Hydrogels:History&ApplicationinDrug Delivery
Hydrogelsarecomposedofhydrophilicpolymerswithathreedimensionalnetwork structurethatcanabsorblargeamountsofwateraswellasbeusedtocarrydrugs Hydrogelspreparedwithsuitablematerialsarebiocompatibleandhavecontrolled mechanicalandviscoelasticpropertiesSincethecoiningoftheterm"hydrogel"inthelate 19thcentury,hydrogelshavebeenwidelyusedindrugdelivery,wounddressings,tissue engineering,andhygieneproductsThisarticleintroduceshydrogelsintermsoftheir history,structuralforms,andapplicationsindrugdelivery.
Figure1.Structureofhydrogelatthemolecularlevel.
HistoryofHydrogels
Thetermhydrogelcanbetracedbackto1894andwasfirstusedtodescribeacolloidof someinorganicsalts.Today,hydrogelhasacompletelydifferentmeaningthanithadat thebeginningThefirsteverhydrogelreportedin1949forbiomedicalimplantwasIvalon, poly(vinylalcohol)crosslinkedwithformaldehyde.Andin1960,PHEMA (Polyhydroxyethylmethacrylate)wasintroducedwhichbringthemarketofhydrogelto boom.Lookingbackatthehistoryofhydrogel,itcanberoughlydividedintothree generations
First-genarationHydrogels
ThefirstgenerationhydrogelsaredividedintothreemaincategoriesThefirstcategoryis polymersofalkenemonomerssubjectedtoradicalinducedchainadditionreactions,
BiopharmaPEG https://wwwbiochempegcom mainlyrepresentedbypolyacrylamide(PAM)andpolyhydroxyethylmethacrylate (pHEMA),whichremainanimportantbiomaterialdespitehavingbeeninventedmorethan 70yearsago.Thesecondcategoryiscovalentlycrosslinkedhydrophilicpolymers,mainly representedbypolyvinylalcohol(PVA)andpolyethyleneglycol(PEG),whicharemainly usedintissueengineeringThethirdcategoryiscellulosebasedhydrogels,whichare mainlyusedasdrugdispersionmatricesindrugdelivery
Second-generationHydrogels
ThesecondgenerationofhydrogelsismainlyPEG/polyesterblockcopolymers,whichare characterizedbytheabilitytoconvertthechemicalenergyofthehydrogelintothe mechanicalenergyofthehydrogeltoachievethespecifiedfunction
Thiscategoryofstimuliresponsivehydrogels,whichcanrespondtoexternal environmentalchanges(suchastemperatureorpH),appearedonthemarketinthe 1970sStimulusresponsivehydrogelscanbebroadlyclassifiedintothreecategories
Theyexhibitaphasetransitionfromgelto solstatefromlowtohightemperatures,mainlyrepresentedbyPluronicsfromBASFor PoloxamersfromImperialChemicalIndustries,UK
pH-sensitivehydrogelsThesepolymersarehydrolyzedathighorlowpH environments,respectively
Thesehydrogelscanrespondtochanges intheconcentrationofspecificbiomoleculesthroughconformationalchangesFor example,glucoseoxidaseincorporatedhydrogelscanbeusedforinsulindelivery.As glucosediffusesinthehydrogelmatrix,itisconvertedtogluconicacidbyglucoseoxidase inthehydrogel,whichcausesadecreaseinthepHoftheenvironment.Thesubsequent increaseinlysisduetoprotonationoftheaminefunctionalgroupofthehydrogelallows insulintobereleasedfromthematrix,formingasystemofselfregulatedinsulinrelease.
Third-genarationHydrogels
Themainfeatureofthirdgenerationhydrogelsis"crosslinking",whichmodulatesthe mechanicalanddegradationpropertiesofhydrogelsmainlythroughstereoconjugation, inclusion,metalligandcoordinationandsynthesisofpeptidechains.Forexample,oneof themainapplicationsofstereoconjugationisthepreparationofinjectablehydrogelsby blockingtwoamphiphiliccopolymers,poly(Llacticacid)(PLLA)andpoly(Dlacticacid) (PDLA)Therearealsostudiesontheuseofcyclodextrininclusioncompoundsto constructhydrogelswithhydrophobiccavitiesthatcanaccommodatedifferentmolecules. Inaddition,therearealsostudiesonsyntheticpeptide(orprotein)hydrogelsconstructed byusingthefoldingstructureofpeptidesingeneticengineering,butsuchhydrogelsare mainlyembodiedinresearch
HydrogelsforDrugDelivery
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Thereisincreasedinterestinhydrogelsfordrugdeliveryduetotheirstimuliresponsive properties,whichcanchangeitsproperties(suchasmechanicalproperties,swelling capacity,hydrophilicity,orpermeabilityofbioactivemolecules)undertheeffectof surroundings,includingtemperature,pH,electromagneticradiation,magneticfield,and biologicalfactorsHere,wewillfocusonhydrogelbaseddeliveryofdrugs
BuccalDrugDelivery
Buccalororalmucosalrouteshavevariousadvantagesfortheadministrationofdrugs whichundergoseverefirst-passmetabolismHydrogelseemedanappropriatematerial forthebuccaldeliverysystemsbecauseofitsmucoadhesiveness,sustainedrelease property,goodfeelinthemouth,andsafety
Theoralcavityislinedbyamucousmembraneconsistingofstratifiedsquamous epitheliumandanunderlyingconnectivetissuelayerThedrugdeliveryprocessintheoral cavitymainlygoesthrough:drugdissolution,drugdiffusionthroughthemucosaby passiveoractivemeanstothelocalbloodcirculationsystemandfinallytothesystemic bloodcirculationTherefore,thepermeabilityofdifferentsitesbringsdifferentdrug deliverymodes
Thesublingualmucosaismorepermeablethanthebuccalmucosaandissuitablefor drugsthatrequirearapidonsetofaction,butdrugdeliverythroughthesublingualmucosa caninterferewithtonguemovementduringspeechIncontrast,drugdeliverythroughthe buccalmucosahaslessimpactontonguemovementandispreferredforthetreatmentof chronicdiseases,whereasdrugdeliverythroughthegingivaisoftenlimitedtolocalaction Mucosaldrugdeliveryresultsinalargeportionofthedrugenteringthegastrointestinal tract,thereforehydrogelswithmucoadhesivepropertiesareconsideredinthedosage formdesign.Hydrogelbasedbioadhesivetabletscanbeusedtocontroltherateofdrug releaseusingwatercooperationCommonmatricesusedinthesehydrogelapplications arehydroxypropylcellulose(HPC),hydroxyethylcellulose(HEC),polyacrylicacid(PA), carboxymethylcellulose(CMC),polyvinylalcohol(PVA),hydroxypropylmethylcellulose (HPMC),chitosan,etc.
