药物制剂的创新与发展2010

Schematic Diagram of the Apparatus Utilizing SCF for Inclusion
（3）生物芯片
三、辅料创新
TIMERx is a patented, controlled release technology based on an agglomerated hydrophilic matrix which consists of locust bean gum and xanthan gum. Interactions between these components in an aqueous environment form a tight gel with a slowly eroding core. The TIMERx delivery system is compatible with a broad range of active drug substances。
节约研发成本（avoidance of laboratory costs） 减少医疗费用（reduction in overall use）
一、药物制剂创新的范畴
新制剂品种和剂型(NDF, new dosage forms) 新的复方制剂 (NC, new combination) 新的用药途径 (NR, new route) 新的剂量(NS, new strength) 新盐、新酯或前药 (NE, new salt or ester) 新晶型 (NP, new polymorphs)
Wowtab Fast Melt Flashdose
Cima Labs Inc., USA
Yamanouchi Pharma Technologies, USA Elan Corporation Fuisz Technologies, USA
Flashtab
EFVDAS(Effervescent Drug Absorption System)
Key Pharmaceuticals
Key Pharmaceuticals Ascent Pediatrics Inc., USA
R.P.Scherer, UK Farmalyoc, France Janssen Pharmaceutica, USA Prographarm, France
Orasolv
Oral Mucosal Vaccines
Medipad Oral vacccine Prolease and Medisorb
Cortecs International Ltd.,UK
Elan Corporation Elan Corporation Alkermes Inc.,
Oral Drug Delivery Technical Platforms
Ethical Holdings Plc,UK
Pharmazome (Microparticulate Drug Delivery Tech) Elan Corporation
Oral Drug Delivery Technical Platforms
PPDS (Pelletized Pulsatile Delivry System Peltab System PRODAS (Programmable Oral Drug Absorption Systems) Reduced Irritation system RingCap SODAS (Spheroidal Oral Drug Absorption System SMHS (Solubility Modulating Hydrogel System Andrx, Pharmaceuticals, USA Andrx, Pharmaceuticals, USA Elan Corporation DepoMed, Inc., Alkermes Inc., USA Elan Corporation Andrx, Pharmaceuticals, USA
药物制剂的创新与发展
Technological Platforms and Development of Drug Delivery Systems
发展药物制剂创新技术的重要意义

