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Introduction to Drugs and Pharmacy

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Introduction to Drugs and Pharmacy Powered By Docstoc
					New Drug Development
 and Approval Process
             Contents
•   Drug discovery and drug design
•   Biological characterization
•   Early formulation studies
•   The investigational New Drug (IND)
    Application(研究性新药申请)
•   The New Drug Application (NDA)
The Federal Food, Drug, and Cosmetic 
Act,as regulated through Title 21 of 
the U.S. Code of Federal Regulations, 
requires a new drug to be approved by the 
Food and Drug Administration(FDA) before 
it may be legally introduced in interstate 
commerce 
To gain approval for marketing, a drug’s 
sponsor (e.g., a pharmaceutical company) must 
demonstrate, through supporting scientific 
evidence, that the new drug or drug product 
is safe and effective for its proposed use. 
The sponsor must also demonstrate that the 
various processes and controls used in 
producing the drug substance and in 
manufacturing, packaging, and labeling are 
properly controlled and validated to ensure 
that the product meets established standards
The process and time course from drug discovery to 
approval for marketing can be divided into following 
process:
New Chemical Entity (synthesis)
Prefomulation studies-define the physical and chemical 
properties
Formulation studies-develop the initial features of the 
proposed pharmaceutical product or dosage form
Investigational new drug application(IND)-for initial 
testing in humans 
Preclinical and Clinical studies
   Phase I-initial testing in humans
   Phase II, Phase III -progressive humanTrials    
New drug application (NDA)-seeking approval 
to market the new product.
 Content of a product’s approved labeling-essential 
chemistry, pharmacology, toxicology, indications 
and contraindication for use, adverse effects, 
formulation composition, dosage, and storage 
requirements.
Treatment IND, Orphan drug
Supplemental new drug application (SNDA)
Abbreviated new drug application(简化新药申请) to 
gain approved to market a duplicate
Antibiotic drug; biologics; Medical devices
 1. Drug Discovery and Drug 
           Design
1)   Sources of new drugs
2)   A goal drug
3)   Methods of drug discovery
4)   A lead compound
5)   Prodrugs
1) Sources of new drugs
• New  drugs  may  be  discovered  from  a 
  variety  of  natural  sources  or  synthesized 
  in the laboratory.

• Plant materials have served as a reservoir 
  of potential new drugs.
• Reserpine (利血平), a tranquilizer (
  镇 定剂 ) and hypotensive agent,
  from the folklore remedy Rauwolfia
  serpentina(萝 芙木属蛇根碱).
• Periwinkle(长 春花), or Vinca rosea,
  in the treatment of diabetes
  mellitus.
• Vinblastine (长 春碱) and vincristine (
  长 春新碱), from Vinca rosea,
  exhibited antitumor capabilities.

• Paclitaxel (Taxol), from an extract of
  the Pacific yew (紫杉)tree, is used in
  the treatment of ovarian cancer.
• After the isolation and structural identification 
  of  active  plant  constituents,  organic  chemists 
  may  recreate  them  by total  synthesis  in  the 
  laboratory.

