改进较差的环境卫生，预防某些疾病。 3这一转变对农村医疗卫生产生了一系列重要影响，合作医疗缺乏资金来源，致使赤脚医生数量减少，这就意味着健康教育、初级保健和家庭保健都受挫，在一些村庄，卫生状况和饮用水(水源检测这个大家自己看哈）很少得到监控。 Unit three 1金刚烷阻碍(阻断）了由m2蛋白质形成的离子通道，这一通道在vRNPs释放进入细胞质的过程中是至关重要的。对金刚烷的排斥（耐药）迅速形成，大多数的人类传染性H1N1和H3N2病毒，一些H5N1病毒，大多数的欧洲猪H1N1、H1N2和H3N2病毒都能抵制（耐受）金刚烷。 2（然而），万一（一旦）发生流行性疾病（大流行），鸡蛋供应就会短缺，相反的是，细胞培养是可高度控制的系统，可以促使疫苗的大批量生产，包括这些对抗高致病性H5N1的禽流感病毒（可以促使包括那些针对高致病性H5N1病毒在内的疫苗大批量生产），通过以狗肾传代细胞或者非洲绿猴子肾细胞生产的流感疫苗的纯度和免疫能力