改进依从性（ compliance ） 改进或独特的临床效果（outcomes）


减少副作用（reduction of adverse effects）
Cp:HPMC =0:1
0.5
1
粘附力（N）
1.5
2
2.5
Macromolecules Drug Delivery Technical Platforms
BEODAS (Bioerodable Enhanced Oral Drug Absorption System DepoFoam DUROS LODAS (Localized Drug Absorption System) Macromol System Elan Corporation DepoTech Corporation, USA Alza, USA Elan Corporation Cortecs International Ltd.,UK
(3) 口腔粘贴
ATRIDOX® 四环素 50mg
丙烯酸树脂-EVA共聚物 100mg 甲基吡咯酮 地塞米松 卡波沫 3ml 5mg 15mg
HPቤተ መጻሕፍቲ ባይዱC
凝胶剂 三乙醇胺 油
5mg
q.s 3ml
粘附片：粘附力、溶胀速率与粘附时间的关系
1
1:0
1
0.9
溶胀速率
溶胀速率
0.9
Cp:HPMC =1:0
1:0.5 1:1
Taste Masking Chewable tablets Flavortech Micromask Elan Corporation Key Pharmaceuticals Key Pharmaceuticals
Liquette
Oraquick Tastemasking Oral fast dispersing dosage forms Zydis LYOC Quicksolv Multiflash
SCOT(Single Composition Osmotic Tablets System) Andrx, Pharmaceuticals, USA
DUREDAS(Dual Release Drug Absorption System)
Gastric retention system GeoMatrix GMHS(Granulated Modulating Hydrogel System
Prographarm, France
Elan Corporation
2、注射给药
—
—— —— —— —— —— ——
脂质体(lipposomes)
微 球(microsheres)
纳米粒(nanoparticles) 脂肪乳(Fatty emulsion) 胶 束(polymeric micells)
新的处方及工艺 特定处方成分（如高分子、稳定剂、促吸剂） 特定的包衣材料和组合 特定的溶出速率 特定的粒径 特定的硬度 不同的药动学参数、 特定包装
二、剂型与制剂的创新
1、经口腔及胃肠道给药
— 缓释及控释技术 — 口腔粘附技术
— 胃肠道定时、定位技术
Oral Drug Delivery Technical Platforms
0.8 0.7 0.6 0 0.5 1
粘附力（N） Cp:HPMC =0:1 1:2 1;3
1:0.5 1;1
0.8
0.7
0.6
Cp:HPMC =0:1
0 5 10 15
1:3
20
1:2
1.5
2
25
30
粘附时间(h)
30
粘附时间(h)
25 20 15 10
1:3
1:2
1;1 1:0.5
1:0
5 0 0
EOP(Elementary Osmotic Pump) MacroCap Micropump(oral controlled delivery system) Modas( Multiporous Oral Drug Absorption System) Zer-Os (Tablet technology) Ceform microsphere technology CONSURF (Constant Surface Area Drug Delivery Shuttle) EOP(Elementary Osmotic Pump) Contramid Dimatrix (Diffusion Controlled Matrix System) DPHS (Delayed Pulsatile Hydrogel System Alza, USA Biovail, Canada Flamel Tech, France Elan, Ireland ADD Drug delivery Tech, AG, Swiss Fuisz Tech, USA Biovail Corp. International Alza, USA Labopharm, Canada Biovail Corp. International Andrx, Pharmaceuticals, USA
二、工艺创新 1、熔融挤出
2、 液 体 填 充 硬 胶 囊
3、 纳米方法 ——（1）高压均质
（2）超临界流体技术
•Rapid Expansion of Supercritical Solution (RESS)
•Precipitation from Gas Saturated Solution (PGSS) •Gas Anti-solvent (GAS) •Aerosol Solvent Extraction System (ASES)
Rhotard
Ethical Holdings Ic.,
剂型创新
定位与定时释放
—
局部疾病的治疗；胃溃疡、肠炎、结肠炎
— 蛋白质及多肽等大分子药物的给药；
— 延长药物的吸收时间；
— 脉冲给药、24小时缓释的重要手段。
（1）胃肠滞留技术
—— 利用高分子的粘附性：Carbopol, HPMC, CMC-Na
Elan Corporation
DepoMed Inc,USA Skye Pharma Plc, USA Andrx, Pharmaceuticals, USA
IPDAS(Intestinal Protedtive Drug Absorption Sys)
Multipor technology
Elan Corporation
埋植剂(implant) PEG化(PEGylation)
（1）Stealth liposome
（2）Immunological Liposome
target cell
drug containing immunoliposome
nontarget cell
no immunospecific binding
（3）两亲性高分子：PLA-PEG
（4）PEG化
（5） 微球与埋植剂
CH 3 CH
O C O H2 C
O C O
O
O
[ CO R OCNH R’ NH ]
O O [ OC R C ]
Poly(urethanes)
Polyanhydrides
CH3 [ CH2 C ]
C
O
OCH3
Poly(methyl methacrylate)
—— 利用低密度辅料: Eudragit, 轻质氧化镁, 长链醇； —— 利用高密度辅料：重质氧化镁，碳酸镁 —— 利用气体（CO2）：NaHCO3 , Mg(OH)CO3 —— 特异性粘附（生物凝集素）: lectins;
（2）胃肠定位技术
—胃肠pH控制
—胃肠转运时间控制
— 酶、细菌降解控制 — 多因素控制
SPDAS (Stabilized Pellet Delivery System)
SQZGel oral controlled-release system KV/24 Meter Release Symatrix Spheroid Orasert Orasite Triglas technology
Andrx, Pharmaceuticals, USA
Macromed, Inc., USA KV Pharmaceuticals, USA KV Pharmaceuticals, USA KV Pharmaceuticals, USA KV Pharmaceuticals, USA KV Pharmaceuticals, USA KV Pharmaceuticals, USA Ethical Holdings Ic.,