四、肺部吸入给药系统ppt课件

1、l优点：面积优点：面积, 上皮细胞间隙，肺泡、血管和淋上皮细胞间隙，肺泡、血管和淋 l 巴管，血流速度，无首过破坏、无促巴管，血流速度，无首过破坏、无促 l 进剂系统进剂系统l l限制和要求：沉着部位及重现性、长期毒性限制和要求：沉着部位及重现性、长期毒性l1955, Metered-does inhaler ( MDI ) ldeveloped by George Maisonl1956 marketed , FDA approvallMay ,1974, Sugarloaf conference lmilestone in the clinical use of aerosolized d

2、rug therapyl1980s-1990s, development and delivery of drug formulationladditional device , oropharyngeal lossldry powder inhalerl2000 lNon-CFC propellantlmedications other than pulmonary diseaseInhalation for airway diseasewLungwTotal surface 80 M2wMajor contact between body & environmentwHost de

3、fense mechanism has evolved to cope with noxious inhaled substanceswA few key processes in asthma pathogenesis are surface processesBenefits of inhalation route for airway diseasewLung has more potential surface area for molecular exchange with blood & rapid absorptionwAction viawabsorption thro

4、ugh wtracheobronchial mucosawlung parenchymal (alveolar-capillary) wtopically react with receptor in airwaywbothlMacromolecules lairway surface ( 3.0 M2 )lnearly impermeablellung periphery ( alveoli , 80-100 M2 )ldo permeateComparison of therapeutic ratio IV Oral Inhaledunits available 100 50 10to e

5、xert effectreaching target tissue 2 1 1reaching other tissues 98 49 9therapeutic ratio 1/49 1/49 1/9( effective drug / drugacting at other tissue )lEfficiently deliver to the lung peripherylReproducible therapeutic drug dose lAccommodate flexible dosinglStable formulation at room Temp. lDevice must

6、be portable and easy to uselAt least 5 companieslAeroGen lAlkermeslAradigm corporation lDura pharmaceuticalslInhale Therapeutic SystemslAventis Beringl-1 proteinase inhibitor for emphysemalBiogenlAVONEX ( IFN-1a) for MSlPfizer , Aventis Pharma linhalable insulinlPain lPanic and anxietylAnaphylaxislC

7、ardiac arrhythmialOther CV conditionslDiarrhealNausea and vomitinglNicotine withdrawallUrinary incontinencelSpasmlInsomnialInsulinlGrowth hormonelAnti-obesity peptideslPTHlOsteoporosis peptidelDiabetes peptideslHuman calcitoninlInterferonslSomatostatinlLHRH analogslVaccineslAntibioticslILs and antag

8、onistslImmune suppression peptideslNerve growth factors lCSFlEPOlFactor IXl1-proteinase inhibitorlAsthma lsteroidlbronchodilatorslcromolynlInfluenza , RSVlRibavirinlPneumocystislpentamidinelFungal infectionlamphotericinlCystic fibrosislantibioticslDynaselImmunizationlvaccineslSarcoidosislsteroidlDMl

9、insulinlDepends lHow far the aerosol will penetrate in tracheobronchial treelHow much will be deposited in tracheobronchial treeFlow RateIndependentElectrical/MechanicalInterfaceMulti-doseDPIsSingle-doseDPIsDoseIndicatorsBreathActuationPress and Breath MDIsNebulizersAqueousNasal PumpSprayNovelFormul

10、ationsControlledReleaseNovelFormulationsSpacersNasal MDIsPocketNebulizersSpray ForceControlUnit DoseIncreasedEfficiencyInhalationDrug DeliveryContinuousChoosing a Pulmonary Delivery SystemlPhysical properties of the drug substancelParticle size, density, shape, static electricity etc.lThe required a

11、erodynamic size range is 0.5 - 5 mlDelivery devicelDose delivery and aerosolisation efficacylPatient inspiration profilelPeak flow rate, time to peak and total volume l(Pato)physiology of the respiratory tractlParticle size , characteristicsl0.5-5 um , uniform lAerosol producing ( delivery ) system

12、lslow-moving fine particulate cloud leasy to uselInhalation patternl lamina flow is better lDegree of airway narrowinglDefinition :lSuspension of very fine particles of liquid or solid in a gas lvary in shape , density , or sizelheterodisperse or monodisperse lImpaction ( 5 m)lresult from inertialde

