Microsoft PowerPoint - 2 The drug developing process_drug delivery .pptx

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1 Pharmaceutical Biotechnology 药物开发过程 : 药物的发现专利申请和递送 The drug development process: discovery of drugs, patenting and drug delivery By Yuqiong Xia 3/5/2017

2 药物发现初始表征临床前试验管理机构批准进行人体试验临床试验 (I 期,II 期,III 期 ) 向管理机构提交销售 / 生产许可申请管理机构审查资料授予 ( 或拒绝授予 ) 销售 / 生产许可证产品进入市场 2 上市后监督

3 Outline Drug discovery: genomics Patenting Drug delivery routes 3

Discovery of biopharmaceuticals Relate to

for diabetes Growth hormone for dwarfism

4 Discovery of biopharmaceuticals Relate to the logical application of our rapidly increasing knowledge of the biochemical basis of how the body functions Insulin for diabetes Growth hormone for dwarfism 4

5 Genomics for drug discovery Provide sequence information of possible protein drugs Discover new drug targets Because most drug targets are proteins (mainly enzymes, hormones, ion channels and nuclear receptors) 5

6 Genomics Definition systematic study of the entire genome of an organism Aim to sequence the entire DNA complement of the cell and to physically map the genome arrangement 6

7 Shotgun to measure DNA sequence Physical method or endonuclease Sequencing both ends, get more information Link to plasmid 7

8 Shotgun to measure DNA sequence An extremely simple example 8

9 Dideoxy Sequencing: ddntp DNA synthesis 9

Dideoxy Sequencing Primer Target sequence Fix reaction mixtures, each contains a ddntp

TAAGTCGTCCTGAT ATTCAGCAGGACTA http://www.scq.ubc.

Target sequence Target sequence: ATTCA GCAGG ACTA Synthesized DNA TAAGT CGTCC TGAT C

10 Dideoxy Sequencing Primer Target sequence Fix reaction mixtures, each contains a ddntp Template C G A T Primer DNA polymerase da(t,c,g)tp ddctp Gel electrophoresis G TAAGTCGTCCTGAT ATTCAGCAGGACTA C T A Synthesized sequence Target sequence Target sequence: ATTCA GCAGG ACTA Synthesized DNA TAAGT CGTCC TGAT C flask: TAAGTC TAAGTCGTC TAAGTCGTCC G flask: TAAG TAAGTCG TAAGTCGTCCTG A flask: TA TAA TAAGTCGTCCTGA T flask: T TAAGT TAAGTCGT TAAGTCGTCCT TAAGTCGTCCTGAT 10

Dideoxy Sequencing Polyacrylamide gel with small pores DNA (10-500 nt) that differ in

in G Lane 2- partial replicas terminating in A Lane 3- partial replicas terminating in

11 Dideoxy Sequencing Polyacrylamide gel with small pores DNA ( nt) that differ in size by only a single nucleotide can be separated Lane 1- partial replicas terminating in G Lane 2- partial replicas terminating in A Lane 3- partial replicas terminating in T Lane 4- partial replicas terminating in C Alberts et al. Molecular Biology of the Cell.

12 12

13 Structural genomics: Physical map Actual physical distance in bps between markers Resolution for human genomics: 0.1 Mb 13

Functional genomics What genes do How genes are regulated The relationship between genes and their activity 14 http://www.ifcc.

14 Functional genomics What genes do How genes are regulated The relationship between genes and their activity 14

15 Gene chip Gene chip can measure the expression of RNA at given time/under given circumstances in a high-throughput process 15

Gene chip RNA to be tested Screening Gene chip Probe DNA Hybridization 1. Anchor nucleic acid sequences on plastic/glass surfaces at very high density 2.

16 Gene chip RNA to be tested Screening Gene chip Probe DNA Hybridization 1. Anchor nucleic acid sequences on plastic/glass surfaces at very high density 2. RNA can be extracted from cells and labeled with fluorophores 3. Hybridization between target RNA and probe DNA 4. Screening to determine target RNA 16

17 Outline Drug discovery: genomics Patenting Drug delivery routes 17

18 What is patent A monopoly ( 垄断 ) granted by a government to an inventor 欧洲专利商标局美国专利商标局日本工业产权数字图书馆 ipdl 中华人民共和国知识产权局

19 What is patent Only the inventor may exploit the invention/ innovation for a fixed period of time (up to 20 years). In return, the inventor makes a detailed technical description of the invention/innovation When the monopoly ( 垄断 ) period has expired, others can exploit the invention/innovation without the inventor s permission 19

20 What is patentable Four criteria novelty non-obviousness sufficiency of disclosure utility 20

Patent types Utility Patent a new and useful process,

new and useful improvement Design patent new and

manufacture Plant patent anyone who has invented or

21 Patent types Utility Patent a new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement Design patent new and non-obvious ornamental design for an article of manufacture Plant patent anyone who has invented or discovered and asexually reproduced any distinct and new variety of plant 21

22 Types of utility patents Product( 产品 ) A specific substance Process( 方法 ) A specific novel process Use ( 应用 ) A novel application Protein 22

23 Patent structure 标题专利号发明人受让人申请日参考文献分类 23

24 Heading of patent application file Patent title Abstract Background to patent application Outline of problems the innovation will solve Detailed technical description of innovation The specific patent claims 24

