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1、Evolution of Oral Controlled/Modified Release Dosage Forms 口服控释/改良释放剂型的发展Oral CR/MR Dosage Forms 口服CR/MR 剂型“Extended-Release” “延长释放” “Delayed-Release” “延迟释放”Controlled Release Modified Release 控制释放 改良释放Potential Benefits of Controlled Release Dosage Forms 控释剂型的潜在优点 Enhanced activity duration for sho
2、rt half-life drugs 提高短半衰期药物的有效作用时间 Reduction of side effects 降低副反应 Less frequent dosing - improved patient compliance 减少给药频率-提高患者顺应性 Protecting labile drugs - improved product stability 保护不稳定药物-提高产品的稳定性 Potential for localization of drug to site of action 将药物固定于起效部位的可能性 Potential for extended patent
3、 protection 延长专利保护的可能性How did we get here and where are we going? 我们是如何达到现在的水平并 将向哪方面发展？Oral CR/MR Dosage Forms 口服CR/MR剂型“蜡丸者, 取其难化, 而旋旋取效也” “Use wax pills for their resistance to dissolve thereby achievingthe effect gradually and slowly”Early Slow-Release Oral Dosage Forms in Chinese Medicine 中药中的早
4、期缓释口服剂型 2nd Century B.C. Animal-fats as binder for pills “Recipes for Fifty-Two Ailment”, Mawangdui Medical Manuscript, dated 168 B.C.公元前2世纪动物脂肪作为丸剂的粘合剂“52种疾病的处方”，马王堆医学手稿，日期公元前168 4th Century A.D. Wax and fat pills “Handbook of Prescriptions for Urgent Cases”, Ko Hung (281-341) 公元4世纪蜂蜡和脂肪丸剂”肘后救卒方 “葛
5、洪 (281-341 13th Century Wax pills for slow-release “Rules and Correspondences in the Useof Drugs”, Li Kao (1180-1251) HPC; PEO; Na Alginate羟丙基甲基纤维素：HPC：聚氧化乙烯：藻(朊)酸钠Examples of Swellable Tablet Products可溶胀片剂产品实例Indocin (Indomethacin; Merck)（吲哚美辛； Merck ）Isoptin SR (Verapamil HCL; Knoll)（盐酸维拉帕米； Knoll
6、 ）Trental (Pentoxifylline; HMR)（己酮可可碱；HMR）Swelling Pfizer)（硝苯地平,； Pfizer） Covera-HS (Verapamil HCl; Searle)（盐酸维拉帕米； Searle） DynaCirc CR (Isradipine; Norvartis)）（依拉地平； Norvartis ） Concerta (Methylphenidate HCl; McNeil)（盐酸哌甲酯； McNeil ）Controlled-Release OROS Delivery Systems (Osmotic Pump) 控释口腔渗透的渗透泵缓
7、释剂（ OROS ）释放系统（渗透泵）Elementary Osmotic Pump 初级渗透泵Constant release rate is maintained by a constant osmotic driving force (from excess soluble drug and/or osmotic adjuvant)通过持续渗透驱动力保持恒定的释放率（从极易溶药物和/或渗透佐剂） Push-Pull Osmotic Pump 推-拉渗透泵Constant release rate is maintained by the constant swelling of hydr
8、ogel push layer通过水凝胶挤压层持续溶胀保持恒定释放率 Useful for delivering low solubility drugs (in a suspension) 对释放不易溶药物有用（在混悬液中） Pulsatile delivery feasible with multiple compartments (OROS Tri-Layer)可行的多层室脉冲式释放（ OROS 三层） Can be adapted for liquid formulations (L-OROS) 适用于液体处方（ L-OROS ）Osmotic Pumping Mechanism:渗透
9、泵原理 Release Characteristics释放特征Phenylpropanolamine OROS Tablet 1st Osmotic Tablet Product: “Acutrim” n-去甲麻黄碱OROS片剂 第一个渗透泵片剂产品：“Acutrim”In Vivo () & In Vitro () Delivery Profiles 体内() & 体内 () 释放曲 线Predicted & Experimental Plasma Concentration Profiles 期望&试验血浆浓度Good and Lee (1984)Membrane Systems - Dr
10、ug core surrounded by a rate-controlling membrane (e.g., microcapsules & coated drug pellets, granules or beads)膜系统-药芯为速率控制膜包围（比如，微胶囊&包衣药物小丸，颗粒或小球）Matrix Systems - Drug dissolved or dispersed in a carrier matrix (e.g., microspheres, beads, pellets, granules & tablets)基质系统-药物溶解或分散于载体基质中（比如，微球，小球，小丸，颗
11、粒& 片剂 ）Hybrid Sysrtems - A combination of membrane and matrix systems (e.g., coated pellets or beads imbeded in a tablet matrix, coated matrix beads, press-coated matrix tablets) 混合系统-膜系统和基质系统的联合使用（比如，包衣小丸或串珠包埋到片剂基质 中，包衣基质串珠，压制包衣基质片剂）Oral CR/MR Dosage Form Classifications 口服CR/MR剂型分类Oral CR Mechanis
12、ms口服 CR机理Diffusion 扩散 Dissolution溶出 Swelling & Erosion 溶胀& 侵蚀 Geometry/Area Changes几何形状/ 面积变化 Nonuniform Drug Distribution/Gradient matrix 不均一药物分布/梯度基质Solution-Diffusion 溶解-扩散 Osmotic Pumping 渗透泵Matrix Systems 基质系统Membrane Systems 膜系统Achievable Release Profiles 完成的释放曲线 First Order (including t depen
13、dence)一级（包括t 依赖性 ） Zero-Order零级 Bimodal (including accelerated release) 双峰（包括加速释放） Pulsatile (including delayed release) 脉冲式（包括延迟释放 ）Major Development Impacting Oral Controlled Release Since the 1950s 自二十世纪五十年代以来影响口服控制剂型的 主要发展The emergence of Physical Pharmacy and Pharmacokinetics as new disciplines
14、 in the 1960s 二十世纪六十年代作为一种新学科出现的物理药剂学和药物代谢动力学 The establishment of controlled release as a field which has grown more interdisciplinary since the 1970s 自二十世纪七十年代开始，控释作为一个学科交叉发展的领域开始建立 Significant progress in the understanding of GI physiology and its impact on controlled release delivery 对胃肠道生理学及其对控
15、释释放的影响出现了重大进步 Integration of biopharmaceutics and pharmacokinetics into the design of oral controlled release dosage forms 生物药剂学和药代动力学与口服控释释放剂型设计的整合Major Development Impacting Oral Controlled Release Since the 1950s (continued) 自二十世纪五十年代以来影响口服控制剂型的主要发展（续）Greater knowledge on material properties, dru
16、g release mechanisms, and physicochemical factors affecting the oral dosage form design and performance 对影响口服剂型设计和性能的材料性质，药物释放原理和物理化学因子 的更多认识 Proliferation of novel drug delivery technologies 新型药物释放技术的增加 Major advances in analytical chemistry, instrumentation, computer modeling, process equipment & monitoring分析化学，仪器操作，计算机模型设计，工艺设备&监控的主要进步Future Pro
