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Intra-AgencyAgreementBetweentheEuniceKennedyShriverNationalInstituteofChildHealthandHumanDevelopment(NICHD)andtheU.S.FoodandDrugAdministration(FDA)OralFormulationsPlatform—Report1Theobjectiveofthisworkistoprovidesomebaselineinformationaboutmarketedpediatricproductsthathavebeenapprovedforadministrationtopediatricpatients.Theseproductsareapprovedeitherforadministrationtopediatricpatientsas-isorbyreconstitutionandcompoundingwithspecificinstructionsontheproductlabel.Asignificantamountcanbelearnedfromtheseapprovedproducts,andtheknowledgegainedcanbeappliedforthedevelopmentofnewformulationsofnewandexistingactivepharmaceuticalingredients(APIs).AspartoftheNationalInstitutesofHealth-FDAinitiative,alistof382productshasbeencompiledsofar.ThislistwascompiledbasedontheapprovedproductslistedontheFDAWebsite(=Reports.ReportsMenu)orfromtheSigler’sPrescriptionDrugCardlist(SFImedicalpublishing,P.O.Box3578,Lawrence,KS66046).Areviewofthecurrentlyavailableproductsindicatethatthepediatricmedicationsareavailableasdrops,syrups,elixirs,suspensions,sprinkles,capsules,injectables,chewabletablets,orallydisintegratingtablets,coatedproducts,metereddoseinhalers(MDIs)anddrypowderinhalers(DPIs),orallydissolvingfilms,minitabs,andothers(e.g.,non-oraldrops,creams,ointments,etc.).Applicationofcomputationalmethodstocategorizethemoleculesofapprovedproductsbasedontheirphysicochemicalandotherpropertiesiscurrentlyunderway.Inthisearlyreport,theoralliquiddosageforms,includingdrops,syrups,elixirs,suspensions,andmodifiedreleaseoraldosageforms,arebeingdiscussed.Inthedevelopmentofpediatricaswellasadultproducts,theBiopharmaceuticsClassificationSystem(BCS)representsaconvenientwaytolookatsolubilityandpermeabilitycharacteristicsofdrugsubstances.ItishelpfultoreviewtheBCSclassificationhere,althoughthissystemwasprimarilydevelopedforadultproducts.Researchisneededforthedevelopmentofapediatric-specificBCSsystem.BCSTheBCSisascientificframeworkforclassifyingdrugsubstancesbasedontheiraqueoussolubilityandintestinalpermeability.1Whencombinedwiththedissolutionofthedrugproduct,theBCStakesintoaccountthreemajorfactorsthatgoverntherateandextentofdrugabsorptionfromimmediate-release(IR)solidoraldosageforms:dissolution,solubility,andintestinalpermeability.AccordingtotheBCS,drugsubstancesareclassifiedasfollows:Class1:HighSolubility—HighPermeabilityClass2:LowSolubility—HighPermeabilityClass3:HighSolubility—LowPermeabilityClass4:LowSolubility—LowPermeability(RautioJ,etal.Prodrugs:designandclinicalapplications.NatureReviewsDrugDiscovery.2008;7:255–270.)Therecommendedmethodsfordeterminingsolubility,permeability,andinvitrodissolutionarediscussedbelow.A.SolubilityThesolubilityclassboundaryisbasedonthehighestdosestrengthofanIRproductthatisthesubjectofabiowaiverrequest.Adrugsubstanceisconsideredhighlysolublewhenthehighestdosestrengthissolublein250mlorlessofaqueousmediaoverthepHrangeof1–7.5.Thevolumeestimateof250mlisderivedfromtypicalbioequivalencestudyprotocolsthatprescribeadministrationofadrugproducttofastinghumanvolunteerswithaglass(about8ounces)ofwater.B.PermeabilityThepermeabilityclassboundaryisbasedindirectlyontheextentofabsorption(fractionofdoseabsorbed,notsystemicbioavailability)ofadrugsubstanceinhumansanddirectlyonmeasurementsoftherateofmasstransferacrosshumanintestinalmembrane.Alternatively,nonhumansystemscapableofpredictingtheextentofdrugabsorptioninhumanscanbeused(e.g.,invitroepithelialcellculturemethods).Intheabsenceofevidencesuggestinginstabilityinthegastrointestinaltract,adrugsubstanceisconsideredtobehighlypermeablewhentheextentofabsorptioninhumansisdeterminedtobe90percentormoreofanadministereddosebasedonamassbalancedeterminationorincomparisontoanintravenousreferencedose.C.DissolutionInthisguidance,anIRdrugproductisconsideredrapidlydissolvingwhennolessthan85percentofthelabeledamountofthedrugsubstancedissolveswithin30minutes,usingU.S.Pharmacopeia(USP)ApparatusIat100rpm(orApparatusIIat50rpm)inavolumeof900mlorlessineachofthefollowingmedia:(1)0.1NHClorSimulatedGastricFluidUSPwithoutenzymes,(2)apH4.5buffer,and(3)apH6.8bufferorSimulatedIntestinalFluidUSPwithoutenzymes.AreviewoftheapprovedproductsindicatethatmostoftheoralsolutionsandsyrupsaredevelopedforBCSClass1andBCSClass3APIs.ThisistobeexpectedbecausethecompoundsarehighlysolubleinwaterorgastrointestinalpHmedia.However,itisnotedthatthereareafewBCSclass2andclass4compoundsthatareformulatedasoralsolutionsorsyrups.Theseproductsutilizespecialtechniquessuchassaltformation,micronization,complexationwithresins,cosolvents,orsurfactantsforsolubilizationinordertoformulateashomogeneousoralliquiddosageforms.Table1showsthelistofall382productsandtheirBCSclassificationbasedonthevaluesobtainedfromliterature.Thistablewillbeupdatedasmoreinformationbecomesavailable.#GenericNameTradeNameBCSClassReferences1abacavirsulfateZiagen31,2,52acetaminophenChildren'sTylenol3,413acetaminophen/codeineacetaminophen/codeine4/31/14acetazolamideDiamox41,2,55acyclovirZovirax4,31,2,3,56albuterolP