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1、Controlled&Sustained-Release Drug Delivery Systems,Pharmaceutics Department China Pharmaceutical University,Learning Objectives,To master the principle of drug release from DDSTo master usual methods to achieve controlled release and their formula designTo understand the evaluation of the in-vitro&i
2、n-vivo of DDS,Outline,DDS development Introduction to DDSbasic concept,classification,advantageMechanism5 typesFormula designCommon principle influencing factors formula designexamples,Chapter 1,History of DDS Development,1）Original：wax pellets、suspensions etc2）Development at overseas3）China,蜡丸是最早的缓
3、释制剂，其作用缓和而持久,研 制：1950s上 市：1970s规模生产：1980s目 前：口服200余种，不同规格余的商品计有400种,80年代初开始已有近百种制剂获国家新药证书,Nimodipine、Nifedipine、Nitrendipine、Felodipine;Diclofenac、Naproxen、Tramadol、Morphine;Nitroglycerol、Clonidine、Isosorbide Mononitrate;Ticlopidine Hydrochloridc、Aspirin;Acopolamine(patch)、Norgestrel(implants),国内部分上
4、市品种,Chapter 2 Basic Concept,1、Definition,Sustained-release preparation,缓释制剂较长时间内持续释药sustained-release,extended-release,prolonged action,repeat-action,retarded preparations,Controlled-release preparation,控释制剂以恒定速度药（狭义）。广义：速度、时间、方向（部位）,Controlled Release vs.Sustained Release,Sustained release种类、品种多（约8
5、0%）处方工艺简单易于工业化大生产,Controlled release种类、品种较少处方工艺较复杂质量标准要求高,Chapter 2 Basic Concept,2、Classification,Types of Drug Delivery Systems,1）骨架型（Matrix）：Hydro gels、Wax、Insoluble matrixes etc.释药过程flash2）膜控型（Membrane）：macro-porous、micro-porous、semi-permeable membrane etc.基本结构picture3）其它（Others）：Osmotic pumps、I
6、mplanted、Impulsive preparations、Transdermal therapeutic system（TTS）、Self-regulated DDS etc.,膜控型微丸基本结构,聚合物缓释包衣层,药物层,色衣层,基丸,骨架型片剂释药示意图,Chapter 2 Basic Concept,3、Characteristics,Theory of DDS,1）Safe：血浓平稳，避免峰谷现象，降低毒副作用；2）Effect：降低胃肠道刺激，提高生物利用度，减少给药总剂量；3）Convenience：延长给药间隔，减少服药频率，提高服药依从性（Compliance）。Qual
7、ity control：成本较高，制造过程复杂，大生产易出现质量问题（特别是膜控型）。,Characteristics,Chapter 3 Mechanism,5 Types of System Rate-controlled mechanism,NoyesWhitney Equation Developed by Noyes Whitney in 1897 If c cs(i.e.,sink conditions),1、Dissolution Controlled,Methods to get extending,According NoyesWhitney Equation1）Reduci
8、ng the Cs2）Reducing the dissolution rate,1）Salification 红霉素 红霉素乳糖酸盐（水溶性）6h（0.20.5g/次）812h（0.10.2g/次）青霉素-普鲁卡因盐（5h24h48h）N-甲基阿托品鞣酸盐（难溶性）等。,（1）Reducing the Cs,Reducing the Cs,2）Esterification 1）醇类药物的酯化，如：雌二醇的苯甲酸酯等。2）核黄素月桂酸酯，6090Day。,Reducing the Cs,3）Amidation or other chemical modification头孢菌素头孢三嗪属于药物
9、化学研究范畴,（2）Reducing the dissolution rate,减少溶出速度1.控制粒子大小（胰岛素等）2.将药物包埋在溶蚀性骨架中（脂肪、蜡类物质等）3.将药物包埋在亲水凝胶骨架中（HPMC、MC等亲水性高分子材料）,2、Diffusion controlled,Ficks Diffusion Law：dM/dt=ADKC/LHiguchi Equation：QDCs(P/)(2A-CsP)t1/2,Diffusion controlled,释药受扩散速率控制1、水不溶性包衣膜：2、含水性孔道的包衣膜3、骨架型药物扩散,Chirico S.,Dalmoro A.,Lamber