25 Biotechnology patents Natural products patentable under US law A pure microbial culture Isolated viruses Specific purified proteins (e.g. erythropoietin) Purified nucleic acid sequences (including isolated genes, plasmids, etc.) Other purified biomolecules (e.g. antibiotics, vitamins, etc.) 25

26 Biotechnology patents It is NOT possible to patent: the human body; the cloning of humans; the use of human embryos for commercial purposes; modifying germ line identity in humans; modifying the genetic complement of an animal if the modifications cause suffering without resultant substantial medical benefits to the animal or to humans. 26

27 Outline Drug discovery: genomics Patenting Drug delivery routes Parental and non-parental routes Rate-controlled delivery Site-specific delivery 27

28 Drug delivery routes Most biopharmaceuticals are administrated by parenteral route IM SC IV 28

29 IV Versus IM and SC 29 IM SC IV Proteins using IV have shorter half-life than those using IM and SC Proteins using SC have more degradation reactions and different deposition

30 Non-parenteral delivery routes 30 Why? In the case of products administered frequently or daily (e.g. insulin to diabetics), non-parenteral delivery routes would be preferred Types oral nasal pulmonary routes others

Oral delivery Patient friendly Low bioavailability Protein degradation in the gastrointestinal (GI) tract due to low ph and digestive enzymes

31 Oral delivery Patient friendly Low bioavailability Protein degradation in the gastrointestinal (GI) tract due to low ph and digestive enzymes Poor permeability of the wall of the GI tract Subjected to first-pass metabolism 31

32 Oral route is suitable for vaccine To elicit an immune response, a little vaccine to target site is enough 32

33 Nasal administration Only work for the nose Low bioavailability if systemic action is required 33

34 Pulmonary( 肺的 )route Best method alternative to parenteral route Moderate bioavailability Patient friendly Fast uptake (faster than SC) 34

35 Outline Drug discovery: genomics Patenting Drug delivery routes Parental and non-parental routes Rate-controlled delivery Site-specific delivery 35

36 Rate-controlled delivery Open loop system Mechanical pumps Osmotically driven systems Biodegradable microspheres Closed loop system Biosensor-pump combinations Self-regulating systems Encapsulated secretory cells 36

37 Open loop systems: mechanical pumps 37 Energy failure, problems with syringe, accidental needle withdrawal, leakage of catheter( 导管 ) and problem with injection site Problem with long-term drug stability The patient has to adapt to the pump rate

38 Osmotically driven systems Subcutaneously implantable, osmotic mini-pump Fixed rate Drug solution leaving via delivery portal Flow moderator Semi-permeable membrane 38 Water entering Drug reservoir

39 Biodegradable microspheres PLGA ( 聚乳酸 - 聚羟基乙酸 ) microspheres prolonged the dosing interval of LHRH agonists from 1~3 months to 6 months 39

40 Biodegradable microspheres Dextran( 葡聚糖 )-based microspheres Dextran microspheres prolonged the release time of IgG from 10~ days to 20+ days 40

41 夏玉琼 Closed loop systems: biosensor-pump combinations A biosensor Measure the plasma level of the protein An algorithm Calculate the required input rate A pump system Administrate the drug at the required rate 西安电子科技大学 41

42 Biosensor-pump combinations 42

43 Self-regulating systems Insulin release as a function of glucose concentration By competitive desorption By enzyme-substrate reaction 43

44 By competitive desorption Con A with glycosylated insulin is administrated ConA can bind to glucose more stronger than glycosylated insulin 44

45 Results of the above insulin delivery Dogs with pancreatic ( 胰的 ) problems Dogs with pancreatic problems after insulin delivery Normal dogs 45

46 By Enzyme-substrate reactions enzyme Glucose Gluconic acid Acid sensitive polymers, enzyme and insulin Enzyme catalyzes glucose to gluconic acid ph becomes low Acid-sensitive polymers release insulin

47 47 Encapsulated secretory cells (implanted)

48 Outline Drug discovery: genomics Patenting Drug delivery routes Parental and non-parental routes Rate-controlled delivery Site-specific delivery 48

49 Site-specific delivery Maximize therapeutic effect Avoid toxic effects 49

50 Site-specific delivery Passive targeting Particles up to 100 nm can enter leaky tumor tissues, but not compact normal tissues 50

51 Site-specific delivery Active targeting An active moiety A carrier A homing/targeting device natural targeting devices : antibody Bispecific antibody 51 Target cells or tissues Bind to effector cells

52 Summary Genomics is very important for drug discovery, in discovering drugs and drug targets. Sequencing, gene chips Patenting Concept, types, examples Drug delivery Parenteral (IV SC IM) and non-parenteral (oral, nasal, pulmonary) Rate-controlled delivery Site-specific delivery Next Pre-clinical trials and clinical trials 52

Microsoft PowerPoint - 5 Pharmacokinetics and pharmacodynamics of peptide and protein drugs

Microsoft PowerPoint - 5 Pharmacokinetics and pharmacodynamics of peptide and protein drugs Pharmaceutical Biotechnology Pharmacokinetics and pharmacodynamics By Yuqiong Xia 2014 Keywords Pharmacokinetics, pharmacodynamics, dose Metabolism, excretion Lymphatic, vascular, renal, hepatic, bile,