• The natural chemical could be also used as the 
  starting  material  in  the  creation  of  slightly 
  different  chemical  structures  through 
  molecular  manipulation.  The  new  structures, 
  termed semisynthetic drugs.
• Animals  have  served  humans  in  their 
  search for drugs in a number of ways.
• Hormonal  substances,  such  as thyroid (
  甲状腺) extract,  insulin,  and  pituitary(
  脑 垂体)hormone  obtained  from  the 
  endocrine  glands  of  cattle,  sheep,  and 
  swine.
• The  use  of  animals  in  the  production  of 
  various  biologic  products,  including 
  serums, antitoxins, and vaccines.
• New  vaccines  for  diseases  as  AIDS  and 
  cancer  are  being  developed  through  the 
  use of cell and tissue cultures.
• A  new  era  in  the  development  of 
  pharmaceutical  products comes  forth  as 
  a  result  of  the  advent  of genetic 
  engineering,  the  manipulation  of  the 
  double helix, the spiral DNA chain of life.
 (药 物产 品发 展的新时 代到来由于基因工
  程,生命DNA链 的双螺旋操作的出现 。)
• Through this process, will come more 
  abundant and vastly purer antibiotics, 
  vaccines, and yet unknown chemical and 
  biological products to combat human 
  disease.
• 通过这 些过 程,将会出现 丰富而大量的
  更纯 的抗生素、疫苗、还 有其他未知的化
  学和生物制品,以抵抗人类 疾病。
  There are two basic technologies that 
  drive the genetic field of drug 
  development
• Recombinant DNA (rDNA)
• Monoclonal antibody (MoAB) 
  production
2) A goal drug (目标药 物)
In theory, a “goal drug” 
• would  produce  the  specifically  desired 
  effect, 
• be  administered  by  the  most  desired  route 
  (generally  orally)  at  minimal  dosage  and 
  dosing frequency,
• have optimal onset and duration of activity,
  理论 上,目标药 物应 能通过 最理想的途径(
  通常为 口服)以最小的剂 量和给药频 率给
  药 ,能产 生特异的期望疗 效,具有最理想的
  起效和持续时间 ,
• exhibit no side effects,
• following its desired effect would be eliminated 
  from the body efficiently, completely, and without 
  residual effect.
• it would be easily produced at low cost,
• be pharmaceutically elegant,
• physically and chemically stable under various 
  conditions of use and storage.
(无副作用,并在发挥疗 效后能完全有效地从体内消
  除,且无残留效应 。它应该 易于生产 ,费 用低,制
  剂产 品美观 ,在不同的使用和贮 藏条件下物理和化
  学上稳 定。)
3) Methods of drug discovery

• Most  drugs  are  the  result  of  carefully 
  designed research programs of screening, 
  molecular  modification,  and mechanism-
  based drug design.

(大多数药 物是精心设计 的研究过 程的结 果,包
 括:筛选 、分子修饰 和基于机制的药 物设计 。)
• To  detect  and  evaluate  biological 
  activity, bioassays  are  used  to 
  differentiate  the  effect  and  potency  of 
  the test agent compared with controls of 
  known action and effect.

                              In vivo
        In vitro
                         Disease-specific
       Cell culture
                          Animal models
• New  methods,  as high  throughput 
  screening,  are  capable  of  examining 
  15000 chemical compounds a week using 
  10-20 biological assays.
• High-throughput  screening  (HTS)  is  a 
  method  for  scientific experimentation 
  especially  used  in drug discovery  and 
  relevant  to  the  fields  of biology  and 
  chemistry.
• To  be  effective,  this  requires  a sizeable 
  and chemically  diverse  collection  of 
  compounds  to  examine,  which  many 
  pharmaceutical and chemical companies 
  have in “chemical libraries.”
(为 了有效地利用它,这 需要有相当大量的
  不同化学物质 来测试 ,通常许 多制药 公
  司或化学品公司有“化合物库 ”)
• Molecular  modification  involves  the 
  chemical  alteration  of  a  known  and 
  previously  characterized  organic 
  compound  for  the  purpose  of enhancing 
  its usefulness as a drug.

(分子修饰 涉及化学改变 已知和特性明了
 的有机化合物以改善其作为药 物的有效
 性。)
 Aims for molecular modification
• Enhancing its specificity for a particular body 
  target site;
• Increasing its potency;
• Improving its rate and extent of absorption;
• Modifying to advantage its time-course in the 
  body;
• Reducing its toxicity;
• Changing its physical or chemical properties to 
  provide pharmaceutically desired features;
             How?
Changes in 
• functional groups
• Ring structures
• Configuration (构型)

(SAR)
• Mechanism-based drug design involves 
  molecular modification in designing a drug 
  that interferes specifically with the known 
  or suspected biochemical pathway or 
  mechanism of a disease process.

