给药系统相关设计与分子学基础

1、给药系统相关设计与分子学基础2中国药典中国药典2010 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美国药典USP28版版 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 concentrationTimeControlled

2、 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 disadvantagesAdvantages (multi-uni

3、t dosage form) Reduce gastrointestinal irritation Reduce the inter- and intra-subject variabilities Better reproducible pharmacokinetic behavior Higher patients compliance Disadvantages (single-unit dosage form) All-or-nothing Un-dividable property of the dosage forms6口服缓释控释制剂的主要类型口服缓释控释制剂的主要类型 片剂片剂

4、 Tablet 微丸微丸 Capsule 混悬剂混悬剂 Suspension 胃漂浮片胃漂浮片 Floating/ buoyant tablets 乳剂乳剂 Emulsion 脂质体脂质体 Liposome 纳米粒纳米粒 Nanoparticle 微球微球 Microsphere 生物粘附片生物粘附片Bioadhesive tablets7口服缓释控释制剂的主要类型口服缓释控释制剂的主要类型1. 骨架型制剂骨架型制剂 Matrix 2. 膜控型制剂膜控型制剂 Reservoir / Coating3. 渗透泵制剂渗透泵制剂 Osmotic pump4. 胃内滞留型制剂胃内滞留型制剂 Gastr

5、ic retention 5. 脉冲给药系统脉冲给药系统 Pulsed8口服缓释控释制剂的主要类型口服缓释控释制剂的主要类型 Rate-specific drug delivery ( (定速定速释放给药系统释放给药系统) ) Site-specific drug delivery ( (定位定位释放给药系统释放给药系统) ) Time-specific drug delivery ( (定时定时释放给药系统释放给药系统) )9Gastric Retention System is retained in the stomach for a number of hours, while it

6、continuously releases the incorporated drug at a controlled rate to absorption sites in the upper intestinal tract.Sustained ReleaseGastric RetentionDrugs with narrow Absorption windowGastric Retention System10Gastric Retention System Oral stomach-retained drug delivery system Appropriate model drug

7、：Narrow absorption window Incomplete release from the drug delivery system above the absorption zoneInstability in alkaline mediumAnti-ulcerate （Stomach, duodenal ）1112Migrating myloelectric cycle (MMC)静止阶段静止阶段间歇性蠕动间歇性蠕动强烈强烈突发性突发性收缩收缩过渡过渡阶段阶段13Migrating myloelectric cycle (MMC) Phase I (basal phase)

8、 lasts from 40 to 60 minutes with rare contractions. Phase II (preburst phase) lasts for 30 to 45 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually. Phase III (burst phase) lasts for 5 to 15 minutes. It includes

9、intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave. Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2 consecutive cycles.

10、14 Digestive motility pattern： comprises continuous contractions 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 i

11、n slowdown of gastric emptying rate. The pH of the stomach 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. 151617Strategies18Case File Floatation Classification of Floating Dr

12、ug Delivery Systems (FDDS) Effervescent Floating Dosage Forms Non-effervescent Floating Dosage Forms191968：漂浮型：漂浮型1974：伸展型：伸展型1980s：膨胀型：膨胀型1980s：粘附型：粘附型胃沉积型胃沉积型Gastric Retention System20MaterialZolpidem tartrate Polyvinyl pyrrolidone K30 (PVP K30) Hydroxypropyl methylcellulose E5LVSodium bicarbonate

13、Eudragit NE 30D Sugar pellets (# 2530, ASTM) Empty hard gelatin capsules (Size 0)Case File FloatationModel drugEffervescent agentCoating material21Eudragit NE 30DEudragit L 30D-55Talc (GMS)TECTween-80Preparation of cast filmsr机械性能机械性能透湿性透湿性22Property of cast films23Case File FloatationDrug layered s

14、ugar pelletsEffervescent layerModified release layerMethod ：Fluidized bed coaterSugar pellets24SEMEffervescent layerModified release layer25Case File Floatation26Floating studiesEudragit NE 30D coated zolpidem tartarate pellets floating at the surface ofthe test fluid after 10 h.27Dissolution studyE

15、udragit NE5 %10 %15 %20 %Q1: With the 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 cont

16、ents have a density close to water (about 1.004 g/cm3).A density close to 2.5 g/cm3 seems necessary for significant prolongation of GRT.30Case File SedimentOsmotic pump tablet 1975: Elementary osmotic pump 1982: Two-layer pushpull 1989: Three-layerDRUGDRUGDRUG31 Model drug: Famotidine (FMTD) 法莫替丁 pr

17、olonged antisecretory effect 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 Sediment32 MaterialsCase File SedimentPolyethylene oxide (PEO) Mw 1,000,000 (WSR

18、 N12K)Pharmaceutical iron powder (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 (

19、X1) NaCl (X2) Pharmaceutical 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 (X

20、3)Coating weight gain of the 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 coefficie

21、nt of drug release profileCase 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 for

22、mulation A:PEO (X1) 73mg; NaCl (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 SedimentOpti

23、mized formulation42Case File 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 Bioadhe

24、sion 44Marketed formulation Lasix 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

25、DefodingIn-vitro film defolding studyCaseCase 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 drugSolvent & Solubilizer of drugSoluphor PCremophore RH 40HPCDPEG 400 (Lutrol E400) Polyvinyl alcohol(Gohnesol)Eudragit RLPOHPMC E4M (Methocel E4M)Carbopol 971