Drug Delivery System 04 891672 891659 891631 891625

Drug Delivery System 藥物投遞系統 生科系 04級 黃玫璇 許哲源 蕭宏展 楊淳竣 891672 891659 891631 891625

藥物釋控系統 1. 何謂藥物釋控 2. 發展釋控的優點 3. 藥物釋控的種類 A. Diffusion controlled B. Chemically controlled C. Solvent-activated controlled

藥物釋控系統 1. 何謂藥物釋控 2. 發展釋控的優點 3. 藥物釋控的種類 A. Diffusion controlled B. Chemically controlled C. Solvent-activated controlled

藥物釋控系統 1. 何謂藥物釋控 2. 發展釋控的優點 3. 藥物釋控的種類 A. Diffusion controlled B. Chemically controlled C. Solvent-activated controlled

Potential Advantages of Controlled Release Systems 1. maintenance of drugs at therapeutically desirable levels 2. the ability to localize drugs to target organs to minimize systemic effects 3. improved patient compliance 4. protection from degradation for drugs with short in vivo lifetimes.

Controlled Release vs. Single Dose Side Effects Desired Range Therapeutic Dose

藥物釋控系統 1. 何謂藥物釋控 2. 發展釋控的優點 3. 藥物釋控的種類 A. Diffusion controlled B. Chemically controlled C. Solvent-activated controlled

Types of Controlled Release Devices 【 Diffusion controlled】 Diffusion through membrane or bulk polymer 【 Chemically controlled】 polymer erosion： surface erosion, bulk erosion ( combination of erosion and diffusion ) ˙ pendent chain ˙ 【 Solvent-activated controlled】 ˙ osmotic transport of water through semi permeable membrane ˙ water penetration into glassy polymer

1. Diffusion controlled 【 Stomach/Intestine – Liquid】 【 Capsule edge – Gel 】 • Biocompatible polymer 【 Capsule center – Dry 】 • Allows for delayed release rates are determined by polymer property and partition coefficient of the drug to be released. △advantage ˙ drug diffuses out of matrix at defined rate △disadvantage ˙ efficiency of diffusion of large molecules ˙ danger of ‘dose dumping’ in barrier systems △

2. Chemically controlled ˙ erosion： Surface erosion, Bulk erosion △ capsule is eroded by the acids in the stomach △ advantage ˙ inject able (micro spheres) ˙ biodegradable (need not be removed surgically) △ disadvantage ˙ difficult to stop once injected

2. Chemically controlled ˙ pendent chain △ drug is covalently bound to the polymer and is released by bond scission owing to water or enzymes

3. Solvent-activated controlled △ the active agent is dissolved or dispersed within a polymeric matrix and is not able to diffuse through that matrix. △ advantage ˙ complex control △ disadvantage ˙ generally more bulky devices and require implantation

Biodegradable Polymers

Application

Targeting moiety for cell 891659 許哲源

Introduction • For the past several decades, researchers and clinicians have been using drugs and radiation to kill tumor cells. • The chemotherapy and radiotherapy are only semiselective for malignant cells. • In contrast, targeting drug therapy has the potential for greater specificity. • With the advent of monoclonal antibody (Mo. Ab) technology, researcher have been able to target different agents to target cells more effectively. Pharmacol. Ther. 1994, 64: 127– 54

EPR effect • The Enhanced Permeability and Retention effect in tumor tissue • Tumor cells show a higher degree of uptake of macromolecules by endocytosis than normal cell. Microvasc. Res. 1996, 51: 327 -346

Introduction • Immunotoxins (Its) contain a targeting moiety for delivery and a toxic moiety for cytotoxicity. • The toxins ( plant or bacterial toxin) are catalytic, fewer than 10 molecules in the cytosol of a target cell enough to be lethal. Pharmacol. Ther. 1994, 63(3): 209– 234

Schematic presentation of ligand-containing, shielded DNA complexes for tumor-targeted gene transfer Journal of Controlled Release 2003, 91: 173 -181

Targeting Moiety • The targeting agents currently used to construct ITs are Mo. Abs, growth factors/cytokines, and soluble receptors. • Mo. Abs are the most frequently used. J. Clin. Immunol. 1992, 12: 391– 405

Targeting Moiety

Targeting Moiety • Bispecific antibodies are novel targeting agents constructed by linking either chemically or genetically two different Fab fragment, one arm of which is directed against a target cell and the other against effector T cells or NK cells (e. g. anti-CD 22/anti-CD 3 RTA). Blood 1993, 82: 2224– 34

Toxin Moiety • The most commonly used toxic moieties are derived from either bacteria[e. g. Pseudomonas exotoxin(PE) or diptheria toxin(DT)], or plants(e. g. abrin or ricin).