(基于机制的药 物设计 包括通过 分子修饰设
 计药 物,这 种药 物能够 特异性地影响疾病
 过 程的已知或可能的生化途径或机制。)
The intention is the interaction of the drug with 
• specific cell receptors, 
• enzyme systems, 
• the metabolic processes of pathogens  or tumor 
  cells,
  resulting in a blocking, disruption, or reversal 
  of the disease process.
(设计 的意图 是影响药 物与特异性受体、酶系统
  、病原体或癌细 胞的代谢 途径的相互作用,导
  致疾病过 程的阻滞、破坏或逆转 。)
Molecular  graphics,  the  use  of  computer 
 graphics  to  represent  and  manipulate  the 
 structure of the drug molecule to “fit” the 
 simulated  molecular  structure  of  the 
 receptor site.
(利用计 算机绘图 来描绘 和操纵药 物分子的
 结 构使之“适合”于受体部位的分子设计 是
 药 物分子设计 的有用的和互补 的工具。)
• Enalaprilat(依那普利拉,Vasotec)-
  inhibits the angiotensin-converting
  enzyme
• Ranitidine (Zantac)-an inhibitor of
  histamine at the H2-receptor
• Sertraline (舍曲林, Zoloft)-inhibits
  the central nervous system neuronal
  uptake of serotonin(5-羟 色胺 )
4) A Lead Compound(先导 化合物)
• is a prototype(原形化学物质 ) chemical
  compound that has a fundamental
  desired biologic or pharmacologic
  activity.

(先导 化合物是一种具有生物学和药 理学活
 性基本要求的原型化学物质 。)
• Although active, the lead compound
  may not posses all of the features
  desired;     i.e.,   potency(效力),
  absorbability(吸收性), solubility, low
  toxicity, and so forth.
• The medicinal chemist may seek to
  modify the lead compound’s chemical
  structure to achieve the desired
  features while reducing the undesired
  one.
• Finasteride (非那雄胺, Proscar) –
  benign prostatic hyperplasia

• Propecia (a lower recommended
  dosage)-male pattern baldness.
5) Prodrugs
• is a term used to describe a compound
  that      requires       metabolic
  biotransformation after administration
  to     produce      the     desired
  pharmacologically active compound.
  (前体药 物使之能够 在给药 后经 体内代谢
  性生物转 化成具有期望的药 理活性化合物
  的化合物。)
• The conversion of an inactive prodrug to
  an active compound occurs primarily
  through enzymatic biochemical cleavage.
• Prodrugs may be designed preferentially
  for the following reasons.
• Solubility
• Absorption
• Biostability
• Prolonged release
• FDA’s definition of a new drug
• According  to  the  FDA,  a  new  drug  is  any  that  is  not 
  recognized  as  being  safe  and  effective  in  the  conditions 
  recommended for its use among experts who are qualified 
  by scientific training and experience.
• A  change  in  a  previously  approved  drug  product’s 
  formulation or method of manufacture constitutes newness 
  under the law
• A  combination  of  two  or  more  old  drugs  or  a  change  in 
  usual proportions of drugs in an established ones
• A proposed new use for an established drug, a new dosage 
  schedule  or  regimen,  a  new  route  of  administration,  or  a 
  new dosage form all cause a drug or drug product’s status 
  to new and triggers reconsideration for safety and efficacy
• Drug Nomenclature
• 系统命名法
2. Biological characterization

1) Pharmacology
2) Drug metabolism
3) Toxicology
Prospective drug substances must
undergo preclinical testing for biologic
activity to assess their potential as
useful therapeutic agents.

  pharmacology         Drug metabolism


                 toxicology
1) Pharmacology 
• embraces the physical and chemical 
  properties,
• biochemical and physiological effects
• mechanisms of action, absorption, 
  distribution, biotransformation, 
  excretion,
• useful applications of drugs.
• Pharmacodynamics is the study of the 
  biochemical and physiological effects of 
  drugs and their mechanisms of action.
• Pharmacokinetics deals with the 
  absorption, distribution, metabolism or 
  biotransformation, and excretion of 
  drugs.
• Clinical pharmacology applies 
  pharmacologic principles to the study of 
  the effects and actions of drugs in humans.
Most diseases arise from
• a biochemical imbalance
• An abnormal proliferation of cells
• An endogenous deficiency
• An exogenous chemical toxin
• Invasive pathogen (病原体)
• Intricate enzymatic reactions
• Structure-activity relationships
  (SAR)
• Relationship between the quantity of
  drug molecules available for
  interaction and the capacity of the
  specific receptor site
• Certain cells within the body are
  capable of binding drugs without
  eliciting a drug effect.
       Cell culture


