1、给药系统设计及分子学基础（优选）给药系统设计及分子学（优选）给药系统设计及分子学基础基础3USP 28 Sustained release Controlled release Prolonged release Extended release Modified release Delayed release4Drug release profilesDrug concentrationTimeControlled Sustained Common Therapeutic windowTimeDrug concentrationQ:the differences between these
2、two drug release profiles?Q:point out sustained,controlled,prolonged,extended,modified,delayed,common drug release profiles.Controlled Sustained Common 5Advantages and disadvantagesAdvantages(multi-unit dosage form)Reduce gastrointestinal irritation Reduce the inter-and intra-subject variabilities B
3、etter 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 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
4、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 Gastric retention 5.脉冲给药系统脉冲给药系统 PulsedThese contractions result in reducing the size of food particles(to less tha
5、n 2 mm),which are propelled toward the pylorus in a suspension form.Coating weight gain of the tablet(X4)Gastric Retention SystemDrug concentrationCase File Sedimentfor controlled tabletsReduce gastrointestinal irritationCarbopol 971P NF Soluphor PCase File FloatationMarketed formulationGlass transi
6、tion near room temperaturePhase II(preburst phase)lasts for 30 to 45 minutes with intermittent action potential and contractions.Cremophore RH 40Digestive motility pattern：comprises continuous contractions as in phase II of fasted state.Eudragit NE 30D coated zolpidem tartarate pellets floating at t
7、he surface of口服缓释控释制剂的主要类型upper gastrointestinal tractCase File SedimentQ2:With the increasing of effervescent agent,drug release rate will increase/decrease?8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 del
8、ivery (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 continuously releases the incorporated drug at a controlled rate to absorption sites in the upper intestinal tract.Sustained ReleaseGastric RetentionDrugs with narrow Absorption windowGastric
9、Retention SystemGood defolding performanceCase File Sediment生物粘附片Bioadhesive tabletsEudragit RLPODigestive motility pattern：comprises continuous contractions as in phase II of fasted state.Case File Floatation给药系统设计及分子学基础Y2 Correlation coefficient of drug release profileComplete DefodingEudragit NE
10、30DIt is due to this wave that all the undigested material is swept out of the stomach down to the small intestine.Case File SedimentEudragit NE 30DPEO(X1)NaCl(X2)ControlledPoor defolding performanceQ2:With the increasing of effervescent agent,drug release rate will increase/decrease?It includes int
11、ense and regular contractions for short period.Optimized formulationAppropriate model drug：脂质体 LiposomeY1 Ultimate cumulative release in 12 hGastric Retention SystemGood defoldingPEO(X1)NaCl(X2)Rate-specific drug delivery口服缓释控释制剂的主要类型Case File SedimentPharmaceutical iron powder(100 mesh)Limitation:T
12、hese contractions result in reducing the size of food particles(to less than 2 mm),which are propelled toward the pylorus in a suspension form.Eudragit RLPOThese contractions result in reducing the size of food particles(to less than 2 mm),which are propelled toward the pylorus in a suspension form.
