Ophthalmic Drug Delivery Systems - part 4 doc

... 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, ... Inc.examinedthetransportkineticsofascorbateusingtherecentlydevelopedconsciousanimalmodelwithmicrodialysissamplingofaqueoushumor.Microdialysisprobeswereplacedintheanteriorchamberofoneeyeandtheposteriorchamberofthefelloweye(53).Basalblood–to–aqueoustransportof 14 C-ascorbatewasestablishedbytheexaminationofaqueoushumorascorbatecorrectedforspecificactivity.Followinga30-dayrecov-eryperiod,therabbitsðn 4) wereplacedinrestrainingdevices,themar-ginalearveinsofrespectiveearswerecannulated,andascorbatewasadministeredviaani.v.bolusloadingdosefollowedbymaintenanceincre-mentalinfusionsinordertocharacterizethelinear-to-nonlinearkineticprofileinbloodtoaqueoushumortransport.BloodandprobeeffluentwereanalyzedviaUVspectrophotometryat265nm.Anonlinearleast-squaresregressionanalysisassessmentofthetransportkineticsofascor-batewasperformed.Contrarytopreviousreports(58,63),ascorbatebloodconcentrations,whichwereincreasedinastepwisefashion(anoverall$twofoldincrease),didnotresultinsaturableascorbateuptakeintoaqu-eous(bloodconcentrationsfrom$14to$21to$30mg/L).Nonlinearleast-squaresregressionanalysisofamodelthatincorporatednonsaturableuptakeintoaqueouswithfirst-ordertranslocationfromtheposteriortotheanteriorchamberandfirst-ordereffluxfromtheanteriorchamber,withanincorporatedlagtimeof$1hour,appearedtodescribethedatabest.Themodelfitstotheserum,anterior,andposterioraqueousascorbateconcentration-timedataarepresentedinFigure3.Physiologicallyrelevantparameterestimateswereobtainedwiththisapproach.Theanalysispro-videdindicationsthatreducedaqueoushumorturnoveroccurredinthisgroupofrabbits(translocationrateconstantswere$0:005minÀ1ascom-paredto0.01minÀ1inintactanimals).Theparameterestimateswerealsoinagreementwiththemodelindependentascorbateocularclearancedeter-minationsð$39mL/minor$0:003minÀ1,whendividedbytheestimatedaqueoushumorvolumeof200mL)(53).Itispossiblethattheapparenttransportofascorbatewasperturbedbysurgery.Surgicaltraumacanresultinincreasedperoxidegenerationasaresultoftheinflammatorycascade(69).Therearenoreportsofstudiesevaluatingbasalascorbatetransportasafunctionofthedegreeofintraocularinflammation.Italsoispossiblethattime-dependentchangestoascorbatebloodtoaqueoustrans-portwereobserved.Inordertoexaminethispossibility,therelationshipbetweenaqueoushumorascorbateconcentrationsandtimepost–probeimplantationwasexamined(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 ... Routes of delivery: casestudies. (7). Ocular delivery of peptide and protein drugs, Adv. Drug Delivery Rev., 8:331–339.81. Chiou, G. C. Y. (19 94) . Systemic delivery of polypeptide drugs through ... Sci., 21:5 04 541 .87. Shell, J. W. (1982). Pharmacokinetics of topically applied ophthalmic drugs,Surv. Ophthalmol., 26:207–218.88. Mikkelson, T. J. (19 84) . Review: Ophthalmic drug delivery, ...

... Absorption of vasopressin 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, ... Pharm.Exp. Ther., 249 : 249 .80. Ahmed, I., and Patton, T. F. (1985). Importance of the noncorneal absorptionroute in topical ophthalmic drug delivery, Invest. Ophthalmol. Vis. Sci.,26:5 84. 81. Pandolfi, ... intestinal absorption of L--methyl-dopa: Carrier kinetics, intestinal permeabilities and in vitro hydrolysis ofdipeptidyl derivatives of L--methyldopa, Pharma. Res., 6:66. 46 . Friedman, D. I.,...

... 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. ... Inc.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....

... 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 ... PECLnanoparticles for carteolol. It was concluded that the drug entrapped inthe oily core is more available for corneal absorption.3H-Labeled hydrocortisone-17-butyrate-21-propionate (3H-HBP)loaded ... chain promoter (-MHC-vIL-10) injected into the graft prolongedallograft survival significantly from 13.9 days to 21 .4 days. When - MHC-vIL-10 was complexed with G5EDA dendrimer, a 60-fold decreasein...

... Mucoadhesive Polymers in Ophthalmic Drug Delivery 40 9ThomasP.Johnston,ClaptonS.Dias,HemantAlur,andAshimK.Mitra 14. Microparticles and Nanoparticles in Ocular Drug Delivery 43 7Murali K. Kothuri, ... of a series of 50-ester prodrugs of 5-iodo-20-deoxyuridine. Pharm.Res. 5:7 34 737, 1988.10 Macha et al.Copyright © 2003 Marcel Dekker, Inc. Ophthalmic Drug Delivery Systems Second Edition, ... Brittam96 Freeze-Drymg/Lyophilization of Pharmaceutical and Biological Prod-ucts, edited by Louis Rey and Joan C May97. Percutaneous Absorption- Drugs-Cosmetics-Mechanisms-Metho-dology,...

... 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 ... blood-ocular transportstudies: application to amino acids. Exp. Eye Res., 54: 471 47 7.Zlokovic, B. V., Mackic, J. B., McComb, J. G., Kaplowitz, N., Weiss, M. H.,andKannan, R. (19 94) . Blood-to-lens ... Weinkam, R. J. (19 84) . Ocular and sys-temic bioavailability of ophthalmic flurbiprofen. J. Pharmacokin. Biopharm.,12:611. 47 . Ding, S., Chen, C C., Salome-Kesslak, R., Tang-Liu, D. D S., andHimmelstein,...

... adenovirus encoding brain-derived neurotrophic factor (Ad-BDNF) coinjected with a free radical scavenger, N-tert-butyl-(2-sulfoph-enyl)-nitrone (S-PBN), resulted in the survival of 63% axotomized ... myocardium.Nature, 41 0(6829):701–705. 48 . Brown, J. M., Weissman, I. L., and Shizuru, J. A. (2001). Immunity to infec-tions following hematopoietic cell transplantation. Curr. Opin. Immunol.,13 (4) :45 1 45 7. 49 . ... 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 phosphorothioates....

... 94: 12 744 –12 746 .99. D. Pogocki and C. Schoneich. (2000). Chemical stability of nucleic acid-derived drugs. J. Pharm. Sci., 89 :44 3 45 6.100. I. Jaaskelainen, J. Monkkonen, and A. Urtti. (19 94) . ... for gene delivery in vitro and in vivo. Adv. Drug Deliv. Rev., 24: 265–271. 84. C. Plank, W. Zauner, and E. Wagner. (1998). Application of membrane-activepeptides for drug and gene delivery ... 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...