Toxin Moiety • Both types of toxins kill cells by inhibiting protein synthesis. – Plant toxins damage 28 S r. RNA, – Bacterial toxins inactivate EF-2 Ann. Rev. Immunol. 1996. 14: 49– 71

Linkers • For in vivo therapy, the toxic moiety of the IT must be coupled to the targeting ligand so that it remains stable in the blood and tissues but is separated from the targeting domain for effective translocation into the cytoplasm.

Factors affecting the potency of an IT • • • Binding affinity of the targeting moiety The density of the target Ag on the cell Naturally internalized or induced to do so. Intracellular routing May promote proliferation of target cell population

Clinical trials • The field of immnotoxin therapy is in its infancy. To date most ITs are just entering Phase II/III trials. • Anti-IT antibodies were generated in most trials

Conclusions • For therapy of cancer, ITs have yielded higher response rates in Phase I/II trials than some of the drugs used today. • The generation of new constructs, combinatorial therapy, and in the case of cancer therapy, treatment of tumors that are amenable to IT-mediated killing will eventually result in effective treatment protocols.

References • Thrush GR. , Lark LR. , Clinchy BC. , and Vitetta ES. Immunotoxins: An update. Ann. Rev. Immunol. 14: 49 -71. 1996. • Rustamzadeh E. , Low WC. , Vallera DA. , and Hall WA. Immunotoxin therapy for CNS tumor. Journal of Neuro-oncology. 64: 101 -116. 2003. • Houshmand P. , and Zlotnik A. Targeting tumor cells. Current Opinion in Cell Biology. 15: 640 -644. 2003 • Ogris M. , Walker G. , Blessing T. , Kircheis R. , Wolschek M. , and Wagner E. Tumor-targeted gene therapy: strategies for the preparation of ligand-polyethylene glycol-polyethylenimine/DNA complexes. Journal of Controlled Release. 91: 173 -181. 2003 • Carlsson J. , Aronsson EF. , Hietala SO. , Stigbrand T. , and Tennvall J. Tumuor therapy with radionuclides: assessment of progress and problems. Radiotherapy and Oncology. 66: 107 -117. 2003.

Overview of Worldwide Drug Market 主講: 蕭宏展

Worldwide drug market sales

2003全球各區域藥品市場銷售額 Total sales: around 5000億美金 資料來源: IMS Health

Drug delivery system market • 2002年 worldwide sales: $41. 1 billion • 2007年(e) worldwide sales: $66 billion 資料來源: Front Line Strategic Consulting, Inc.

Drug delivery system Oral controlled release Polymer Pulmonary Transdermal Transmucosal others

Oral controlled release • Sustained release or extended release drug • Compound is less susceptible to gastric degradation • Company: Elan Corp. and J&J Alza • Product: Nexium (R) Esomeprazole ($3302 millino) 、Losec/Prilosec for treatment of gastric ulcer.

Polymer • A method of drug delivery in which a therapeutic is encapsulated in polymeric matrix and is slowly released at the site of action via diffusion and surface erosion. • Inactive in the bloodstream • Company: J&J Alza 、Atrix • Product: PEG-Intron (pegylated interferon) for treatment of chronic hepatitis C

Pulmonary • Improve patient compliance associated with the relative comfort and convenience of inhalers. • Company: Glaxo. Smith. Kline、Aerogen, Inc. 、 Nektar therapeutics • Product: Aerodose® Insulin Inhaler、 Seretide/Advair for treatment of asthma