13、Case File FloatationGood defoldingDelayed releaseDesigned formulationCase File Sediment10Gastric Retention System Oral stomach-retained drug delivery system Appropriate model drug：Narrow absorption window Incomplete release from the drug delivery system above the absorption zoneInstability in alkali
14、ne 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Case File SedimentGastric Retention SystemCase File Sediment63(g cm3)Good defoldingIsopropanol:Water(3:1)Case File SedimentProlonged releasePharmaceutical iron powder(X3)Case File Sed
15、imentnon-complianceY2 Correlation coefficient of drug release profileFamotidine(FMTD)Reduce the inter-and intra-subject variabilitiesMagnesium stearateRretard drug releaseupper gastrointestinal tractThe critical responses were ultimate cumulative release in 12 hEudragit NEHigh glass transition tempe
16、ratureModified release layerCorrelation coefficient of drug release profileCase File Bioadhesion13Migrating myloelectric cycle(MMC)Phase I(basal phase)lasts from 40 to 60 minutes with rare contractions.Phase II(preburst phase)lasts for 30 to 45 minutes with intermittent action potential and contract
17、ions.As the phase progresses the intensity and frequency also increases gradually.Phase III(burst phase)lasts for 5 to 15 minutes.It includes 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 intest
18、ine.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.14 Digestive motility pattern：comprises continuous contractions as in phase II of fasted state.These contractions result in reducing the size of food particles(t
19、o 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 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 or
20、al dosage form raises the pH of stomach contents to 6.0 to 9.0.151617Strategies18Case File Floatation Classification of Floating Drug 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 Ret
21、ention System20MaterialZolpidem tartrate Polyvinyl pyrrolidone K30(PVP K30)Hydroxypropyl methylcellulose E5LVSodium bicarbonateEudragit NE 30D Sugar pellets(#2530,ASTM)Empty hard gelatin capsules(Size 0)Case File FloatationModel drugEffervescent agentCoating material21Eudragit NE 30DEudragit L 30D-5
22、5Talc(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 sugar pelletsEffervescent layerModified release layerMethod：Fluidized bed coaterSugar pellets24SEMEffervescent layerModified release layer25Case File FloatationFormulationsEfferves
23、cent layered pellets50g50g50g50gEudragit NE 30D5%10%15%20%Talc 1g2g4g6gPurified water10g15g30g40g26Floating studiesEudragit NE 30D coated zolpidem tartarate pellets floating at the surface ofthe test fluid after 10 h.27Dissolution studyEudragit NE5%10%15%20%Q1:With the increasing of Eudragit NE 30D,
24、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(about 1.004 g/cm3).A density close to
25、 2.5 g/cm3 seems necessary for significant prolongation of GRT.Pharmaceutical iron powder(X3)Characterization DSC给药系统设计及分子学基础PEO(X1)NaCl(X2)Effervescent layerCase File SedimentMagnesium stearateGastric Retention SystemDrug concentrationNo crystals on surfaceExtended releaseDrugs with narrow Absorpti
26、on windowRiboflavin HPMC tabletErratic absorption,poor bioavailabilityNarrow absorption windowNarrow absorption windowSustained ReleaseCoating weight gain of the tablet(X4)30Case File SedimentOsmotic pump tablet 1975:Elementary osmotic pump 1982:Two-layer pushpull 1989:Three-layerDRUGDRUGDRUG31 Mode
27、l drug:Famotidine(FMTD)法莫替丁 prolonged 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 oxid
28、e(PEO)Mw 1,000,000(WSR 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 comp
29、osite design PEO(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 po
30、wder(X3)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 coefficien
31、t 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 formulationPEO(X1)60-85mgNaCl(X2)30-35mgPharmaceutical
32、 iron powder(X3)110-120mgCoating weight gain of the tablet(X4)6.25-7.25%39Optimized formulationOptimized formulation A:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceutical iron powder(X3)115mg;Coating weight gain of the tablet(X4)7%.Effervescent agentTime-specific drug delivery脂质体 LiposomeCremophore RH 40Coating
33、 weight gain of the tablet(X4)prolonged antisecretory effect in the therapy of duodenal,gastric,and peptic ulcerEudragit NE 30D coated zolpidem tartarate pellets floating at the surface ofOptimized formulationDrug release profilesPharmaceutical iron powder(X3)As the phase progresses the intensity an
