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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 short half-
2、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 protection延长专利保护的可能性H
3、ow did we get here and where are we going?我们是如何达到现在的水平并我们是如何达到现在的水平并将向哪方面发展？将向哪方面发展？Oral CR/MR Dosage Forms口服口服CR/MR剂型剂型“蜡丸者,取其难化,而旋旋取效也”“Use wax pills for their resistance to dissolve thereby achieving the effect gradually and slowly”Early Slow-Release Oral Dosage Forms in Chinese Medicine中药中的早期中药中
4、的早期缓释缓释口服剂型口服剂型 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“葛洪(
5、281-341 13th Century Wax pills for slow-release“Rules and Correspondences in the Use of 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 actingthey provide the drug g
6、radually 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，长效制剂的类型，1959Coating the active drug with gastro-resistant and slowly enterosoluble substances(e.g.fats,waxes,fatty acids,ets.)使用抗胃液和减慢肠溶解的物质包裹
7、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，该基质可缓慢释放活性有效成分From:J.Lazarus and J.Coope
8、r,J.Pharm Pharmacol.,11,257(1959)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(194
9、0s through 1990s)半合成和合成聚合物用于肠溶包衣（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）
10、（1952）和Contac（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(
11、1970s through 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(
12、1959)Reasons for enteric protection肠溶包衣的目的溶包衣的目的 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
13、放ENTERIC COATING SYSTEMS肠溶包衣系溶包衣系统Enteric Coatings肠溶包衣肠溶包衣1884 Dr.Paul Unna introduced keratin-coated pills1884 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-formal
14、dehyde 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 phthalat
15、e(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散系用于片剂包衣 The devel
16、opment 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 culminatin
17、g 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Multiparticulate Drug Delivery多颗粒药物释放CLINICAL ADVANTAGES（临床优点）Disperse freely in the GI tract,invariably maximize drug absorption,reduce peak plasma fluctuation,and minimize potential side effects.容易通过胃肠道，
18、有利药物吸收，降低不良反应Reduce variations in gastric emptying rates and overall transit times.Thus inter-and intra-subject variability of plasma profiles is minimized.减少因胃排空速率和转运时间不同而产生的差异。从而提高体外释放和体内血浆药物浓度的相关性High local concentration of bioactive agents,which may inherently be irritative or anesthetic,can be
19、avoided.避免具有刺激性和麻醉性的生物活性物质在局部浓度过高Less susceptible to dose dumping than the reservoir-type,single unit formulations.相对于膜控释单剂量药物单元，可减少药物突释的可能性水分蒸发水分蒸发,聚合物塑化细小颗粒紧密聚集在一起 Poorly plasticised system部分愈合的的薄膜完全愈合薄膜Tg聚合物水分散体成膜机理聚合物水分散体成膜机理分散物堆积在颗粒表面包衣薄膜包衣薄膜基底基底控释膜示意图Major Historical Milestones Affecting the D
20、irection of Oral Controlled Release Dosage Forms影响口服控释剂型方向的主要历史里程碑影响口服控释剂型方向的主要历史里程碑Availability of semi-synthetic and synthetic polymers for enteric coating(1940s through 1990s)在肠溶包衣中使用半合成和合成聚合物（20世纪40年代至90年代）。Introduction of first oral sustained release products by Smith Kline&French using the Spa
21、nsule technology:Dexedrine(dextroamphetamine sulfate)(1952)and Contac,the cold remedy(1960).Smith Kline和French引入了首例口服缓释产品Dexedrine（右旋安非他明硫酸盐，1952年）和Contac（感冒药，1960年），使用的是分时溶解药囊（Spansule）技术。Introduction of semi-synthetic and synthetic hydrophilic gel forming polymers for designing oral sustained rele