Transdermal • Enable the passage of drug molecules across skin • Lower dosing of medications result in few adverse side effects • Company: J&J Alza 、Noven Pharmaceutical • Product: Catapres-TTS® (clonidine) for treatment of hypertension 、 Nico. Derm® CQ® (nicotine) and Clear Nico. Derm® CQ®

Transmucosal • Drug is introduced to the body across a mucous membrane which allows for the avoidance of the gastrointestinal tract and first pass liver metabolism and consequently allows therapeutic to directly enter into circulation. • Company: Nastech Pharmaceutical Co. 、Pherin Pharmaceuticals • Product: Premarin (estrogen) for treatment of symptom of menopause in women. Nasonex for treatment of specific allergy situation

Major drug delivery company stock 2004. 5. 4 Name Last change ALKERMES INC 15. 42 +0. 08 +0. 52% ANDRX GROUP 23. 37 +0. 53 +2. 32% ATRIX LABS 31. 34 +1. 18 +3. 91% BIOVAIL CORP 19. 5 +0. 50 +2. 63% CIMA LABS 31. 95 +0. 26 +0. 82% ELAN CORP PLC 22. 03 +0. 43 +1. 99% FLAMEL TECHNOL 27. 94 +1. 58 +5. 99% NASTECH PHARM 13. 94 +0. 06 +0. 43% NEKTAR THERAP 21. 49 資料來源: www. pharmcast. com +1. 22 +6. 02%

ALZA • 1968 ALZA Corporation was founded by Dr. Alejandro Zaffaroni in 1968 to realize his vision of sophisticated pharmaceutical products that precisely control the targeting, timing and dosing of therapeutic compounds.

Products • OROS® Technology (11) • D-TRANS® Transdermal Technology (7) Catapres-TTS® (clonidine), Duragesic® (fentanyl), Estraderm® (estradiol), Nico. Derm® (nicotine), Transderm -Nitro® (nitroglycerin) • STEALTH® Liposomal Technology Doxil® (doxorubicin) an anti-cancer drug for the treatment of ovarian cancer • DUROS® Implant Technology Viadur® (leuprolide acetate implant) treatment for prostate cancer

• 1995 Pfizer introduces Glucotrol XL®, its second oncedaily product using ALZA's OROS® technology. It is introduced as an adjunct to diet for the control of hyperglycemia in patients with non-insulin dependent diabetes. • 2001 ALZA Becomes a Member of the Johnson & Johnson Family of Companies ALZA continues as a leader in the development and manufacture of pharmaceutical products incorporating its novel, proprietary drug delivery technologies for its partners in the global healthcare industry.

Biogen Idec (BIIB) • In November 2003, Biogen Idec Inc. was formed from the merger of two of the world’s leading biotechnology companies, Biogen, Inc. and IDEC Pharmaceuticals Corporation. • Core therapeutic areas are in neurology, oncology, and dermatology

http: //www. biospace. com/company_profile. cfm? Company. ID=1303

http: //www. biogenidec. com/site/025. html

RITUXAN (R) • RITUXAN (Rituximab): monoclonal antibody of CD 20, for treatment of non. Hodgkin's lymphoma (NHL) • Approved by FDA in November 1997 • Revenues for the first quarter of 2004: $542 million • RITUXAN (R): $134 million , about 25% and in U. S. $362 million

http: //quote. money. cnn. com/quote? symbols=biib&submit 3. x=29&submit 3. y=7

Alkermes • AIR® Pulmonary Drug Delivery System is a proprietary drug delivery technology composed of dry powders ideally suited for delivery to the lungs

http: //www. biospace. com/company_profile. cfm? Company. ID=1688

• The unique AIR particle is a low density, porous structure with a geometric diameter of 5 - 30 µm * * Particles with mass densities less than 0. 4 g/cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs’ natural clearance mechanisms until the inhaled particles delivered their therapeutic payload David A. Edwards, * Justin Hanes, …. , SCIENCE. VOL. 276. 20. JUNE. 1997

Ease of use • Due to the inherent features of the AIR particles, a simple breath-actuated inhaler can be utilized without any additional power such as fans or motors. • Alkermes® is developing a family of inhalers that combine compact size with low cost and ease of use

The End