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  • 8/18/2014

    1

    DevelopingandOptimizingTransdermalDeliverySystems

    TerriSebree

    AdvantagesofTransdermalDelivery

    Avoids GI tract Prevents first pass metabolism Eliminates drug absorption issues with GI stasis

    Common with migraine, prior gastric surgery, diabetes mellitus Treats conditions associated with nausea and vomiting

    Reasonably constant delivery can be maintained (as opposed to peaks and valleys associated with oral and parenteral delivery)

    Reduces need for active administration (some patches applied for 7 days)

    For patches, dosing can be stopped by removal Easy to apply, convenient administration

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    2

    TransdermalMarket

    Globaltransdermalmarketforecastedtogrowfrom$21.5bin2010to$31.5bby20153

    3

    $8.0

    $12.7

    $21.5

    $31.5

    $0.0

    $5.0

    $10.0

    $15.0

    $20.0

    $25.0

    $30.0

    $35.0

    2002 2005 2010 2015

    U.S.TransdermalMarket2002 2015(1) MarketsAddressed(2)

    (In$US

    Dbillion

    s)

    1 Jain PharmaBiotech report. Transdermal drug delivery-technologies, markets and companies. 2005.2 Frost & Sullivan, US Transdermal Drug Delivery Market, August 2006.3 PharmaLive Special Report: Transdermal Medicine Review and Outlook, September 2011

    TransdermalDeliveryWhyitmatterstoPharma

    Productlineextensions buprenorphine,rivastigmine,methylphenidate

    DeliveryofNCEswithlowbioavailabilityrotigotine

    EffectivedeliveryofNCEsforpatientswithGIconditionsand/orsyptoms

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    FirstGenerationTransdermalSystems

    Suitableforlowmolecularweight,lipophilicAPIswhichareefficaciousatlowdoses

    Patches,gels,liquidsprays Deliverylimitedandcontrolledbystratumcorneum

    SecondGenerationTransdermalSystems

    Utilizechemicalenhancerstoincreaseskinpermeability

    Balancemustbeachievedtooptimizedrugdeliveryandpreventskinirritation

    TestosteroneGel AndroGel isopropylmyristate Testim pentadecalactone

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    Testimvs AndroPatch PK

    TestimsignificantlyincreasedtestosteroneandDHTserumconcentrationsfrombaselinecomparedtoAndroPatch(2patches) Consistentfindingsat30,60,and90days

    7McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int. 2003;91(1):6974.

    Testimvs AndroGel PK

    8

    Testim provided 30% higher serum testosterone levels compared to AndroGel with a similar safety profile.

    Steidle, CP, New Advances in the Treatment of Hypogonadism in the Aging Male, Rev Urol. 2003;5(suppl 1):S34-S40.

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    5

    TestimEfficacy

    DaysofTreatment LeanBodyMass(Muscle)(kg)

    TotalFatMass(kg) %BodyFat

    Baseline 61.6 29.4 30.9

    Day90 63.3 28.6 29.8

    ChangefromBaseline 1.6 0.8 1.1

    9

    At Day 90, mean increase from baseline in lean body mass and mean decreases from baseline in total fat mass and percent fat in Testim-treated patients was significant when compared to placebo-treated patients.

    Testim Prescribing Information

    Safety SkinIrritationTestimvsAndroPatch

    10

    The distribution of men with positive application-siteirritation scores at 30 (open bars), 60 (green bars) and 90 days (red stippled bars).

    There were significant differences (P< 0.001) for each of the Testim vs Andropatch comparisons at each time.

    McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int. 2003;91(1):6974

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    Disadvantages

    Undesirablephysicalproperties Stickiness Fragrance

    Blackboxwarningofsecondaryexposuretotestosterone Adverseeffectpotentialoftransferrisktochildrenandwomenuponclosecontactwithskin

    11

    ActiveDelivery

    Iontophoresis Noncavitationalultrasound Microneedles

    12

    Goal of these delivery systems is to enhance delivery across the stratum corneum while protecting deeper, living tissues.

  • 8/18/2014

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    Iontophoresis

    13

    compound

    Iontophoresis provides an electrical driving force for transport of compounds across stratum corneum

    Charged drugs are move via electrophoresis

    IontophoresisDeliveryDesignandOptimization

    Indesigninganiontophoreticdeliverysystem: Dosedelivered,dosingfrequency,andpharmacokineticprofilemustbedefined

    Earlystudiesidentifymetalsforelectrodes,powersource,designofpatch(integratedpowersourceorattachablepowersource)

    Formulationmustbedevelopedwhichallowsiondeliveryandprotectsskin

    Optimizationstudiesdefineionicstrength,formulation,currentdensity,andpatchsizeandshape

    14

  • 8/18/2014

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    Optimization IonicStrengthParameters Foriontophoresistooccur,thedrugsubstancemustbeionized Bothinsolutionandpossessacharge

    Parametersaffectingiontophoresis: Molecularsizeandmolecularweightofdrugion

    Optimumrangesmallerandhydrophilic

    Ionicstrengthandpresenceofotherions Ifaboverangewilldecreasedrugdeliveryasextraneousionscompetewithdrugions

    InfluenceofpH Ifaboverangewillincreaseriskofvascularreaction

    15 Dhote V, Bhatnagar P, Mishra PK, Mahajan SC, Mishra DK. Iontophoresis: A potential emergence of a transdermal drug delivery system. Sci Pharm.2012;80:1-28.