13、position when they collide with a surfacelSedimentation (1-5 m)ldue to gravityloccurs when the aerosol lose inertialDiffusion ( 3 m)lBrownian movement气雾粒子沉积位置气雾粒子沉积位置 气雾粒子大小气雾粒子大小 太大无法进入太大无法进入 50 50 m m 口口. .鼻鼻. .咽部咽部 10-50 10-50 咽部咽部. .气管气管. .支气管支气管 3-103-10 細支气管細支气管. .肺泡管肺泡管. .肺泡肺泡 0.5-30.5-3 可能隨呼

14、出气体飘至大气不沉积可能隨呼出气体飘至大气不沉积 0.05 0.05 mmlMMAD ( Mean Mass Aerodynamic Diameter )lthe mean size of particles in micronslthe larger the MMAD, the larger is the median particle size lBest size 0.5-5umlGSD ( Geometric Standard Derviation)lthe range of sizes of particles in an aerosollthe greater the GSD ,

15、the more heterodisperse is the aerosolPercent improvement in FEV1 following inhalation of sulbuterol as aerosol with MMAD 3.3 um & 7.7 um0 0101020203030404050506060250mg250mg500mg500mg1000mg1000mg2000mg2000mg3.3 um3.3 um7.7 um7.7 um%FEV1Chest 1989:96:1-1000.050.10.150.20.250.30.350.40.250.512345

16、6T Ti im me e( (H H) )inhaled oralsublingualplaceboChange from baseline in FEV1 in 7 patients given placebo,200ug MDIinhaled sulbutamol , oral 2mg or sublingual 2mg sulbutamolFEV1(L)0501001502002503003500.5123456Tim e %TremorInhaled oral subligualplacebo lParticle size: 1-5 micrometerslLung depositi

17、on- Amount- Location- Molecular target- Efficiency; Side effectslDose; Dose consistencylPhysical/Chemical propertiesl粉雾剂、气雾剂粉雾剂、气雾剂l给药装置：计量式吸入器、喷雾器、气雾给药装置：计量式吸入器、喷雾器、气雾器器l微粉化及其方法：研磨、喷干、超临界粉微粉化及其方法：研磨、喷干、超临界粉碎、搅拌离心碎、搅拌离心l稳定剂：稳定剂： -干扰素与山梨醇、人血清蛋白干扰素与山梨醇、人血清蛋白和氯化钠、胰岛素与乳糖、柠檬酸钠和甘和氯化钠、胰岛素与乳糖、柠檬酸钠和甘露醇、人生长激素

18、露醇、人生长激素hGH与吐温与吐温20l促吸剂：亮丙瑞林促吸剂：亮丙瑞林/1%甘油或甘油或Azone，胰岛素胰岛素/25%癸酸钠癸酸钠lPatient compliance issueslOnce per day dosinglReduced dosinglTaste; Taste-maskinglSafety; Lock-out featureslBreath actuationlDose counters; Dose indicatorslDoses per unitlSampleslCosts; TimelineslDevelopmentlManufacturinglRadiolabel

19、ed aerosol studieslInhaled radiolabelled particles, followed by gamma scintigraphylCharcoal ingestion methodslinhaled drug is simultaneously administrated with charcoal which block oral absorptionlTimed urinary excretion surrogates of lung bioavailability lbiphasic renal excretion followed inhaled d

20、rug lGoal :lTarget the lung peripherylMethod :ladequate size : 1-3 um ( 2 um)lbreathing pattern : slow , deep inhalationlbetter delivery device lMDI, DPI, Nebulizer : for airway diseaselnot to deliver drugs into lung peripherylacceptable for large therapeutic window and potent drug ( 5-20 ug) lincon

21、sistent dose reproducibilitylnot able to deliver most macromoleculesllow systemic efficiency and drug mass per pufflpoor formulation stability and dose reproducibilityCanister(holds formulation)Metering valvePlastic mouthpieceSpray officelConsistent dosinglWide dose range per actuation with no bulki

22、ng agentslSelf-contained power sourcelDose is independent of inspiration effortlEasy to use; Similar method of operationlCompact; PortablelDurablelSealed to environment; Long shelf lifelRelatively inexpensive to manufacturelDo not contain ozone depleting CFC propellantslNo cold freon effect presentl

23、Inspiration-actuation co-ordination not neededlHigh lung depositionlRelative simple to formulatelHFAs are not directly an alternative for CFCslManipulation of particle - particle adhesionlFine particle (5 m) aerosolisationlElectrostatics - moisture content - capillary force lOther physical character