 Isolated animal tissues


   Whole animal studies


Animal models of human disease
  The primary objective of the animal 
  studies is 
• to obtain basic information on the drug’s 
  effects that may be used to predict safe 
  and effective use in humans.
2) Drug Metabolism
  A series  of animal  studies  of a proposed 
  drug’s  metabolism  are  undertaken  to 
  determine: 
• the rate,  primary  and  secondary sites, 
  and mechanism of the drug’s metabolism 
  in the body, 
• the chemistry  and pharmacology  of  any 
  metabolites.
• Drugs  that  enter  the hepatic(肝脏的) 
  circulation after absorption from the gut, 
  as  after  oral  administration,  are 
  particularly  exposed  to  rapid  drug 
  metabolism. 
• This  transit  through  the  liver  and 
  exposure to the hepatic enzyme system is 
  termed the first-pass effect.
• Drug metabolism or biotransformation 
  frequently results in the production of one 
  or more metabolites of the administered 
  drug, some of which may be 
  pharmacologically active compounds.
• When metabolites are found, they are 
  chemically and biologically characterized 
  for activity and toxicity.
3) Toxicology is the area of pharmacology that 
  deals  with  the adverse,  or undesired,  effects 
  of drugs.
• In  drug  development  programs, preclinical 
  drug safety evaluation or toxicity studies are 
  undertaken to determine: 
- The  substance’s  potential  for  toxicity  with 
  short-term  (acute  effects)  or  long-term  use 
  (chronic effects).
- the substance’s potential for specific organ 
  toxicity,
- the mode, site, and degree of toxicity,
- dose-response relationships, for low-high-
  and intermediate doses over a specified 
  time course,
- gender, reproductive, or teratogenic (产生
  畸形的) toxicities,
- the substance’s carcinogenic and genotoxic 
  (遗传毒性的)potential.
① Acute or short-term toxicity studies
These studies are designed to determine 
• the toxic effects of a test compound 
• when administered in a single dose and/or 
  in multiple doses 
• over a short period, usually a single day.
    The test compound is administered at
    various dose levels, with toxic signs
    observed for
•   onset (观 察毒性反应 的开始)
•   progression or reversal (发 展或逆转 )
•   severity (严 重性)
•   mortality (死亡率)
•   rates of incidence (事件的发 生率)
    The animals are observed and
    compared with controls for
•   eating and drinking habits,
•   weight change,
•   toxic effects,
•   psychomotor changes(精神变 化),
•   any other signs of untoward effects,
    usually over a 30 day postdose period.
② Subacute (亚 急性) or subchronic (亚
 慢性)studies
• Animal toxicity studies of a minimum of 2
  weeks duration of daily drug administration
  at three or more dosage levels to two animal
  species are required to support the initial
  administration of a single dose in human
  clinical testing.
• These studies are termed subacute or
  subchronic.
Chronic toxicity studies,
For drugs intended to be given to
humans for a week or more, animal
studies of 90 to 180 days in length
must demonstrate safety.
③ Carcinogenicity studies (致癌性研究)

 Carcinogenicity testing is usually a
 component of chronic testing,is
 undertaken when the compound has
 shown sufficient promise as a drug to
 enter human clinical trials.
• Carcinogenicity studies are usually
  carried out in a limited number of rat
  and mouse strains for which there is
  reasonable information on
  spontaneous tumor incidence(自发 性
  肿 瘤形成).
④ Reproduction studies (生殖研究)
• These studies are undertaken to reveal any
  effect of an active ingredient on mammalian
  reproduction. Included in these studies are
• fertility and mating behavior (抚 养和交配行
  为)
• Early embryonic and pre- and post-natal
  development (胚胎早期、早产 和产 后发 育)
• Multigenerational effects (多代影响)
• Teratology (致畸性)
   3. Early formulation studies
1) Preformulation studies
2) Initial product formulation and clinical 
   trial materials
        Physical
                        Clinical
        chemical
                        trials
       properties