34、d frequency also increases gradually.脂质体 LiposomeThese contractions result in reducing the size of food particles(to less than 2 mm),which are propelled toward the pylorus in a suspension form.Coating materialPolyethylene oxide(PEO)Mw 1,000,000(WSR N12K)Case File FloatationNaCl(X2)Good defolding40Ca
35、se 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 SedimentConventional tablet43 FurosemideBCS IVpKa 3.9Half life less than 2 hSolubility pH dependentSide effect：Pea
36、k diuresis effectMajor absorption site：upper gastrointestinal tract Erratic absorption,poor bioavailability 3-4 times a day，non-complianceCase File Bioadhesion 44Marketed formulation Lasix Retard 60mgLimitation:insufficient time in the stomachOptimization FormulationDrug concentrationSugar pelletsCo
37、ating weight gain of the tablet(X4)Polyethylene oxide(PEO)Mw 1,000,000(WSR N12K)Reduce gastrointestinal irritationAs the phase progresses the intensity and frequency also increases gradually.Gastric Retention System is retained in the stomach for a number of hours,while it continuously releases the
38、incorporated drug at a controlled rate to absorption sites in the upper intestinal tract.Effervescent layerDrugs with narrow Absorption windowBioadhesiveHigher patients compliance Good defoldingGastric Retention SystemPEO(X1)NaCl(X2)Gastric RetentionEudragit RLPOGastric contents have a density close
39、 to water(about 1.Coating weight gain of the tablet(X4)Bioadhesion&ExpansionThe critical responses were ultimate cumulative release in 12 hSustained Release45CR LayerIR LayerDesigned formulationTotal:60 mg Loading dose30%Maintenance dose70%Bioadhesion&Expansion46CR LayerIR LayerIn-vitro film defoldi
40、ng study47CaseCase Poor defoldingGood defolding48Complete 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 transi
41、tion 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 971P NF Soluphor PCremophore RH 40HPCDCR layer IR layer Materials
42、PlasticizerPolymer matrixPolymer matrixBioadhesiveRretard drug releaseProlonged releaseUn-dividable property of the dosage forms脂质体 LiposomeBioadhesion&ExpansionCoating materialCase File Sediment63(g cm3)Sustained ReleasePEO(X1)73mg;NaCl(X2)33mg;Pharmaceutical iron powder(X3)115mg;Erratic absorption
43、,poor bioavailabilityCase File SedimentGastric Retention SystemCase File SedimentProlonged releaseSide effect：Peak diuresis effectMaintenance dose63(g cm3)Poor defoldingCase File SedimentGood defolding performanceTotal:60 mg51Characterization SEMNo crystals on surface Side view IR layer CR layer52Ch
44、aracterization XRD53Characterization DSCDrug was uniformly entrapped in the polymeric matrices 220.8054Optimization FormulationIR layerDrug1HPCD1.5PEG 4000.75Ployvinyl alcohol15water100CR layerDrug1HPCD1.5Soluphor P1.75Cremophor RH 401.75Eudragit RLPO5HPMC E4M0.95Carbopol 971P NF0.05Isopropanol:Wate
45、r(3:1)100In-vitro drug releaseMucoadhesionMechanical performance Marketed formulation骨架型制剂 MatrixThese contractions result in reducing the size of food particles(to less than 2 mm),which are propelled toward the pylorus in a suspension form.Designed formulationCase File SedimentCoating material口服缓释控
46、释制剂的主要类型Disadvantages(single-unit dosage form)Higher patients compliance Drug concentration（优选）给药系统设计及分子学基础脂质体 LiposomeY2 Correlation coefficient of drug release profilePurified water脉冲给药系统 PulsedTherapeutic windowEffervescent layerGood defoldingPEG 400(Lutrol E400)Modified release layerEffervescent
47、 Floating Dosage FormsZolpidem tartrate55Materials Riboflavin-containing collagen sponges Magnesium stearate Hydroxypropylmethylcellulose(HPMC)for controlled tabletsCase file-Expansion 56Formulation Riboflavin：25mg Magnesium Stearate 0.08mg Total：256mgExpansion 57Hydrocolloid tablets for controlForm
48、ulation Riboflavin25mgHPMC3.75mgMagnesium stearate0.08mgRiboflavin collagen tabletRiboflavin HPMC tabletCase File SedimentCoating weight gain of the tablet(X4)给药系统设计及分子学基础Y2 Correlation coefficient of drug release profileModified release layerCharacterization SEMThese contractions result in reducing
49、 the size of food particles(to less than 2 mm),which are propelled toward the pylorus in a suspension form.Optimized formulationGastric contents have a density close to water(about 1.Eudragit NE 30D coated zolpidem tartarate pellets floating at the surface ofPoor defoldingOptimization FormulationMag
50、nesium stearate3-4 times a day，63(g cm3)Solvent&Solubilizer of drugTotal：256mg口服缓释控释制剂的主要类型Reduce gastrointestinal irritationPolyvinyl pyrrolidone K30(PVP K30)Conventional tabletComplete DefodingOral stomach-retained drug delivery systemDuring the fed state onset of MMC is delayed resulting in slowd
