Ophthalmic Drug Delivery Systems - part 10 ppsx

... Rel, 11 :79 (19 90). 11 . S. D. Klyce and C. E. Crosson. Transport processes across the rabbit cornealepithelium: a review. Curr. Eye Res. 4:323–3 31, 19 85. 12 . A. K. Mitra. Ophthalmic drug delivery. ... octanol-water partition coefficients. J.Pharm. Sci. 67:786–788, 19 78. 16 . M. M. Narurkar and A. K. Mitra. Prodrugs of 5-iodo-20-deoxyuridine forenhanced ocular transport. Pharm. Res. 6:887–8 91, 19 89. 17 . ... Theinnermostlayerofthecornea,separatedfromthestromabyDescermet’smembrane,istheendothelium.Theendotheliumislipoidalinnature;however,itdoesnotofferasignificantbarriertothetranscornealdiffusionofmostdrugs.Endothelialpermeabilitydependssolelyonmole-cularweightandnotonthechargeofhydrophilicnatureofthecompound (13 ,14 ).Transcellulartransportacrossthecornealepitheliumandstromaisthemajormechanismofocularabsorptionoftopicallyappliedophthalmicpharmaceuticals.ThistypeofFickiandiffusionisdependentuponmanyfactors,i.e.,surfacearea,diffusivity,theconcentrationgradientestablished,andtheperiodoverwhichconcentrationgradientcanbemaintained.Aparabolicrelationshipbetweenoctanol/waterpartitioncoefficientandcor-nealpermeabilityhasbeendescribedformanydrugs (15 19 ).Theoptimallogpartitioncoefficientappearstobeintherangeof1–3.Thepermeabilitycoefficientsof11steroidsweredeterminedbySchoenwaldandWard (15 ).Thepermeabilityversuslogpartitioncoefficientfitthetypicalparabolicrelationship,withtheoptimumlogpartitioncoefficientbeing2.9.NarurkarandMitrastudiedahomologousseriesof50aliphaticestersof5-iodo-20-deoxyuridine(IDU) (16 ,17 ).Invitrocornealpermeabilitieswereoptimizedatalogpartitioncoefficientof0.88,ascanbeseengraphicallyinFigure3andinTable1,whereCMPrepresentsthecornealpermeabilityvalues...

... Ocularpharmacokineticsincludesthefeaturesofabsorption,distribu-tion,andexcretionfoundwithsystemicadministrationbutappliedtotheeye.However,owingtotheuniqueanatomyandphysiologyoftheeyeandsurroundingtissue,ocularpharmacokineticsisconsiderablymoredifficulttodescribeandpredictthanitssystemiccounterpart.Thetaskisfurthercomplicatedbythevariousformulations,routes,anddosingregimenstypi-callyencounteredinophthalmology.Pharmacodynamicsisthemeasurementofpharmacologicalresponserelativetodoseorconcentration.Thepharmacologicalresponseinducedbyadrugcanvarygreatlyfromindividualtoindividualduetodifferencesinfactorssuchaseyepigmentation,thepathologicalstateoftheeye,tearing,orblinkrate.Theapplicationofpharmacologicalendpointsisparticularlyusefulinthestudyofdrugsinthehumaneye,wheretheabilitytodeterminetheocularpharmacokineticsbasedonoculartissueconcentrationsisseverelylimited.Thischapterdiscussestheocularpharmacokineticsassociatedwithtopicalocular,intravitreal,periocular,andsystemicadministration.Inaddi-tion,thepharmacodynamicsrelatedtoophthalmicdrugsandtheroleofoculardrugmetabolismarereviewed.II.OCULARPHARMACOKINETICSApplicationofclassicalpharmacokineticstoophthalmicdrugsisprob-lematicbecauseofthecomplexitiesassociatedwitheyeanatomyandphy-siology.Asaresult,mostoftheliteratureislimitedtomeasuringconcentrationsinoculartissuesovertimefollowingsingleormultipleadministration.Thisapproach,whileinformative,doesnoteasilyyieldquantitativepredictionsforchangesinformulationordosageregimen.Compoundingtheproblemisthefactthatmoststudieshavebeenconductedinrabbiteyes,whichdiffersignificantlyfromhumaneyesinanatomyandphysiology(seeTable1).themostobviousdifferencesareinblink ... Ocular drug delivery. Pharmacokinetic considera-tions. Clin. Pharmacokinet., 18 :25 5.6. Lang, J. C., and Stiemke, M. M. Biological barriers to ocular delivery. In:Ocular Therapeutics and Drug Delivery ... of -blocking agents III: In vitro– in vivo correlations. J. Pharm.Sci., 72: 127 9.46. Tang-Liu, D. D. S., Liu, S. S., and Weinkam, R. J. (1984). Ocular and sys-temic bioavailability of ophthalmic...