from initial    from pilot       large
  to final       plant to        scale
formulation      scale-up    manufacturing
1) Preformulation studies (处 方前研究)
  Each drug substance has intrinsic (固有的) 
  chemical and physical characteristics that 
  must be considered before the development 
  of a pharmaceutical formulation
① Drug solubility
• A drug substance administered by any 
  route must possess some aqueous 
  solubility for systemic absorption and 
  therapeutic response.
• Poorly soluble compounds (less than 
  10mg/ml) may exhibit either incomplete 
  or erratic(不稳 定) absorption and thus 
  produce a minimal response at desired 
  dosage.
  Enhanced aqueous solubility may be 
  achieved by 
• preparing more soluble derivatives of the 
  parent compound, such as salts or esters;
• by chemical complexation;
• by reducing the drug’s particle size.
② Partition coefficient
 To produce a pharmacologic response, a 
 drug molecule must first cross a biologic 
 membrane of protein and lipid, which 
 acts as a lipophilic barrier to many drugs.
A drug’s partition coefficient is 
• a measure of its distribution in a 
  lipophilic/hydrophilic phase system,
• indicative of its ability to penetrate 
  biologic multiphase systems.
        (二)分配系数

• 油/水分配系数是分子亲脂特性的度量,
  在药剂学研究中主要用于预见药物对在
  体组织的渗透或吸收难易程度。
• 分配系数(partition coefficient ,P
  )代表药物分配在油相和水相中的比例
  。
         在油相中药物的质量浓度
  P=
        在水相中药物的质量浓度
③ Dissolution rate
• The  rate  at  which  a  drug  substance 
  dissolves  in  a  medium  is  called  its 
  dissolution rate.
• Dissolution  rate  data,  when  considered 
  along  with  data  on  a  drug’s  solubility, 
  dissolution  constant,  and  partition 
  coefficient,  can  provide an  indication  of 
  the  drug’s  absorption  potential  following 
  administration.
• For a chemical entity, its acid, base,
  or salt forms, as well as its physical
  form (e.g. particle size), may result in
  substantial differences in the
  dissolution rate.
④ Physical form
 The crystal or amorphous forms and
 particle size of a powdered drug can
 affect the dissolution rate, and thus
 the rate and extent of absorption, for
 a number of drugs.
⑤ Stability
 The chemical and physical stability of
 a drug substance alone, and when
 combined      with     formulation
 components, is critical in preparing a
 successful pharmaceutical product.
2) initial product formulation and clinical
  trial materials
  An initial product is formulated
- using the information gained during the
  preformulation studies
- with consideration of the doses, dosage
  form, route of administration desired
  for the clinical studies and for the
  proposed marketed product.
• For phase 1 studies, orally administered
  drugs, capsules are employed containing
  the active ingredient alone, without
  pharmaceutical excipients.
• Excipients are included in the formulation
  for Phase 2 trials.
• Different formulations may be prepared
  and examined to develop the one having
  the desired characteristics.
• During phase 2, the final dosage form is
  selected and developed for Phase 3 trials.
   药物制剂处方设计前工作
      一、任务和要求

• 一个药物从合成到最后上市,大致经历:
  ①药理活性的筛选;②初步药理学及分析
  方法研究;③处方前工作;④临床研究
  ;⑤处方与制备工艺研究; ⑥ 制剂药理、
  毒理研究;⑦申报工作。
• 其中处方前工作在整个研制过程中占有重
  要地位。
   处方前工作的主要任务:

• 处方前工作将为该药物制剂的开发提供
决定性的参考价值:

①获取新药的相关理化参数;

②测定其动力学特征;

③测定与处方有关的物理性质;

