制药工程_专业英语_Unit_5.ppt

the professional english of pharmaceutical engineering,wang xinliang east china university of science and technology 05.03.2012,words,attrition rate indications new chemical entities differentiation formulary toxicity toxicology dossier dosage form synergism antagonism genotoxicology carcinogenicity abnormality pharmacy pharmacognosy pharmacodynamics pharmacokinetics pharmacotherapeutics,淘汰率 n. 适应症 新化学实体（新化合物） n. 区别；变异 n. 公式集；处方集 n. 毒性 n. 毒物学；毒理学 n. 档案，卷宗；病历表册 剂型；药物剂型 n. 协调作用 n. 拮抗作用(反协调作用) n. 基因毒理学 n. 致癌性；致癌毒性 n. 异常；畸形 n. 药剂学；制药业 n. 生药学 n. 药效学 n. 药物(代谢)动力学 n. 临床药物治疗学,1.引言 药品开发是一个非常复杂的过程，需要在广泛的不同功能性团队之间进行大量的协调和沟通。这个过程是昂贵的，特别是在临床开发的后期阶段，其中涉及到对数百名病人的研究。据目前的估计，一个新药的开发成本约2.3亿美元（1987年的美元），并且从起动临床前的开发阶段到首次上市（不包括监管延迟），需要花费7-10年。,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).,unit 5 drugs development (i),药物开发是一项高风险业务，虽然（淘汰）比率不断上升，在完成了首次人体研究的每十个新化学实体中，大约只有一个会成为产品。随着候选药物开发的进行，失败的风险在前进的道路上，会象跨栏似的降低。失败的典型原因包括：不可接受的毒性，缺乏功效，或不比竞争产品有优势（图1）。,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).,图1. 淘汰率和终止的原因,attrition rate of new chemical entities (nces) entering development. on average only about i in 4001000 compounds.,进入开发阶段的新化学实体（nces）的淘汰率。平均每400 1000个所合成的化合物只有1个能进入开发过程。,（不包括抗感染药）nces开发终止的原因： 1：缺乏疗效 2：药代动力学 3：动物毒性 4：其他因素 5：对人的不良影响 6：商业上的原因,reasons for termination of development of nces (excluding anti-infectives) 1: lack of efficacy 2: pharmacokinetics 3: animal toxicity 4: miscellaneous 5: adverse effects in man 6: commercial reasons,2.开发的规划 对候选药物是否有可能提供有竞争力的优势方面的评估，首先强调的需要是达到一整套的产品目标或目标产品的特性。应当特别注意竞争者（指药物）之间的差异。随着对有限的处方、医疗保健费用以及药物经济学（本章稍后讨论）的日益关注（强调），这种情况变得越来越重要。,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 more and more critical with the increasing emphasis on limited formularies，healthcare costs, and pharmacoeconomics (discussed later in the chapter).,包括诸如每日一次给药、更快的起效作用、比主要竞争者具有更低副作用的特性等目标在内，（药物开发的）目的特性将定义候选药物将被开发的（疾病）适应症。随着候选药物的开发阶段的进展，以及候选药物或竞争药物的新数据的获得，（药物开发的）目的特性可以再定义或修正。合乎逻辑的下一个步骤就是明确开发战略，例如，哪个（疾病）适应症要优先开发，以哪些国家作为药物的目标市场，然后确定能获得监管机构的批准和商业成功的必要核心临床研究（内容）。,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.,本章将描述一个新药成功开发过程所需的主要活动。所有这些活动，其中许多是相互依存的，需要认真规划和协调。与高质量数据的收集打交道的速度是成功的关键。确定需要测定花费时间来获得登记的活动的步骤，以项目管理术语而言，被称为关键步骤。在研究开始之前，计划和准备、并监控和管理问题以确保关键步骤如期进行，这是非常重要。,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.,由于增加的经济压力和竞争强度，企业探索如何缩短这一关键步骤是重要的。