给药系统设计及分子学基础-2015课件

1、给药系统设计及分子学基础口服缓控释制剂潘昕中山大学药学院Email：pxin_2中国药典2010年版 缓释制剂：缓慢地非恒速释放，给药频率 控释制剂：缓慢地恒速或接近恒速释放，给药频率 血药浓度平稳美国药典USP28版 不区分缓释、控释 extended-release modified-release3USP 28 Sustained release Controlled release Prolonged release Extended release Modified release Delayed release4Drug release profilesDrug concentra

2、tionTimeControlled Sustained Common Therapeutic windowTimeDrug concentrationQ: the differences between these two drug release profiles?Q: point out sustained, controlled, prolonged, extended, modified, delayed, common drug release profiles.Controlled Sustained Common 5Advantages and disadvantagesAdv

3、antages (multi-unit dosage form)Reduce gastrointestinal irritationReduce the inter- and intra-subject variabilities Better reproducible pharmacokinetic behaviorHigher patients compliance Disadvantages (single-unit dosage form)All-or-nothingUn-dividable property of the dosage forms7口服缓释控释制剂的主要类型1. 骨架

4、型制剂 Matrix 2. 膜控型制剂 Reservoir / Coating3. 渗透泵制剂 Osmotic pump4. 胃内滞留型制剂 Gastric retention 5. 脉冲给药系统 Pulsed8口服缓释控释制剂的主要类型Rate-specific drug delivery (定速释放给药系统)Site-specific drug delivery (定位释放给药系统) Time-specific drug delivery (定时释放给药系统)10Gastric Retention SystemOral stomach-retained drug delivery syst

5、emAppropriate model drug：Narrow absorption window Incomplete release from the drug delivery system above the absorption zoneInstability in alkaline mediumAnti-ulcerate （Stomach, duodenal ）1112Migrating myloelectric cycle (MMC)静止阶段间歇性蠕动强烈突发性收缩过渡阶段14Digestive motility pattern： comprises continuous con

6、tractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to less than 2 mm), which are propelled toward the pylorus in a suspension form. During the fed state onset of MMC is delayed resulting in slowdown of gastric emptying rate.The pH of the stoma

7、ch in fasting state is 1.5 to2.0 and in fed state is 2.0 to 6.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0. 1517Strategies18Case File Floatation Classification of Floating Drug Delivery Systems (FDDS)Effervescent Floating Dosage For

8、msNon-effervescent Floating Dosage Forms191968：漂浮型1974：伸展型1980s：膨胀型1980s：粘附型胃沉积型Gastric Retention System20MaterialZolpidem tartrate Polyvinyl pyrrolidone K30 (PVP K30) Hydroxypropyl methylcellulose E5LVSodium bicarbonateEudragit NE 30D Sugar pellets (# 2530, ASTM) Empty hard gelatin capsules (Size 0

9、)Case File FloatationModel drugEffervescent agentCoating material21Eudragit NE 30DEudragit L 30D-55Talc (GMS)TECTween-80Preparation of cast filmsr机械性能透湿性22Property of cast films24SEMEffervescent layerModified release layer25Case File Floatation27Dissolution studyEudragit NE5 %10 %15 %20 %Q1: With th

10、e increasing of Eudragit NE 30D, drug release rate will increase/decrease?Q2: With the increasing of effervescent agent, drug release rate will increase/decrease? 28Stability studiesTemperature of 40 C and a relative humidity of 75%29Case File SedimentGastric contents have a density close to water (

11、about 1.004 g/cm3).A density close to 2.5 g/cm3 seems necessary for significant prolongation of GRT.30Case File SedimentOsmotic pump tablet1975: Elementary osmotic pump1982: Two-layer pushpull1989: Three-layerDRUGDRUGDRUGDRUGDRUGDRUG31Model drug: Famotidine (FMTD) 法莫替丁 prolonged antisecretory effect

12、 in the therapy of duodenal, gastric, and peptic ulcer low solubility 25 g/ml relatively short elimination half-life time (about 3 h) in humans as well as low bioavailability(4550%) Case File Sediment32MaterialsCase File SedimentPolyethylene oxide (PEO) Mw 1,000,000 (WSR N12K)Pharmaceutical iron pow

13、der (100 mesh)NaClCellulose acetate (CA)Acetone Polyethylene glycol 4000 (PEG 4000)Technetium-99m (99mTcO4)Commercially available FMTD conventional tabletsHigh density gastric resident osmotic pump tablet Coating material33Case File SedimentCentral composite design PEO (X1) NaCl (X2) Pharmaceutical

14、iron powder (X3) Coating weight gain of the tablet (X4)4 factor5 level34SedimentY1 The critical responses were ultimate cumulative release in 12 h Y2 Correlation coefficient of drug release profileCentral composite design35PEO (X1) NaCl (X2) Pharmaceutical iron powder (X3)Coating weight gain of the

15、tablet (X4)Y1 Ultimate cumulative release in 12 h Y2 Correlation coefficient of drug release profileCase File Sediment36PEO (X1) NaCl (X2) Pharmaceutical iron powder (X3)Coating weight gain of the tablet (X4)Y1 Ultimate cumulative release in 12 h Y2 Correlation coefficient of drug release profileCas

16、e File Sediment37PEO (X1) NaCl (X2) Pharmaceutical iron powder (X3)Coating weight gain of the tablet (X4)Y1 Ultimate cumulative release in 12 h Y2 Correlation coefficient of drug release profileCase File Sediment38Optimized formulation39Optimized formulationOptimized formulation A:PEO (X1) 73mg; NaC

17、l (X2) 33mg; Pharmaceutical iron powder (X3) 115mg;Coating weight gain of the tablet (X4) 7%.40Case File SedimentOptimized formulationConventional tabletV= 3.1420.352 0.2 = 0.077 cm3 Density=M/V = (40 + 73 + 33 + 115)(1 + 7%)/0.077 = 3.63 (g cm3) 41Case File SedimentOptimized formulation42Case File

18、SedimentConventional tablet43 FurosemideBCS IVpKa 3.9Half life less than 2 hSolubility pH dependentSide effect：Peak diuresis effectMajor absorption site ：upper gastrointestinal tract Erratic absorption, poor bioavailability 3-4 times a day，non-complianceCase File Bioadhesion 44Marketed formulation L

19、asix Retard 60mgLimitation : insufficient time in the stomach45CR LayerIR LayerDesigned formulationTotal: 60 mg Loading dose30% Maintenance dose70%Bioadhesion & Expansion46CR LayerIR LayerIn-vitro film defolding study47CaseCase Poor defoldingGood defolding48Complete DefodingIn-vitro film defolding s

20、tudyCaseCase Poor defolding performanceGood defolding performance49Eudragit RLPOHPMC E4M (Methocel E4M)Carbopol 971P NF CR layer High glass transition temperatureIR layer Polyvinyl alcohol (Gohnesol) Glass transition near room temperatureMechanism:Prolonged Shape Memory50Solvent & Solubilizer of dru

21、gSolvent & Solubilizer of drugSoluphor PCremophore RH 40HPCDPEG 400 (Lutrol E400) Polyvinyl alcohol(Gohnesol)Eudragit RLPOHPMC E4M (Methocel E4M)Carbopol 971P NF Soluphor PCremophore RH 40HPCDCR layer IR layer MaterialsPlasticizerPolymer matrixPolymer matrixBioadhesiveRretard drug release51Characterization SEMNo crystals on surface Side view IR layer CR layer52Characterization X