④测定新药物与普通辅料间的相互作用。
                二、文献检 索
• 1、光盘检索:CA、IPA、Medline、Drug & 
     Pharmacology、中国生物医学文献光盘数据库、中国
     科技期刊光盘数据库等。 
• 2、网络检索:Medline、Rxlist、griffin、pharmacy、
     US patent、FDA、中国生物科技期刊库、万方数据库
     、CPA等 
• 3、期刊检索:J Pharm Sci, Pharm Res, DDIP, J Contr 
     Rel, Int J Pharm, 
             IPA, CA, 中国药学文摘、国内药学期刊杂志等。 
• 4、书刊检索: 
• 5、工具书检索:USP、BP、CP、PDR、Mardindale
     、Pharm Project等。 
•  6、专利检索: 
• The Investigational New Drug (IND)
  Application
• Under the Food, Drug, and Cosmetic Act as
  amended, the sponsor of a new drug is required
  to file with the FDA an IND before the drug
  may be given to human subjects.
• This is to protect the rights and safety of the
  subjects and to ensure that the investigational
  plan is sound and is designed to achieve the
  stated objectives
• After submission of the IND, the sponsor must
  delay use of the drug in human subjects for not
  less than 30 days from the date the FDA
  acknowledge receipt of the application.
• (1) Content of the IND
• (2) The Clinical Protocol
• (3) Pre-IND Meetings
• On request, the FDA will advise a sponsor on
  scientific, technical, or formatting concerns
  relating to the preparation and submission of an
  IND
• (4) FDA Review of an IND Application
• The FDA’s objectives in reviewing an IND are to
  protect the safety and rights of the human
  subjects and to help ensure that the study allows
  the evaluation of the drug’s safety and
  effectiveness.
• (5) FDA Drug Classification system
• Upon receipt and examination of an IND or
  NDA, the FDA classifies the drug by chemical
  type and therapeutic potential. Page 49
• (6) Phases of a Clinical Investigation
• An IND may be submitted for one or more
  phases of a clinical investigation,namely Phase
  1, Phase 2, or Phase 3
• Phase 1 includes the initial introduction of an
  investigational drug into humans and is primarily
  for the purpose of assessing safety.
• Phase 1 studies are designed to determine the
  human pharmacology of the drug, structure-
  activity relationship, side effects associated
  with increasing doses, and if possible, early
  evidence of effectiveness.
• Phase 2 trials are controlled clinical studies to
  evaluate the effectiveness of a drug in patients
  with the condition for which the drug is
  intended and to assess side effects and risks
  that may be revealed. Because this phase uses
  patients as subjects, side effects or toxicity
  symptoms that were not shown in the preclinical
  animal studies or in Phase 1 studies with
  healthy volunteers may be revealed for the
  first time.
• Phase 3 studies may include several hundred to
  several thousand patients in controlled and
  uncontrolled trials.The objective is to determine
  the usefulness of the drug in an expanded
  patient base.
• (7) Clinical Study Controls and Designs
• Phase 2 and some Phase 3 studies are controlled,
  that is, the effects of the investigational drug
  are compared with another agent.The second
  agent may be a placebo (placebo control) or an
  active drug (positive control), a standard or
  comparator drug product.
• For studies that are blinded, the identities of
  the investigational drug and the control and
  controls are not revealed to certain participants
  to decrease bias
• In designing a clinical trial, many addition factors
  are considered, including the scheme of the
  study design and the duration of the treatment
• (8) Drug dosage and Terminology
•      A major part of any clinical drug is the
  determination of a drug’s safe and effective dose.
  Dose and dose ranging studies are conducted
  during Phase 2 and concluded during Phase 3
  clinical trials.
•      The safe and effective dose of a drug depends
  on a number of factors, including characteristics
  of the drug substances, the dosage form and its
  route of administration, and a variety of patient
  factors including age, body weight, general health
  status, any pathologic conditions, and concomitant
  drug therapy. All of these factors and others are
  integral to clinical drug trials
•       The dose of a drug may be described as an
    amount that is enough but not too much; the idea is
    to achieve the drug’s optimum therapeutic effect
    with safety but at the lowest possible dose
•       The effective dose of a drug may be different
    for different patients.
•       Usual adult dose; usual dosage range;usual
    pediatric dose
•       The schedule of dosage, or the dosage regimen,
    is determined during the clinical investigation and is
    based largely on a drug’s inherent duration of
    action, its pharmacokinetics, and the characteristics
    of the dosage form.
•   Initial dose; priming dose; loading dose;
•         Prophylactic dose (预防剂量); therapeutic dose
  To provide systemic effects, a drug must be
  absorbed from its routs of administration at a
  suitable rate, be distributed in adequate
  concentration to receptor sites, and remain there
  for a sufficient period.
Minimum effective concentration (MEC);
Minimum toxic concentration (MTC); Median
  effective dose; therapeutic index
 Some factors of patients considered in determining
  a drug’s dose in clinical investigations and in
  medical practice include the following:
Age,Body weight, Body Surface Area, Sex,
  Pathologic state,Torlerance, Concomitant Drug
  Therapy,Time and Conditions of Administration,
  Dosage Form and Route of Administration
• (9)Treatment IND
• A treatment IND or a treatment protocol permits
  the use of an investigational drug in the trentment
  of patients not enrolled in the clinical study but
  who have a serious or immediately life-threatening
  disease for which there is non satisfactory
  alternative therapy.
• (10) IND for an Orphan Drug
• (11) Withdrawal or Termination of an IND
• The New Drug Application
• If the three phases of clinical testing during the
  IND period demonstrate sufficient drug safety
  and therapeutic effectiveness, the sponsor may
  file a NDA with the FDA. This filing may be
  proceded by a pre-NDA meeting between the
  sponsor and the FDA to discuss the content and
  format of the new drug application.
• The purpose of the NDA is to gain permission to
  market the drug product in the United states.
• (1) General Content of the NDA Submission