并行开展这些活动，或将通常按顺序开展的研究进行重叠，往往会涉及到风险的增加；但节省时间的红利可以使这种战略值得做。 新药开发的关键步骤贯穿于化合物的初期合成、亚急性毒理学研究和随后的临床计划。一个展示典型的候选药物的关键步骤活动的图表如fig. 2所示。,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 the clinical program. a chart showing the critical path activities for a typical drug candidate is shown in fig. 2.,adme is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism. the four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug.,11,“adme”即“毒药物动力学”，指机体对外源化学物的吸收、分布、代谢及排泄等过程；这些过程可能同时发生。可概括为药物的转运和转化，或称为机体对药物的处置。 药动学研究所反映出的药物在动物或者人体内的动态变化规律，除了可作为药效学和毒理学研究的借鉴外，也是指导新药研究与开发，进行先导化合物的设计和筛选，以及申报临床研究或进一步申报生产所必须提交的重要资料。 对外源化学物adme过程的研究有重要意义： 1、可能用来确定与毒性发生有关的靶器官或组织的暴露特征。 2、可能为在其他的毒性研究的剂量选择提供有用数据。 3、有助于阐明两种或两种以上外源化学物联合毒作用的机制。 4、可通过改变外源化学物adme过程，以预防和治疗外源化学物中毒。,12,下列各部分突出了和药物开发工作的具体目标和活动内容。在每个技术学科里的活动按时间前后排列的顺序大致作了介绍。在任何时候，在所有这些领域的工作可能是平行进行。这些大多数工作的时序和所出成果对其他学科里的工作有着直接的影响。,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.,药物开发的主要阶段是临床前期（化合物可给人体服药前的所需的研究）、i阶段（通常在健康志愿者身上的临床研究）、期（病人身上的初期疗效和安全性和治疗剂量调查研究）和期（在几百个病人的研究）。然后附述一个由国家监管当局随后审查的上市申请档案的汇编。,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 ( initial efficacy and safety and dose finding studies in patients)，and phase (studies in several hundred patients). there then follows assembly of a marketing application dossier for subsequent review by country regulatory authorities.,3化学品的开发 候选药物的快速开发是取决于足够数量的化合物的可获得性。该化合物的纯度需要达到一定的标准，以便它用于安全性（毒理学）、药学的和临床的研究。最初，化学家将进行小到中等规模的研究，考察采用几种不同方法制备该化合物，以便确定该化合物的最佳合成路线。,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.,这里“最佳” 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。最终产品和中间体及杂质的分析在确定最佳的合成方法起着关键作用。分析方法的开发和验证对于支持工艺开发和保证原料药的纯度是必要的。,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.,在某些情况下，杂质的含量可能高得令人无法接受，要么需要开发改进的纯化程序，要么需要对合成过程大量调整。其主要目的是确保化合物的成分可知，最终所制备的物料尽可能的纯净。,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.,随着候选药物开发的进展，所需化合物的数量越来越大。不同测试所需的物料的数量，往往取决于化合物的实际效力和剂型。中试工厂可以被看作是一个小型规模的制造机构。在转入中试工厂前，需要对化学合成进行广泛的评估和测试，以确保任何的改变和危害降至最低。,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.,（制备）程序要优化，特别注重开发环境可接受的处置废弃物的方法。一旦被批准和销售，药品的生产所用的大量原料药，其商业化生产将可能采取更大规模进行或在登记的制造工厂进行。,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配方开发 药物的剂型，是指病人服用药物的方式。存在形式繁多的从贴剂到吸入到鼻腔内药品的可能的剂型。较常见的剂型包括口服片剂或胶囊、口服液、外用药膏或霜剂、和注射剂。或特定候选药物所的剂型或形态的选择在将目标特性中也要被定义。,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.,有时，一个更简单的剂型，例如口服液，会被选择来进行早期人类临床研究。