    Optimization CurrentDensity Currentdensityiskeyfactorindeterminingdrugdelivery,rateofdelivery,and

    skintolerability Currentdensityiscalculatedbydividingcurrent(usuallyinmilliamps)divided

    bythedrugdeliverysurfacearea(usuallyincm2)

    Currentdensityoptimizationstudiesmustbeconductedinvivo Porcinemodelmosteffectiveforevaluatingcurrentdensityandtolerabilityissues Studiesshouldbeconductedwithformulationtobeusedinanimalandhuman

    studies

    16 1. Siegel SJ, O'Neill C, Dube LM, et al. A unique iontophoretic patch for optimal transdermal delivery of sumatriptan. Pharm Res. 2007;24(10):1919-26

  • 8/18/2014

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    Optimization SizeandShape Optimizationstudiesinvitroandinvivoinvestigatesizeandshapeof: Reservoirpad

    Oval,circle,rectangle Patchconfiguration

    Oval,rectangle,figure8 Electrodes

    Oval,candelabra,rectangle,circle

    17

    ZecuitySumatriptanIontophoreticTransdermalSystem

    Intelligent,activetransdermaldelivery Microprocessorsupportshighlycontrolledandconsistentdelivery

    Multiplesafetycheckswithinsecondsofactivation

    Continuousfeedbacksystemthroughoutdosinginterval

    Controlsboththerateandamountofdrugdelivered

    NodifferenceinPKregardlessofage,race,orgender

    Simpleforpatients pressabutton(noinputsoradjustments)

    18

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    ZecuitySumatriptanIontophoreticTransdermalSystem

    19

    Applied to upper arm or thigh.

    IontophoreticDevice

    20

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    ReservoirCard

    21

    ZecuityPharmacokinetics

    22

    Oral 100 mg tabletSQ 6 mgNasal spray 20 mgZecuityZecuity

    SumatriptanPlasmaConcentrationGroupMean(95%Cl)OverTime

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    12

    ZecuityHumanFactorsUsabilityStudy

    Zecuitycanbeassembled,applied,andactivatedsuccessfullyduringamildtoseveremigraineattack

    Inaclinicalstudy,allparticipants(96.9%withmoderatetoseveremigraineheadachepain)wereabletoassemble,apply,andactivateZecuity

    PatientswithmigraineratedZecuityveryhighforeaseofassemblyandeaseofapplication/activation.

    23 Meadows, K., et al, Sumatriptan transdermal system (TDS) can be correctly assembled, applied, and activated during migraine attacks, Headache Journal 07 April 2014.

    ZecuityHeatStudy ExternalHeatSource:Aheateffectstudyin12healthyadultsubjects

    demonstratedsimilarpharmacokineticvalueswithoutandwiththeapplicationofanexternalheatsource(400 CheatwrapplacedovertopoftheZECUITYTDSforthe4hourdosingperiod).

    24

    SumatriptanPlasmaConcentrationGroupMean(95%Cl)OverTime

    Zecuity patch worn for 4 hours with a heat wrap applied over top the patchZecuity patch worn for 4 hours without a heat wrap applied over top the patch

    Freeman, JC, et al, A Phase I, Single Center, Open Label, Randomized, Single-Dose, Two Way Crossover Study to Compare Pharmacokinetics of Two Patch Applications With and Without Controlled Heat, American Headache Society, 54th Annual Scientific Meeting, Los Angeles, CA June 2012.

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    ZecuityEfficacy Painreliefandnauseafreedomtwohoursfollowingpatchactivation TwiceasmanypatientstreatedwithZecuityachievefreedomfromheadachepaincomparedtoplacebo

    53%ofpatientstreatedwithZecuityachievedrelieffromheadachepaincomparedwith29%forplacebo

    84%ofpatientstreatedwithZecuitywerenauseafreecomparedwith63%forplacebo

    25 Pivotal Phase 3 Data (HEADACHE October 2012)

    ZecuitySafety

    26

    Zecuity Placebo

    Applicationsitepain 26% 17%

    Applicationsitetingling 9% 16%

    Applicationsiteitching 8% 7%

    Applicationsitewarmth 6% 3%

    Applicationsitediscomfort 6% 6%

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    AllergicContactDermatitis(ACD) Definedascaseshavinghigherirritationscores,acrescendo

    clinicalcourse,orprolongedrecovery PutativecasesofACDidentifiedthroughmedicalsafetyreview

    werecombinedwiththecasesreportedasACD ForZecuity,allputativecaseswereevaluatedandclassifiedby

    dermatologyconsultantandACDspecialist,HowardMaibach,MD,(UniversitySanFrancisco) ACDisexpecteddiagnosis

    ForZecuity,twolongtermstudyresultswhereatleast2patcheswereapplied: Probable=3% ProbableandPossible=8%

    27

    TransdermalDeliveryandProDrugs

    Prodrugsareanenablingtechnologytodeliverdrugsintocirculationt

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