•   (2) Drug Product Labeling
•   (a) Description of product
•   (b)Clinical pharmacology;
•   (c) Indications and usage
•   (d) Contraindications
•   (e) Warnings (f) Precautions
•   (g) Adverse reactions
•   (h) drug abuse and dependence (i) Overdosage
•   (j) Dosage and administration (k) How supplied
• FDA Review and Action Letters
• The completed NDA is carefully reviewed by the
  FDA, which decides whether to allow the sponsor
  to market the drug, to disallow marketing, or to
  require additional data before rendering a
  judgement.
• Phase 4 stuidies and Postmarketing
  Surveillance
• The receipt of marketing status for a new drug
  product does not necessarily end a sponsor’s
  investigation of the drug. Continued clinical
  investigations, often called Phase 4 studies.
• Annual Reports
• Supplemental, Abbreviated, and
  Other applications
• Supplemental New Drug Application
•      A sponsor of an approved NDA may make
    changes in that application through the filing of a
    supplemental new drug application (SNDA)
• Abbreviated New Drug Application
•   An abbreviated new drug application (ANDA) is
    one in which nonclinical laboratory studies and
    clinical investigations may be omitted, except
    those pertaining to the drug’s bioavailablility
• Biologics License Application
• Animal Drug Applications
• Medical Devices

• International Conference on
  Harmonization of Technical
  Requirements for Registration of
  Pharmaceuticals for Human Use
            Questions
•  Describe the methods of drug discovery
•  Define the following phrases:
   - prodrugs
   - a lead compound
   - a goal drug
3. What physical and chemical properties of
   drug substances must be characterized
   during preformulation studies? Explain.
4. What biological characterization should
   be studied in drug development process
   ?
  新药制剂的研究与申报

• 《药品注册管理办法》适用于在中华
人民共和国境内从事药物研究和临床
研究,申请药物临床研究、药品生产
或者进口,以及进行相关的药品注册
检验、监督管理。
    一、药 品注册申请
• 药品注册是指依照法定程序,对拟上市
销售的药品的安全性、有效性、质量可
控性等进行系统评价,并作出是否同意
进行药物临床研究、生产药品或者进口
药品而决定的审批过程,包括对变更药
品批准证明文件的申请及其附件中声明
内容的审批。
• 药品注册申请包括新药申请、已有国家标准药
  品的申请和进口药品申请及其补充申请。
• 新药申请是指未曾在中国境内上市销售药品的
  注册申请。已上市药品改变剂型、改变给药途
  径的,按照新药管理。
• 已有国家标准药品的申请是指在国内已经生产
  由国家药品监督管理局颁布的标准药品注册申
  请。
• 进口药品申请是指在境外生产的药品在中国上
  市销售的注册申请。
• 补充申请是指新药申请、已有国家标准药品的
  申请或者进口药品申请经批准后,改变、增加
  或取消原批准事项或内容的注册申请。
• 审批过程中的药品注册申请、已批准的临床研
 究申请需进行相应变更的,以及新药技术转让
 、进口药品分包装、药品试行标准转正,按补
 充申请办理。
• 国家食品药品监督管理局主管全国药品注册管
  理工作,负责对药品的临床研究、药品生产和
  进口的审批。
• 网址:http://www.sda.gov.cn
     二、新药 的分类
     (一)化学药品注册分类
1.未在国内外上市销售的药品
① 通过合成或者半合成的方法制得的原料药及
  其制剂;
② 天然物质中提取或者通过发酵提取的新的有
  效单体及其制剂;
③ 用拆分或者合成等方法制得的已知药物中的
  光学异构体及其制剂;
④ 由已上市销售的多组分药物制备为较少组分
  的药物;
⑤ 新的复方制剂
    (一)化学药品注册分类