在药物开发过程的早期的、高风险阶段，这可以节省时间和预付成本。后期的临床研究将使用预期要销售的剂型。,sometimes a more simple dosage form, for example, an oral solution, is chosen for early 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.,无论是什么剂型，药物和其他物料的组合构成它必须符合一定标准。最重要的标准之一是有足够的稳定性。这意味着，预先确定的效力水平必须，例如，两年或三年后，能继续保持。一种剂型所产生的稳定剂数据将决定它的保质期（贮藏寿命）和推荐的储存条件。在开发的早期，其保质期可能仅限于数月。只要药品的使用期限足以超过临床研究或研究的阶段，这就不会是个问题。,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药理学 在候选药物考虑到人之前，它对主要系统的药理作用研究往往在大量的物种上进行了研究。所研究的身体系统包括心血管的，呼吸的和神经系统；对总体行为的影响也会研究。,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.,由于它们的特殊的作用或者因为它们的共同使用，有时进行实验是为了理解候选药物是否对其他药物的作用有干扰，这些药物可能要与候选药物同时服用。应当对药物的任何协同作用或拮抗作用进行研究，任何必要的警告必须发布给临床研究者。（这可能被认为有必要在临床研究进一步研究这些作用，以及任何潜在的或已被证明的药物相互作用可能记录在药物的产品标签上。）,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.),特别是如果该候选药物的治疗窗宽很小时，确定一种物质可能应用于过剂量的管理的情况，这也可能是适当的。,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安全性评价 在药品开给人服用前所开展的动物毒理学测试的目标，是为了排除不可接受的毒性化合物，识别潜在的靶器官和药物不良反应的时序。这意味着，在早期人类研究中这些器官和组织可以特别注意而得到监测。对有毒作用是可逆的还是不可逆转的、它们是否可以预防的、（如果可能的话）毒理学作用机制的确定，是重要的。使药物在人类的血中浓度和各种动物物种的血中浓度的响应建立相互关联也是重要的。,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.,对于在人候选药物评价所需的毒理学研究，将与所推荐的临床应用时的给药途径和临床研究的治疗持续时间有关。剂量的大小和使用频率，以及毒理学研究的持续时间在人体获准测试的主要决定因素。许多国家，包括英国、美国、澳大利亚和北欧国家，都有涉及在人类治疗持续时间和需要在两个物种中进行的毒性研究的时间长短的监管指南。指南的要点引用在随后的章节里。,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.,最初，增加测试物质剂量的药理作用建立于少量动物的急性毒性研究，一般采用两种给药途径（一种用于人体）。（所得的）结果给随后的慢性毒性试验，提供了一个最大耐受剂量的参考值，有助于剂量水平的选择，以及确定靶标器官。,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.,随后的亚急性毒性试验的主要目的是确定候选药物在动物长期给药后是否有足够的耐受性，从而作为对人类可能产生的不良反应的参考。使用与人相同的给药途径，在先于人的该化合物的给药前，两个物种（一个为非啮齿类）的两到四个星期（每日剂量）的研究是必需的。三个剂量水平通常是必要的：每天的低剂量应是所期望的治疗剂量的低一数量级，最高剂量应显示出一定的毒性。,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.,评价新化学实体的通用指南应该是一个为期14天以上毒理学研究需要支持正常的志愿者在第i阶段的单剂量接触一个新的候选药物。支持7至10天时间的临床研究，要求为期30天的毒理学研究。而超过7至10天直至30天的临床研究则需要有至少90天的毒理学研究的支持。,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 i. 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.,这些要求应在计划药物开发之前就明确说明。未来临床试验的持续时间和大概的时序安排需要提前好好地深思熟虑，以便做好安排并进行适当的毒理学研究，以支持临床计划并避免任何延误。,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.,两种类型的安全测试是用来检测候选药物在人体产生肿瘤的能力。第一类是短期的体外遗传毒性试验，例如细菌试验。第二类是是在小鼠和大鼠身上进行的动物长期致癌性研究；他们往往二年的时间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，容易获得。此外，有关这些物种的特定种族的自发疾病及肿瘤所积累的知识，大大有助于解释研究结果。,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 accu