... calculated at 4, 12, and 24 hours after injection,increased as the drug diffusivity was reduced. Furthermore, the rate of drug elimination, which is inversely related to the drug s elimination half-life, ... examinedthetransportkineticsofascorbateusingtherecentlydevelopedconsciousanimalmodelwithmicrodialysissamplingofaqueoushumor.Microdialysisprobeswereplacedintheanteriorchamberofoneeyeandtheposteriorchamberofthefelloweye(53).Basalbloodtoaqueoustransportof 14 C-ascorbatewasestablishedbytheexaminationofaqueoushumorascorbatecorrectedforspecicactivity.Followinga30-dayrecov-eryperiod,therabbitsn 4) wereplacedinrestrainingdevices,themar-ginalearveinsofrespectiveearswerecannulated,andascorbatewasadministeredviaani.v.bolusloadingdosefollowedbymaintenanceincre-mentalinfusionsinordertocharacterizethelinear-to-nonlinearkineticproleinbloodtoaqueoushumortransport.BloodandprobeeuentwereanalyzedviaUVspectrophotometryat265nm.Anonlinearleast-squaresregressionanalysisassessmentofthetransportkineticsofascor-batewasperformed.Contrarytopreviousreports(58,63),ascorbatebloodconcentrations,whichwereincreasedinastepwisefashion(anoverall$twofoldincrease),didnotresultinsaturableascorbateuptakeintoaqu-eous(bloodconcentrationsfrom$14to$21to$30mg/L).Nonlinearleast-squaresregressionanalysisofamodelthatincorporatednonsaturableuptakeintoaqueouswithrst-ordertranslocationfromtheposteriortotheanteriorchamberandrst-ordereuxfromtheanteriorchamber,withanincorporatedlagtimeof$1hour,appearedtodescribethedatabest.Themodeltstotheserum,anterior,andposterioraqueousascorbateconcentration-timedataarepresentedinFigure3.Physiologicallyrelevantparameterestimateswereobtainedwiththisapproach.Theanalysispro-videdindicationsthatreducedaqueoushumorturnoveroccurredinthisgroupofrabbits(translocationrateconstantswere$0:005min1ascom-paredto0.01min1inintactanimals).Theparameterestimateswerealsoinagreementwiththemodelindependentascorbateocularclearancedeter-minations$39mL/minor$0:003min1,whendividedbytheestimatedaqueoushumorvolumeof200mL)(53).Itispossiblethattheapparenttransportofascorbatewasperturbedbysurgery.Surgicaltraumacanresultinincreasedperoxidegenerationasaresultoftheinammatorycascade(69).Therearenoreportsofstudiesevaluatingbasalascorbatetransportasafunctionofthedegreeofintraocularinammation.Italsoispossiblethattime-dependentchangestoascorbatebloodtoaqueoustrans-portwereobserved.Inordertoexaminethispossibility,therelationshipbetweenaqueoushumorascorbateconcentrationsandtimepostprobeimplantationwasexamined(Fig .4) (17,53, 54) .At0minutes,physiologi-cally ... Marcel Dekker, Inc. 46 . Kulkarni, P. S., and Srinvasan, B. D. (1987). Nonsteroidal anti-inflammatorydrugs in ocular inflammatory conditions. In Nonsteroidal Anti-inflammatoryDrugs, A. J. Lewis,...