22、ase products(1950s and 1960s)引入半合成和合成亲水胶成型聚合物，用于设计口服延释产品（20世界50年代和60年代）。Invention and first commercialization of oral osmotic drug delivery systems by ALZA(1970s through 1980s)ALZA发明并首次商业化口服渗透性药物传递系统（20世纪70至80年代）。Ethylcellulose乙基纤维素Cellulose Acetate乙酸纤维素,醋酸纤维素Methacrylic Acid Copolymer甲基丙烯酸共聚物Hydrox
23、ypropyl Methylcellulose(HPMC)羟丙基甲基纤维素Hydroxypropyl Cellulose羟丙基纤维素Carbomer卡波姆Sodium Alginate海藻酸钠Polyethylene Oxide聚氧化乙烯White Wax白蜡Carnauba Wax巴西棕榈蜡Shellac紫胶PolymersOtherExamples of Release Controlling Excipients inExamples of Release Controlling Excipients in Current Oral CR Products Current Oral CR
24、 Products目前口服控释产品中释放控制辅料的实例目前口服控释产品中释放控制辅料的实例目前口服控释产品中释放控制辅料的实例目前口服控释产品中释放控制辅料的实例Earliest Example of a Controlled-Release Tablet Using Swellable&Erodible Hydrophilic Gums including HPMC使用含有使用含有羟丙基甲基纤维素的可溶胀性可溶胀性&易侵蚀亲水树胶的早易侵蚀亲水树胶的早期控释片剂实例期控释片剂实例“In swelling,a relatively water impermeable barrier is fo
25、rmed at the surface of the tablet which prevents further entry of water into the interior of the tablet.This soft mucilaginous gum gel barrier formed on the surface of the tablet is worn away by the motion of the tablet in the gastro-intestinal tract,and some of the admixed medicinal agent is carrie
26、d away with it and released.The fresh surface of the tabletbecomes hydrated and swells thus renewing the protective coating.As a result,the tablet is slowly disintegrated rather than dissolved and the medicament contained therein is release at a substantially uniform rate.”“溶胀时，在 片剂表明形成一层相对不透水层，这可防止
27、水进一步渗入片剂内部。在片剂表面所形成的这种柔软的粘性树胶凝胶层随片剂在胃肠道移动而磨损，并且一部分混合在内药物随磨损并释放。片剂新鲜形成的表面与水结合并溶胀因而替换了保护性包衣。结果，片剂不仅仅是溶解而是缓慢分解并且所含药物基本以均匀速率释放。”US Pat.3,065,143,Christenson and Dale(1962)美国专利3,065,143,Christenson and Dale(1962)Mechanism of Drug Release from HPMC Matrix Tablets药物从HPMC基质片剂释放原理Dry Tablet干燥片剂Ingestion of T
28、ablet咽下片剂Gel Layer凝胶层Dry Core干燥片芯Insoluble Drug-released by exposure via tablet erosion.不溶性药物经片剂侵蚀暴露释放Soluble Drug-released mainly by diffusion through the gel layer and less via tablet erosion.可溶性药物主要通过凝胶层扩散而极少经过片剂侵蚀释放Tablet ErosionPolymer concentration at gel surface reaches a threshold disentangl
29、ement value and dissolution/erosion of tablet takes place.片剂侵蚀凝胶表面的聚合物浓度达到崩解阈值，从而片剂发生溶出/侵蚀Growth of Gel Layer凝胶增变厚凝胶增变厚Water swelling front penetrates into the tablet,gel layer thickness increases,and soluble drug diffuses out of the gel layer.水溶胀上层渗透入片剂，凝胶层厚度增加，可溶性药物通过凝胶层扩散 Initial Hydration&Swelli
30、ngTablet surface wets and HPMC polymer begins to hydrate,forming a gel layer.Initial burst of soluble drug is released from the tablet surface layer.初期的水合作用初期的水合作用&溶胀溶胀片剂表面湿润并且HPMC聚合物开始形成水合物，形成凝胶层。可溶性药物的突释作用从片剂表层开始。Source:Modified from Dow technical brochure来源：Dow技术手册改进Formulations are relatively st
31、raightforward 处方相对简单Standard production equipment 不需要特殊设备Reproducible release profiles resistant to drug dumping 释药重现性好，不易产生药物突释Release rate generally insensitive to compression force/tablet hardness 药物释放率不易受压片力/片芯硬度的影响Through choice of excipients/polymer level,able to modify release kinetics 通过选择辅料
32、/聚合物水平，可以调节药物释放动力学参数Advantages（优点）:HYDROPHILIC MATRICES亲水凝胶骨架The most commonly used polymers are cellulose ethers 最为常用的聚合物是纤维素醚类，特别是羟丙基甲基纤维素Dynamic Gel Thickness Development in a Swellable Matrix Tablet溶胀基质片剂中凝胶厚度的动态变化Current Understanding of Swelling&Erosion Controlled Systems目前对溶胀目前对溶胀&侵蚀控制系统的理解侵蚀
