1、给药系统设计及分子学基础1（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23USP 28 Sustained release Controlled release Prolonged release Extended release Modified release Delayed release34Drug release profilesDrug concentrationTimeControlled Sustained Common Therapeutic windowTimeDrug concentrationQ:the differences between the
2、se two drug release profiles?Q:point out sustained,controlled,prolonged,extended,modified,delayed,common drug release profiles.Controlled Sustained Common 45Advantages and disadvantagesAdvantages(multi-unit dosage form)Reduce gastrointestinal irritation Reduce the inter-and intra-subject variabiliti
3、es Better reproducible pharmacokinetic behavior Higher patients compliance Disadvantages(single-unit dosage form)All-or-nothing Un-dividable property of the dosage forms56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 Lipo
4、some 纳米粒纳米粒 Nanoparticle 微球微球 Microsphere 生物粘附片生物粘附片Bioadhesive tablets67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 Pulsed7These contractions result in reducing the size of food particles(to l
5、ess than 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
6、 transition 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 floati
7、ng at the 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 d
8、rug delivery (定时定时释放给药系统释放给药系统)89Gastric 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 window
9、Gastric Retention System9Good 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 DefodingEud
10、ragit NE 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 inc
11、ludes intense 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)Lim
12、itation: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.Eudragit RLPOThese contractions result in reducing the size of food particles(to less than 2 mm),which are propelled toward the pylorus in a suspens
13、ion form.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
14、in alkaline mediumAnti-ulcerate（Stomach,duodenal）10111112Migrating 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12Case File SedimentGastric Retention SystemCase File Sediment63(g cm3)Good defoldingIsopropanol:Water(3:1)Case File SedimentProlonged releasePharmaceutical iron powder(X
15、3)Case File Sedimentnon-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 t
16、ransition temperatureModified 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 potenti
17、al 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 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 t
18、he 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.1314 Digestive motility pattern：comprises continuous contractions as in phase II of fasted state.These contractions result in reducing the size of
19、 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 stomach in fasting state is 1.5 to2.0 and in fed state is 2.0 to 6.0.A large volume of water admini
20、stered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0.141515161617Strategies1718Case File Floatation Classification of Floating Drug Delivery Systems(FDDS)Effervescent Floating Dosage Forms Non-effervescent Floating Dosage Forms18191968：漂浮型：漂浮型1974：伸展型：伸展型1980s：膨胀型：膨胀型1980s
21、：粘附型：粘附型胃沉积型胃沉积型Gastric Retention System1920Material Zolpidem tartrate Polyvinyl pyrrolidone K30(PVP K30)Hydroxypropyl methylcellulose E5LV Sodium bicarbonate Eudragit NE 30D Sugar pellets(#2530,ASTM)Empty hard gelatin capsules(Size 0)Case File FloatationModel drugEffervescent agentCoating material2
22、021Eudragit 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2122Property of cast films2223Case File FloatationDrug layered sugar pelletsEffervescent layerModified release layerMethod：Fluidized bed coaterSugar pellets2324SEMEffervescent layerModified release layer24
23、25Case File FloatationFormulationsEffervescent layered pellets50g50g50g50gEudragit NE 30D5%10%15%20%Talc 1g2g4g6gPurified water10g15g30g40g2526Floating studiesEudragit NE 30D coated zolpidem tartarate pellets floating at the surface ofthe test fluid after 10 h.2627Dissolution studyEudragit NE5%10%15
24、%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?2728Stability studiesTemperature of 40 C and a relative humidity of 75%2829Case File SedimentGastric contents have a density cl
25、ose to water(about 1.004 g/cm3).A density close to 2.5 g/cm3 seems necessary for significant prolongation of GRT.29Pharmaceutical 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
26、on surfaceExtended releaseDrugs with narrow Absorption 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:Tw
27、o-layer pushpull 1989:Three-layerDRUGDRUGDRUG3031 Model 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 S
28、ediment3132 MaterialsCase File SedimentPolyethylene oxide(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