2.改变给药途径且尚未在国内外上市销售的
  制剂。
3.已在国外上市销售,但尚未在国内上市销
  售的药品
①已在国外上市销售的原料药及其制剂;
②已在国外上市销售的复方制剂;
③改变给药途径并已在国外上市销售的制剂
 。
   (一)化学药品注册分类

4.改变已上市销售盐类药物的酸根、碱基
  (或者金属元素),但不改变其药理作
  用的原料药及其制剂。
5.改变国内已上市销售药品的剂型,但不
  改变给药途径的制剂。
6.已有国家药品标准的原料药或者制剂。
   (二)中药、天然药物注册分类

1.未在国内上市销售的重要、天然药物中提取的
  有效成分及其制剂。
2.未在国内上市销售的来源于植物、动物、矿物
  等药用物质制成的制剂。
3.中药材的代用品。
4.未在国内上市销售的中药材新的药用部位制成
  的制剂。
5.未在国内上市销售的由中药、天然药物中提取
  的有效部位制成的制剂。
6.未在国内上市销售的由中药、天然药物制成的
  复方制剂。
7.未在国内上市销售的由中药、天然药物
  制成的注射剂。
8.改变国内已上市销售药品给药途径的制
  剂。
9.改变国内已上市销售药品剂型的制剂。
10.改变国内已上市销售药品工艺的制剂
 。
11.已有国家标准的中成药和天然药物制
 剂。
  三、申请 新药 需上报 的项 目

      (一)综述资料
1、药品名称。
2、证明性文件。
3、立题目的与依据。  
4、对主要研究结果的总结及评价。
5、药品说明书样稿、起草说明及最新参考
  文献。
6、包装、标签设计样稿。
(二)药学研究资料
7、药学研究资料综述。
8、原料药生产工艺的研究资料及文献资料;制剂处
  方及工艺的研究资料及文献资料。
9、确证化学结构或者组份的试验资料及文献资料。
10、质量研究工作的试验资料及文献资料。
11、药品标准草案及起草说明,并提供标准品或者
  对照品。
12、样品的检验报告书。
13、辅料的来源及质量标准。
14、药物稳定性研究的试验资料及文献资料。
15、直接接触药品的包装材料和容器的选择依据及
  质量标准
(三)药理毒理研究资料
16、药理毒理研究资料综述。
17、主要药效学试验资料及文献资料。
18、一般药理研究的试验资料及文献资料。
19、急性毒性试验资料及文献资料。
20、长期毒性试验资料及文献资料。
21、过敏性(局部、全身和光敏毒性)、溶
 血性和局部(血管、 皮肤、粘膜、肌肉等
 )刺激性等主要与局部、全身给药相关的
 特殊安全性试验研究和文献资料。
22、复方制剂中多种成份药效、毒性、药
   代动力学相互影响的试验资料及文献
   资料。
23、致突变试验资料及文献资料。
24、生殖毒性试验资料及文献资料。
25、致癌试验资料及文献资料。
26、依赖性试验资料及文献资料。
27、动物药代动力学试验资料及文献资料
   。
(四)临床研究资料

28、国内外相关的临床研究资料综述。

29、临床研究计划及研究方案。

30、临床研究者手册。

31、知情同意书样稿、伦理委员会批准件。

32、临床研究报告。
四、申报 新制剂 的主要内容

1.处方、制备工艺、辅料等
2.稳定性试验
3.溶出度或释放度试验
4.生物利用度

				
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