33、控制系统的理解Synchronization of swelling&erosion fronts can lead to near zero order release(e.g.in PVA and NaCMC systems)外部溶胀&侵蚀的同时发生会引发近似零级释放（比如，在侵蚀的同时发生会引发近似零级释放（比如，在PVA和和NaCMC 系系统中）统中）In HPMC systems,the gel layer thickness continues to increase with time在HPMC系统中，凝胶层厚度随时间不断增加For water soluble drugs,dif
34、fusion is the dominant mechanism with a time-dependent increase in diffusion coefficient and surface area as a result of continuous swelling对于水溶性药物，扩散是主导机理，由于持续溶胀的结果，扩散系数以及表面积随时间相应增加For insoluble drugs or soluble drugs at high loading,the erosion mechanism will dominate对于不溶药物或高载药量的可溶性药物，侵蚀机理占主导。Typi
35、cal Rate-Controlling Matrix Material代表性的速率-控制基质材料HPMC;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）Trental(Pentoxifylline;HMR)（己酮可可碱；HMR）Swelling&Erosion Controlled Matrix
36、 Systems控制溶胀控制溶胀&侵蚀基质系统侵蚀基质系统Osmotic Pumping Mechanism渗透泵原理渗透泵原理US Pat 3,845,770(1974)by F.Theeuwes and T.Higuchi美国专利3,845,770(1974),F.Theeuwes 和 T.Higuchi所有Precise Rate-Controlled Drug Delivery(Various Temporal Patterns)精确的控制药物释放速度（各种暂时模式）Delivery Rate Independent of pH不依赖PH的释放速度Rate-Controlling Se
37、mipermeable Membrane控制半渗透薄膜速度Cellulose Acetate醋酸纤维素Push Layer(Swellable Hydrophilic Polymers)挤压层（可溶胀亲水性聚合物）Polyethylene Oxide聚氧化乙烯Selected Examples所选实例Procardia XL(Nifedipine;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
38、(Methylphenidate HCl;McNeil)（盐酸哌甲酯；McNeil）Controlled-Release OROS Delivery Systems(Osmotic Pump)控释控释口腔渗透的渗透泵缓释剂（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
39、/或渗透佐剂）Push-Pull Osmotic Pump推-拉渗透泵Constant release rate is maintained by the constant swelling of hydrogel 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
40、三层）Can be adapted for liquid formulations(L-OROS)适用于液体处方（L-OROS）Osmotic Pumping Mechanism:渗透泵原理Release Characteristics释放特征Phenylpropanolamine OROS Tablet1st 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()&体内体内()释放曲线Predicted&Experimental P
41、lasma Concentration Profiles期望期望&试验血浆浓度试验血浆浓度Good and Lee(1984)Membrane Systems-Drug 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.,microsph
42、eres,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/
43、MR Dosage Form Classifications口服口服CR/MR剂型分类剂型分类Oral CR Mechanisms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
44、 Profiles完成的释放曲线First Order(including t dependence)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自二十世纪五十年代以来影响口服控制剂型的主要发展主要发展The emergence of
45、 Physical Pharmacy and Pharmacokinetics as new disciplines 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
46、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 Contro
47、lled 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）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,drug 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 dr
48、ug 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 Prospects未来展望未来展望Challenges in Controlled Release Oral Delivery控释口服释放所面临的挑战Improving Bioavailability of Poorly Soluble Drugs提高难
49、溶药物的生物利用度Prolongation of GI Transit Time延长胃肠道通过时间Delivery of Peptide and Protein Drugs肽类和蛋白药物的释放Approaches to Improve Solubility&Rate of Dissolution提高溶解度提高溶解度&溶出速度的方法溶出速度的方法Particle Size Reduction(surface area)颗粒尺寸降低（表面积增加）Micronization微粉化Nanosized Systems纳米系统Complexation/Solubilization(solubility&s
50、urface area)络和作用/增溶作用（溶解度&表面积）Surfactants/Self-Emulsifying Systems表面活性剂/自身乳化系统Cyclodextrins环糊精Molecular Dispersion in Carriers(solubility&surface area)载体中的分子分散作用（溶解度&表面积）Solid Solutions(Coprecipitates)固溶体（共沉物）Solid Dispersions固态分散体Chemical Modification(solubility)化学修饰（溶解度）Soluble Prodrugs可溶前体药物Solub