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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
2、 short 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 pa
3、tent 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 Medici
4、ne 中药中的早期缓释口服剂型, 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
5、剂”肘后救卒方 “葛洪 (281-341 , 13th Century Wax pills for slow-release “Rules and Correspondences in the Useof Drugs”, Li Kao (1180-1251) & “Medications Administered as Decoctions”, Wang Hao-ku (mid-13th century) 13世纪缓慢释放的蜡丸” 药物使用中的规则和依据“Li Kao (1180-1251) & ”按汤剂服用“,“丸者缓也,其用药之舒缓而治之意也” “Such pills are slow a
6、ctingthey provide the drug gradually and slowly for treatment”,Earliest record of slow-release dosage forms for therapeutic use! 治疗所用缓释剂型的早期记载,Types of Long-Acting Preparations, 1959 长效制剂的类型，1959,Coating the active drug with gastro-resistant and slowly enterosoluble substances (e.g. fats, waxes, fat
7、ty acids, ets.) 使用抗胃液和减慢肠溶解的物质包裹活性药物（比如，脂肪，蜂蜡，脂肪酸等等） The use of ion exchange resins to bind active drugs 使用离子交换树脂与活性药物结合 The formation of chemical addition compounds or complexes 化学添加物或合成物的形成 Impregnating or embedding the drug in a base which gradually releases the active principle 将药物浸渍或包埋在一个基质中，该基
8、质可缓慢释放活性有效成分,From: J. Lazarus and J. Cooper, J. Pharm Pharmacol., 11, 257 (1959),Major Historical Milestones Affecting the Direction of Oral Controlled Release Dosage Forms 影响口服控释剂型发展方向的主要历史里程碑,Availability of semi-synthetic and synthetic polymers for enteric coating (1940s through 1990s) 半合成和合成聚合物用
9、于肠溶包衣（二十世纪四十年代到九十年代） Introduction of first oral sustained release products by Smith Kline & French using the Spansule technology: Dexedrine (dextroamphetamine sulfate) (1952) and Contac, the cold remedy (1960). Smith Kline & French介绍了首个口服持续释放产品，使用了缓释胶囊剂（Spansule）技术： Dexedrine（右旋硫酸右苯丙胺）（1952）和Contac（
10、复方盐酸苯丙醇胺），感冒药（1960） Introduction of semi-synthetic and synthetic hydrophilic gel forming polymers for designing oral sustained release products (1950s and 1960s) 半合成和合成亲水凝胶形成的聚合物介入口服持续释放产品设计（二十世纪五十年代和六十年代） Invention and first commercialization of oral osmotic drug delivery systems by ALZA (1970s thr
11、ough 1980s) ALZA发明并首次商业使用的口腔渗透药物释放系统（二十世纪七十年代到八十年代）,“The delayed action tablet which was an extension of the enteric coating principle, represented the initial approach in controlling the release of a drug in the gastro-intestinal tract” “延迟起效片剂是肠溶包衣原理的扩展，它代表在胃肠道中控制药物释放开始起步” - Lazarus and Cooper (19
12、59),Reasons for enteric protection 肠溶包衣的目的,Prevention of gastric irritation 避免胃的刺激Protection of drugs unstable in gastric fluids 避免药物在胃酸条件下被破坏Delivery of drug to local site in intestine 药物在肠道特定部位释放Delivery of drug to best absorption site in intestine 药物在肠道最佳吸收部位释放Delayed drug release 药物延迟释放,ENTERIC
13、COATING SYSTEMS 肠溶包衣系统,Enteric Coatings 肠溶包衣,1884 Dr. Paul Unna introduced keratin-coated pills 1884 Paul Unna 博士引入了角质素包衣丸剂 Late 1880s to 1930s Numerous substances and their combination were used for enteric coating such as keratin, salol, tolu, shellac, casein, zein, stearic acid, gelatin-formaldeh
14、yde product, tannic acid-gelatin product, cetyl alcohol, etc. 十九世纪八十年代晚期到二十世纪30年代众多物质及其混合物用于肠溶包衣，比如角质素，水杨酸苯酯，妥鲁香脂,紫胶，酪蛋白，玉米蛋白，硬脂酸，明胶甲醛产品，鞣酸明胶产品，十六烷醇 等等。 1940s Cellulose acetate phthalate (CAP) introduced 二十世纪四十年代引进醋酞纤维素（CAP） 1970s Polyvinyl acetate phthalate (PVAP) and hydorxypropyl methylcellulose
15、phthalate (HPMCP) became available 二十世纪七十年代可使用聚醋酸乙烯邻苯二甲酸酯(PVAP) 和羟丙基甲基纤维素邻苯二甲酸酯（HPMCP） 1980s - Methacrylate-methacrylic acid coplymers on the market 二十世纪八十年代异丁烯酸-甲基丙烯酸共聚物出现在市场 1980s to 1990s Various aqueous dispersions of enteric polymers introduced for tablet coatingshang 二十世纪八十年代到二十世纪九十年代各种肠溶聚合物水分
16、散系用于片剂包衣, The development of Spansule provided the impetus to the further development of sustained release dosage forms in subsequent years Spansule 的发展为延释剂型在今后几年中进一步发展提供了推动力 It also stimulated numerous human studies regarding the absorption, distribution and fate of drugs delivered by such dosage forms, thus culminating the start of the study of biopharmaceutics 也刺激了众多针对在使用这种剂型后吸收，分布和药物释放途径的人类研究，因而使生物药剂学的研究开始到达顶峰,