... of drugs in perspective vis-a-vis ocular drug delivery. First, the noncorneal penetration pathway involves the per-meation of drug across the conjunctiva and sclera and may contribute sig-nificantly ... of the eye, Biomaterials.,21 :64 9 66 5.131. Peyman, G. A., and Ganiban, G. J. (1995). Review: Delivery systems forintraocular routes, Adv. Drug Delivery Rev., 16: 107–123.132. Velez, G., and ... intraocularroutes, Adv. Drug Delivery Rev., 16: 107–123.129. Geroski, D. H., and Edelhauser, H. F. (2000). Review: Drug delivery forposterior segment eye disease, Invest. Ophthal. Vis. Sci.: 961 – 964 .130....

... analogue, 1- desamino -8 - D-arginine-vasopressin (dDAVP), in human intestinal epithelialcell line, CaCO-2, Int. J. Pharm., 64: 181 .43. Amidon, G. L., Sinko, P. J., Hu, M., and Leesman, G. D. (1 989 ). ... rhodop-sin mutation were protected from apoptosis by recombinant adeno-associated virus-mediated production of fibroblast growth factors fgf-2,fgf-5, and fgf- 18 (30,31), while lens epithelium-derived ... nearfuture. We hope that novel drug delivery systems will be developed todeliver potent polypeptide drugs through the ocular route.REFERENCES1. Lee, V. H. L. (1 987 ). Ophthalmic delivery of peptides...

... S. G.( 199 9). Stable transgene expression in rod photoreceptors after recombinantadeno-associated virus-mediated gene transfer to monkey retina. Proc. Natl.Acad. Sci. USA, 96 (17) :99 20 99 25.130. ... ( 199 6). Phosphorothioate-modified oli-godeoxyribonucleotides, III. NMR and UV spectroscopic studies of the Rp-Rp, Sp-SP, and Rp-Sp duplexes, [d(GGSAATTCC)]2, derived from diaster-eomeric O-ethyl ... ( 199 8).Ribozyme-targeted destruction of RNA associated with autosomal-dominantretinitis pigmentosa. Invest. Ophthamol. Vis. Sci., 39( 5):681–6 89. 213. Tombran-Tink, J., and Johnson, L. V. ( 198 9)....

... pharmaceu-tical drug product will be essential.The commercial consideration for development of an ophthalmic drug delivery system is not limited to new therapeutic agents. Many existing ophthalmic drugs ... will vary with the particular dru g and the novelty ofthe particular delivery system. The approach of one company in establishingthe safety/toxicity profile of ophthalmic drugs and devices has ... analytical procedures must be specified to ana-lyze routinely the identity and purity of the drug. If the drug is in an of - cial pharmacopeia, the monograph for the drug may be referenced;however, the...

... LibraryofCongressCataloging-in-PublicationDataAcatalogrecordforthisbookisavailablefromtheLibraryofCongress.ISBN: 0-8 24 7-4 12 4-2 Thisbookisprintedonacid-freepaper.HeadquartersMarcelDekker,Inc.270MadisonAvenue,NewYork,NY10 016 tel: 21 2-6 9 6-9 000;fax: 21 2-6 8 5-4 540EasternHemisphereDistributionMarcelDekkerAGHutgasse4,Postfach 812 ,CH-4001Basel,Switzerlandtel:4 1- 6 1- 2 6 0-6 300;fax:4 1- 6 1- 2 6 0-6 333WorldWideWebhttp://www.dekker.comThe ... byJames W. Munson 12 . Techniques of Solubilization of Drugs, edited by Samuel H. Yalkow-sky 13 Orphan Drugs, edited by Fred E. Karch 14 . Novel Drug Delivery Systems: Fundamentals, ... grants R 01 EY0 917 1 and R 01 EY10659.Overview of Ocular Drug Delivery 9Copyright â 2003 Marcel Dekker, Inc. DRUGS AND THE PHARMACEUTICAL SCIENCESA Series of Textbooks and Monographs 1. ...

