Drug Delivery System
藥物投遞系統
生科系04級
生科系04級
生科系04級
生科系04級
黃玫璇
許哲源
蕭宏展
楊淳竣
891672
891659
891631
891625
藥物投遞系統
(Drug Delivery System)
【必要時將必要限度藥物對必要部位之供應】
2. 市場分析
3. 公司簡介
1. 原理
目標導向
(Target)
傳輸
(Transport)
控釋
(Controlled Release)
藥物釋控系統
黃玫璇 891672
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】：Drug Controlled Release System
將藥物以特殊的化學包覆，讓藥物在某一種狀態(如PH值改變)下
適時(ex:延長)適量釋出。
這種控釋劑型的技術發展，目前廣泛地應用於一般的製藥化學工
業中。
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
Single Dosages
Controlled Release
Concentration
Side Effects
Desired
Range
Therapeutic Dose
Time
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
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 (MoAb)
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 MoAbs, growth factors/cytokines, and
soluble receptors.
• MoAbs 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-CD22/anti-CD3RTA).
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 28S rRNA,
– 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 the 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
區域銷售率
北美
Total sales: around 5000億美金
歐洲地區
8% 4%
11%
日本
49%
28%
資料來源:IMS Health
亞洲(不包含日
本)、非洲、澳
洲
拉丁美洲
全球十大藥物銷售
Drug delivery system market
• 2002年 worldwide sales: $41.1 billion
• 2007年(e) worldwide sales: $66 billion
Transmuco
sal, 7%
Transderm
al, 10%
Pulmonary,
19%
Polymer,
10%
market share
Oral controlled
release
Polymer
others, 1%
Oral
controlled
release,
53%
Pulmonary
Transdermal
Transmucosal
others
資料來源:Front Line Strategic Consulting, Inc.
Drug delivery system
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: GlaxoSmithKline、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 、 NicoDerm® CQ®
(nicotine) and Clear NicoDerm® 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 the 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), NicoDerm® (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?CompanyID=1303
http://www.biogenidec.com/site/025.html
RITUXAN (R)
• RITUXAN (Rituximab): monoclonal
antibody of CD20, for treatment of nonHodgkin'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/quote?symbols=biib&submit3.x=29&submit3.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?CompanyID=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 0.4g/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
東洋製藥核心技術
1.微脂體劑型
2.緩釋劑型
3.新藥開發
微脂體
•1998年取得第一項微脂體藥品許可證LipoDox針劑.
•全球第三家、台灣第一家核准Doxorubicin
微脂體劑型藥物
長效舒緩劑型---釋控技術
•長效劑型愛舒可羅錠Regrow(長效型止咳錠)
取得新藥核可,在1999年上市,突破短效藥
物需服用多次缺點.
•長效化痰劑與解熱鎮痛劑,已進入臨床試驗
階段
2000
2001
2002
2003
營收（百萬 745
元）
843
1245
1380
研發金額
63
（百萬元）
員工總數
197
(人)
106
143
222
240
研發人員總 27
數(人)
研發費用/ 8.4%
營收
33
44
12.6
11.5%
研發人員/
員工總數
14.9
16.7%
13.7%
東洋(4105)之經營績效
單位:億元
年度
期末股本
92
5
91
90
89
88
87
86
85
84
4
3
2
2
2
2
2
2
營業收入
13.8 12.4
8.4
7.5
7.0
5.4
4.3
4.7
3.4
每股營收
(元)
27.5 33.8 30.4 31.3 29.2 25.3 23.3 23.7 17.2
稅前盈餘
2.6
2.5
1.1
0.5
0.5
0.0
0.1
0.2
0.2
稅前EPS
5.2
6.8
4.0
2.1
2.1
0.0
0.5
1.0
1.0
稅後純益
2.4
2.1
1.0
0.4
0.4
0.0
0.1
0.1
0.2
稅後EPS
4.8
5.7
3.6
1.7
1.7
0.0
0.5
0.5
1.0
資料來源:日盛證券
The End