10、ti G.,et al.Analysis and modeling of swelling and erosion behavior for pure HPMC tablet.J Control Release,2007,122(2):181-188.,Methods with Diffusion controlled,coating microcapsule、microparticle等Insoluble matrixes*Increasing viscosity implant emulsions,3、Corrosion/Diffusion/Dissolution Combine Cont
11、rolled,混合型生物溶蚀系统 亲水凝胶骨架系统 膨胀控释骨架系统,Conti S.,Maggi L.,Segale L.,et al.,Matrices containing NaCMC and HPMC 2.Swelling and release mechanism studyJ.In J Pharm,2007,333,143151,4、Osmotic Pressure Controlled,（1）渗透压动力释药（2）恒速释药促渗剂：乳糖、果糖、葡萄糖、甘露糖等推进剂：聚羟甲基丙烯酸烷基酯、PVP等,Elementary osmotic pump,multichamber osmoti
12、c pump,Two-compartment OP with two drug chambers,Two-chamber OP with expanding compartment,Verma RK,Krishna DM,Garg S.Formulation aspects in the development of osmotically controlled oral drug delivery systemsJ J Control Release,2002,79(1-3):7-27,5、ion exchange Controlled,树脂+-药物-X-树脂+-X-药物-树脂-药物+Y+树
13、脂-Y+药物+,Chapter 4 Drug&Formula Design1、Common Choice,1）药物一般选择原则：1）给药剂量2）水溶性、pKa、分配系数3）稳定性2）药物的剂量设计：一般情况：缓控释制剂总剂量=普通剂量缓释间隔/普通间隔,3）剂型选择：根据临床评价，血浓波动、个体差异、治疗效果等：1）骨架型包衣型（渗透泵除外）；2）高聚物骨架脂肪骨架；3）贴剂时滞长，植入“突释”严重。4）处方和工艺设计药物特性剂型处方制备工艺质量控制,2、Influencing Factors,1）Physico-chemical property of drugsA、Solubility（c
14、ommon0.01mg/ml）一般：溶解度愈小，溶出、吸收愈慢，起效愈慢，疗效愈差（生物利用度愈低）。若溶解度太小，应首先增加其溶出速度（微粉化、固体分散体、包合物等）,B、Particle size（indissolvable drug）S=W/D6/dW、D分别为药物质量、密度，d为粒径故：极微溶解的固体药物常微粉化（110m）其他因素：多晶型、溶剂化药物等,1）Physico-chemical property of drugs,C、Dosage（0.51.0g）D、pKa、degree of dissociationE、Oil-Water Coefficient of Distribu
15、tion 1（较佳）F、Stability（注意胃肠道破坏）,1）Physico-chemical property of drugs,2）Biological Factor,A、Biological half-life（评估消除速度）1h t1/224hB、Absorption全胃肠道吸收药物主动吸收药物C、Metabolism胃肠道首过效应生物利用度（增加剂量）,A、Gastric emptying对被动吸收药物：胃蠕动胃排空吸收（一般）；对主动吸收药物：胃蠕动胃排空吸收B、Breakdown in the GITC、Food influence,3）Physiologic Factor,
16、Michel MC,Korstanje C,Krauwinkel W,et al.The pharmacokinetic profile of tamsulosin oral controlled absorption system(OCAS)J.Eur Urol Suppl,2005,4(2):15 241,Chapter 3 QualityEvaluation,in vitro and in vivo,1）in-vitro release testa.试验测定方法b.释放介质及pH水性缓冲液0.5%SLS水溶液混合溶剂（慎用）c.取样点和释放标准 3点：2 4 8h(12h)2 6 12h
17、(24h)释放度：30%50%70%,2）In vivo bioavailability参比制剂：同类公认高质量制剂试验方案：随机交叉（双盲）、单剂量和多剂量3）in vitro-in vivo correlations线、点或参数相关,Chapter 4 Example,1、Furazolidone sustained-release tablets,Formulation,Furazolidone 100gHexadecadrol 70gHPMC 43gEudragit 40gSLS QSMS QS,Chapter 5 Homework,1、Topic of disscussion,题目：Theophylline为治疗支气管哮喘的常用药物，设计符合其特点的定时释药系统。背景：哮喘具有时辰药理学特点，定时释药系统可根据生理和治疗需要定时定量释药，既可降低毒副作用，又可达到最佳疗效Theophylline理化性质：微溶于冷水、乙醇，稍溶于热水，易溶于酸和碱溶液。设计要求：处方及工艺设计；详细阐述其设计要点、质量评价和工业生产中可能存在的问题。,END!,