... intraocular sur-gery. Ophthalmology 98:227–228, 1991. 24. Peyman, G. A., and Schulman, J. A. Intravitreal drug therapy. In: IntravitrealSurgery. Norwalk: Appleton-Century-Crofts, pp. 40 7 45 5.25. ... Similarrelationshipsbetweenretinalpermeability,vitreousdiffusivity,mole-cularweight,andhalf-lifehavebeenshownbyMaurice(32,36).Withintherangestudied,half-lifeisinverselydependentonthevitreousdiffusivityandretinalpermeability.Thehalf-lifehasagreaterdependenceonthevitreousdiffusivitythanontheretinalpermeability,althoughneitherrelationshipislinear.Astheretinalpermeabilityeitherdecreasestowardszeroorincreasestoahighvalue,thehalf-lifeapproacheseitherahighoralowlimit,respec-tively.Thisisconsistentwithexpectationsbecausealldrugiseliminatedacrossthehyaloidmembranewhentheretinalpermeabilityiszero.Therefore,thehalf-lifewillbedependentontherateatwhichdrugreachesthehyaloidmembrane,whichisdeterminedbythedrugdiffusivitythroughthevitreous.Likewise,whentheretinalpermeabilityishigh,therateofeliminationwillbelimitedbytherateofdiffusionacrossthevitreous.Althoughtherangeofdrugdiffusivitiesconsideredisnotlargeenoughtoshowtheeffectofextremevaluesofdiffusivityonhalf-life,itisexpectedthatasthevitreousdiffusivitydecreases,thehalf-lifeshouldincreasewithoutbound.However,asthevitreousdiffusivityincreases,drugeliminationwouldoccurprimarilythroughthehyaloidmembraneintotheaqueoushumorandultimatelythroughtheaqueous/bloodbarrier.Sincediffusivityintheaqueoushumorshouldbeatthesameasinthevitreousandhyaloid,theflowingaqueoushumorshouldnotrepresentalimitingmasstransferbarrier.Althoughthefiniteelementmodeldidnotaccountfortheaqueous/bloodbarrier,thepropertiesofthisbarrierwoulddictatethelowerlimitofvitreoushalf-lifewhenvitreousdiffusivityincreasestolargevalues.Mostdrugsadministeredintravitreallyhavemolecularweightsran-gingfrom300to500Da;therefore,Figure 14( foravitreousdiffusivityof5:6Â10À6cm2/s,354Da)willberepresentativeofmostdrugs.However,forsmallerorlargercompounds,thequantitativerelationshipbetweenhalf-lifeandthepermeabilitywillbedifferent,aswillthelimitingvalues.Nevertheless,thesamequalitativerelationshipshouldstillbeobserved,regardlessofthevitreousdiffusivity.Consequently,Figure14permitsqua-litativecomparisonsbetweentheeliminationofdifferentdrugs(molecularweightaffectsdiffusivity).Furthermore,Figure14demonstratestheimpor-tanceofdoseadjustmentifadrugisadministeredintoaneyecompromisedbyretinalinflammationorotherdiseasethatalterthepermeabilityoftheblood-retinalbarrier. 4. ResultsofAphakiaonDrugDistributionintheVitreousFigure15showsthemodelcalculatedconcentrationprofileoffluoresceinonhalf ... Therap.13(5) ;44 5 45 9, 1997.30. Kaiser, R., and Maurice, D. M. The diffusion of fluorescein in the lens. Exp.Eye Res. 3:156–165, 19 64. 31. Sebag, J. Aging of the vitreous. Eye 1:2 54 262, 1987.32....

... PECLnanoparticles for carteolol. It was concluded that the drug entrapped inthe oily core is more available for corneal absorption.3H-Labeled hydrocortisone- 1 7- butyrate-21-propionate (3H-HBP)loaded ... including polymer -drug complex sys-tems, erodible microspheres, responsive particulates, in situ gelling systems, ion-exchange systems, and nanoparticles (15).B. Local Injectable Systems When the ... Inc. II. PARTICULATE SYSTEMS IN OCULAR DRUG DELIVERY A. Topical Systems The isolation of the vitreous caused by the blood-retinal and blood-aqueousbarriers creates difficulties for effective drug therapy...