GMP,药品,药学,制药,新药,色谱,药品生产,中药,药材,原料药,医药,中间体,药用辅料

缓释给药系统——药剂学幻灯片

时间: 2010-05-06 21:25:24 作者: admin 来源: 未知 字号:

内容包括

1 Controlled & Sustained-Release Drug Delivery SystemsPharmaceutics Department
China Pharmaceutical University
By JianPing Zhou
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2 Learning ObjectivesTo master the principle of drug release from DDS
To master usual methods to achieve controlled release and their formula design
To understand the? evaluation of the in-vitro & in-vivo of DDS
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3 OutlineDDS development
Introduction to DDS
basic concept, classification, advantage
Mechanism
5 types
Formula design
Common principle
?influencing factors
?formula design
examples
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4 Chapter 1History of DDS Development
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5 "1)Original:wax pellets、suspensions..."1)Original:wax pellets、suspensions etc
2)Development at overseas
3)China
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6 "Nimodipine、Nifedipine、Nitrendipine、Felodipine"Nimodipine、Nifedipine、Nitrendipine、Felodipine;
Diclofenac、Naproxen、Tramadol、Morphine;
Nitroglycerol、Clonidine、Isosorbide Mononitrate;
Ticlopidine Hydrochloridc、Aspirin;
Acopolamine (patch)、Norgestrel (implants)
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7 Chapter 2?
Basic Concept1、Definition
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8 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


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9 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)
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10 Controlled Release vs. Sustained ReleaseSustained release
种类、品种多(约80%)
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
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11 Chapter 2? Basic Concept2、Classification
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12 Types of Drug Delivery Systems1)骨架型( Matrix):Hydro gels、Wax、Insoluble matrixes etc.?? 释药过程flash
2)膜控型(Membrane) :macro-porous 、micro-porous 、semi-permeable membrane etc.
??? 基本结构picture
3)其它(Others):Osmotic pumps、Implanted 、 Impulsive preparations、 Transdermal therapeutic
??? system(TTS)、Self-regulated DDS etc.
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13 膜控型微丸基本结构
14 骨架型片剂释药示意图
15 Chapter 2? Basic Concept3、Characteristics
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16 Theory of DDS
17 Characteristics1)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)。


Quality 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)。
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18 Chapter 3
?????????????? Mechanism5 Types of System
Rate-controlled mechanism
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19 1、 Dissolution ControlledNoyes-Whitney Equation
? Developed by Noyes?? Whitney in 1897
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? If c << cs (i.e.,sink conditions)


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20 →Methods to get extendingAccording Noyes-Whitney Equation


1)Reducing the Cs
2) Reducing the dissolution rate


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21 (1)Reducing the Cs1)Salification
????????????????? 红霉素?????? 红霉素乳糖酸盐(水溶性)
???? 6h(0.2~0.5g/次)???? 8~12h(0.1~0.2g /次)
青霉素-普鲁卡因盐(5h→24h~48h)
N-甲基阿托品鞣酸盐(难溶性)等。
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22 Reducing the Cs2)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,60~90Day。
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23 Reducing the Cs3)Amidation or other chemical
????? modification
头孢菌素——头孢三嗪


属于药物化学研究范畴
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24 (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)
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25 2、Diffusion controlledFick‘s? Diffusion Law :
dM/dt=ADK△C/L



Higuchi Equation:
Q=[DCs(P/λ)(2A-CsP)t]1/2
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26 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
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27 Chirico S., Dalmoro A., Lamberti G., et al.
Analysis and modeling of swelling and
erosion behavior for pure HPMC tablet.
J Control Release, 2007,122(2): 181-188.
28 Methods with Diffusion controlledcoating
microcapsule、microparticle等
Insoluble matrixes *
Increasing viscosity
implant
emulsions
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29 3、Corrosion/Diffusion/ Dissolution Combine Controlled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
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30 Conti S. , Maggi L., Segale L., et al., Matrices containing NaCMC and HPMC 2. Swelling and release mechanism study[J] .In J Pharm,2007,333, 143–151
31 4、Osmotic Pressure Controlled
32 "(1)渗透压动力释药"(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
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33 multichamber osmotic pump


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34 5、ion exchange Controlled树脂+--药物- + X- →树脂+--X- + 药物-



树脂---药物++ Y+→树脂---Y+ +药物+
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35 Chapter 4 Drug & Formula Design
1、Common Choice1)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
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36 "3)剂型选择"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
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37 2、 Influencing Factors1)Physico-chemical property of drugs
A、Solubility(common>0.01mg/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)
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38 1)Physico-chemical property of drugsB、Particle size(indissolvable drug )


???????????????????????????????????? S=W/D×6/d
W、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(1~10μm)
其他因素:多晶型、溶剂化药物等
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39 1)Physico-chemical property of drugsC、Dosage(0.5~1.0g)
D、pKa、degree of dissociation
E、Oil-Water Coefficient of Distribution →1(较佳)
F、Stability(注意胃肠道破坏)
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40 2)Biological FactorA、Biological half-life(评估消除速度)
1h < t1/2<24h
B、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)
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41 3)Physiologic Factor

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 GIT
C、Food influence
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42 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
43 Chapter 3? Quality
Evaluationin vitro and in vivo
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44 "1"??? 1) in-vitro release test
a.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 (24h)
????????????? 释放度:?? 30%??????? 50%??????? >70%
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45 "2)In vivo bioavailability"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
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46 Chapter 4 Example1、Furazolidone sustained-release tablets
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47 [Formulation]Furazolidone?????? 100g
Hexadecadrol????? 70g
HPMC???????????????? 43g
Eudragit?????????????? 40g
SLS???????????????????? QS
MS????????????????????? QS
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48 Chapter 5? Homework1、 Topic? of? disscussion
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49 "题目:Theophylline为治疗支气管哮喘的常用..."
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