24、istics of the particleslMaintaining physical stability and flow properties of the inhalation powder lDelivered dose consistency - bulking agent(s)lConventional ordered mixture - carrier systemslCorrosion - hot spot theorylFine particle multiples in a carrier system优点：面积优点：面积, 上皮细胞间隙，血管和淋巴管，血上皮细胞间隙，血

25、管和淋巴管，血 流速度，无首过破坏限制：鼻腔纤毛的流速度，无首过破坏限制：鼻腔纤毛的节节 律运动；鼻腔蛋白水解酶；鼻纤毛毒性律运动；鼻腔蛋白水解酶；鼻纤毛毒性要求：鼻粘膜浓度高；与接触面积大；易吸收，要求：鼻粘膜浓度高；与接触面积大；易吸收， 不影响鼻腔功能不影响鼻腔功能 措施：延长滞留时间；吸收促进剂；酶抑制剂；措施：延长滞留时间；吸收促进剂；酶抑制剂； 剂型作用剂型作用 都市 基基底底细细胞胞 萎萎 缩缩 淀淀 粉粉微微 球球 粘粘附附 溶溶 胀胀 形形成成 凝凝胶胶 l胆盐、脂肪酸、皂角苷、辛酸钠胆盐、脂肪酸、皂角苷、辛酸钠, 月桂酸月桂酸钠钠, 聚丙烯酸等梭链孢酸衍生物如牛磺酰聚丙烯酸

26、等梭链孢酸衍生物如牛磺酰二氢梭链孢酸盐、环糊精二氢梭链孢酸盐、环糊精l喷雾给药、沉着部位、清除速率、病理变喷雾给药、沉着部位、清除速率、病理变化等化等药物药物 氨基酸个数氨基酸个数 BA（%）N BA（%）Y 脑啡肽类似物脑啡肽类似物 5 54 94 (甘胆酸盐）甘胆酸盐） LHRH类似物类似物 11 1-5 40-50甘胆酸盐）甘胆酸盐）胰高血糖素胰高血糖素 29 1 70-90 （甘胆酸盐）（甘胆酸盐）生长激素释放因生长激素释放因 40-44 1 2-20 （特殊溶剂）（特殊溶剂）降钙素降钙素 32 1 15-20甘胆酸盐）甘胆酸盐）胰岛素胰岛素 51 1 10-30 （甘胆酸盐）（甘胆酸

27、盐）Ozone and CFCsOzone ( O3) absorbing UV-B balance between its formation and breakdown to O2 (O2+ O+ O3 + )Powerful destroyer of Ozone atmospheric pollutants ( halocarbons ) CFCs ( chlorofluorocarbons ) Nitrous oxide, CCl4 .Ozone pole and CFCs Ozone pole ( first observed over south pole) CFCs concen

28、trated over south pole , vortex release free chlorine atoms by intense UV radiation destroy thousands of ozone molecule O2+ O+ O3 + ,CFC Cl-+ FC Cl-+ O+=ClO ozone destroyed and ozone pole noted greenhouse effect CFCs 1000-fold more potent “ greenhouse ”agents than CO2Montreal Protocol and CFCsChlori

29、ne concentration : Natural condition : 0.7 ppb October 1987 ( Antarctic Ozone Hole ) : 2.0 ppb 1990 : 2.8 ppb 1995 : about 4 ppb if stopped by 1995 to 2.0 : 2055 (stopped in 1995) , 2073 (in 2000)Montreal Protocol : 1987 international agreement restricting the use of CFCs complete phase out of CFCs

30、production by 2000Montreal Protocol : 1987 international agreement restricting the use of CFCs reduction 50 % of 1986 level by July 1998Revised in 1990 complete phase out of CFCs production and use in the developed countries by 2000 envisaged all CFC-MDIs replaced by 2005 Montreal Protocol Aerosol t

31、herapy without CFCsNew propellant without CFCs HFA 134 ( hydroxyfluoroalkane )New propellant-free technologies dry powder inhaler patient-driven to power-driven sophisticated metered dose liquid inhaler AERx , Respimat nebulizer breath-actuated nebulizer , smart nebulizerComparison of CFC and HFAConsistent dosing through the end of canister life at all storage orientationReliable dose delivery even at low temperature ( Journal of Aerosol Medicine Vol 12,3 ,1999, 151) Better lung deposition HFA-BDP 55% : CFC-BDP 4% 2.6-fold & 3.2-fold lower dose FEV1 & FEF 25-75% ( J