29、 tablet Coating material3233Case File SedimentCentral composite design PEO(X1)NaCl(X2)Pharmaceutical iron powder(X3)Coating weight gain of the tablet(X4)4 factor5 level3334SedimentY1 The critical responses were ultimate cumulative release in 12 h Y2 Correlation coefficient of drug release profileCen
30、tral composite design3435PEO(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 Sediment3536PEO(X1)NaCl(X2)Pharmaceutical iron powder(X3)Coating weight gain of the tablet(X4)
31、Y1 Ultimate cumulative release in 12 h Y2 Correlation coefficient of drug release profileCase File Sediment3637PEO(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 Sediment
32、3738Optimized formulationPEO(X1)60-85mgNaCl(X2)30-35mgPharmaceutical iron powder(X3)110-120mgCoating weight gain of the tablet(X4)6.25-7.25%3839Optimized formulationOptimized formulation A:PEO(X1)73mg;NaCl(X2)33mg;Pharmaceutical iron powder(X3)115mg;Coating weight gain of the tablet(X4)7%.39Efferves
33、cent agentTime-specific drug delivery脂质体 LiposomeCremophore RH 40Coating 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 profil
34、esPharmaceutical iron powder(X3)As the phase progresses the intensity and 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(
35、PEO)Mw 1,000,000(WSR N12K)Case File FloatationNaCl(X2)Good defolding40Case 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)4041Case File SedimentOptimized formulation4142Case File SedimentConventional tablet4243 Furose
36、mideBCS 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 4344Marketed formulation Lasix Retard 60mgLimitation:insuffici
37、ent time in the stomach44Optimization FormulationDrug concentrationSugar pelletsCoating 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
38、 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.Effervescent layerDrugs with narrow Absorption windowBioadhesiveHigher patients compliance Good defoldingGastric Retention System
39、PEO(X1)NaCl(X2)Gastric RetentionEudragit RLPOGastric contents have a density close 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 dose
40、30%Maintenance dose70%Bioadhesion&Expansion4546CR LayerIR LayerIn-vitro film defolding study4647CaseCase Poor defoldingGood defolding4748Complete DefodingIn-vitro film defolding studyCaseCase Poor defolding performanceGood defolding performance4849Eudragit RLPOHPMC E4M(Methocel E4M)Carbopol 971P NF
41、CR layer High glass transition temperatureIR layer Polyvinyl alcohol(Gohnesol)Glass transition near room temperatureMechanism:Prolonged Shape Memory4950Solvent&Solubilizer of drugSolvent&Solubilizer of drugSoluphor PCremophore RH 40HPCDPEG 400(Lutrol E400)Polyvinyl alcohol(Gohnesol)Eudragit RLPOHPMC
42、 E4M(Methocel E4M)Carbopol 971P NF Soluphor PCremophore RH 40HPCDCR layer IR layer MaterialsPlasticizerPolymer matrixPolymer matrixBioadhesiveRretard drug release50Prolonged releaseUn-dividable property of the dosage forms脂质体 LiposomeBioadhesion&ExpansionCoating materialCase File Sediment63(g cm3)Su
43、stained ReleasePEO(X1)73mg;NaCl(X2)33mg;Pharmaceutical iron powder(X3)115mg;Erratic absorption,poor bioavailabilityCase File SedimentGastric Retention SystemCase File SedimentProlonged releaseSide effect：Peak diuresis effectMaintenance dose63(g cm3)Poor defoldingCase File SedimentGood defolding perf
44、ormanceTotal:60 mg51Characterization SEMNo crystals on surface Side view IR layer CR layer5152Characterization XRD5253Characterization DSCDrug was uniformly entrapped in the polymeric matrices 220.805354Optimization FormulationIR layerDrug1HPCD1.5PEG 4000.75Ployvinyl alcohol15water100CR layerDrug1HP
45、CD1.5Soluphor P1.75Cremophor RH 401.75Eudragit RLPO5HPMC E4M0.95Carbopol 971P NF0.05Isopropanol:Water(3:1)100In-vitro drug releaseMucoadhesionMechanical performance 54Marketed formulation骨架型制剂 MatrixThese contractions result in reducing the size of food particles(to less than 2 mm),which are propell
46、ed toward the pylorus in a suspension form.Designed formulationCase File SedimentCoating material口服缓释控释制剂的主要类型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 PulsedTh
47、erapeutic windowEffervescent layerGood defoldingPEG 400(Lutrol E400)Modified release layerEffervescent Floating Dosage FormsZolpidem tartrate55Materials Riboflavin-containing collagen sponges Magnesium stearate Hydroxypropylmethylcellulose(HPMC)for controlled tabletsCase file-Expansion 5556Formulati
48、on Riboflavin：25mg Magnesium Stearate 0.08mg Total：256mgExpansion 5657Hydrocolloid tablets for controlFormulation Riboflavin25mgHPMC3.75mgMagnesium stearate0.08mgRiboflavin collagen tabletRiboflavin HPMC tablet57Case File SedimentCoating weight gain of the tablet(X4)给药系统设计及分子学基础Y2 Correlation coeffi
49、cient of drug release profileModified release layerCharacterization SEMThese contractions result in reducing 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
50、NE 30D coated zolpidem tartarate pellets floating at the surface ofPoor defoldingOptimization FormulationMagnesium 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 Defod