Thehydrogeldrugscurrentlyonthemarketforbuccaldelivery,mainlyfororalcareand rehydrationorforcontinuousdeliverysystemsforanginaprevention,arelistedinthetable below
Table1Hydrogelsforbuccaldrugdelivery
IntravaginalDrugDelivery
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Thevaginahasbeentraditionallyusedasarouteofadministrationfordelivering anti-microbialandanti-viraldrugs,asbacteria,fungiorvirusescaneasilymultiplyinthe vaginaandcauseavarietyoflesionsthatinducevaginitis.Inaddition,vaginaldeliveryis alsoanalternativetoparenteralroutesofadministrationofpropranolol,humangrowth hormone,insulin,andsteroidsduetoitslargesurfacearea,highperfusionoftissues,and highpermeabilitytopeptidesandproteins,etcThemainobstacletovaginal administrationisthechangeinvaginalfluidcontentandpermeabilityofthevaginal mucosacausedbychangesinageandhormonelevels,whichinturnaffectsdrugrelease andpharmacokinetics
Currently,twoapproachesareusedtoovercomethislimitation:theuseofmucosal adhesivestoprolongtheresidencetimeofthedrugonthevaginalmucosa,andtheuseof stimulisensitivehydrogelswithasolgeltransitioninthevaginalenvironmentBoth solutions,inturn,relyheavilyonmatrixexcipientsThemostcommonlyusedpolymersin vaginalpreparationsarehydrogels:polyacrylates,chitosan,cellulosederivativessuchas carboxymethylcellulose(CMC),hydroxypropylmethylcellulose(HPMC)andhyaluronic acid,alginateandgelatin.Themaindrugscurrentlyonthemarket,mainlycareproducts andgynecologicaldrugs,arelistedinthetablebelow
Table2Hydrogelsforintravaginaldrugdelivery
TransdermalDrugDelivery
Transdermaladministrationisaspecificrouteofadministrationsuitableforpoorly absorbedoraldrugswithhighfirst-passeffectsandforpatientswhoareintolerantto injectionsTheskinisaninhomogeneousmembranewithverylowpermeability characteristicsthatreducewaterlossandstoptheflowoftoxinsintothebody
Theoutermostlayeroftheskinisthestratumcorneum,whichisonly2025μmthickand preventsthepenetrationofforeignsubstances,butisalsothegreatestobstacleto transdermaldrugdeliveryConventionaltransdermalpatchdeliveryrequiresdrugswith lowmolecularweight,highlipophilicity,andsmalldosesIn1979,thefirsttransdermal systemforsystemicdrugdelivery,scopolaminetransdermalpatch,wasapprovedinthe UnitedStatesTenyearslater,nicotinepatchesweremarketed,whichnotonlyfeatured
https://wwwbiochempegcom highpatientcompliancebutalsogreatlyincreasedthevisibilityoftransdermal formulationsamongpatients
Conventionaltransdermalpatchesmarketedinrecentyearscanbedividedintotwomain categories:reservoir-basedpatchesandmatrix-basedpatchesThefirsttypeis characterizedbykeepingthedruginasolutionorgelandcontrollingdrugdeliverythrough amembranelocatedbetweenthedrugreservoirandtheskinThelattercombinesthe adhesiveandmechanicalpropertiesoftheformulation,andthedrugdeliveryrateis controlledsolelybyskinpermeabilityOvercomingskinpermeabilityisthusthekeytothe problem,ashydrogelspromoteskinpenetrationofthedrugthroughskinhydrationfor bothtopicalandsystemiceffectsListedbelowaresomeofthecommercialproducts basedontransdermaldrugdeliveryhydrogelsavailableinthemarket,whichcovera relativelywiderangeofdrugdeliveryfromdermatologicalconditionstosystemicdrug delivery
Table3.Hydrogelsfortransdermaldrugdelivery
OcularDrugDelivery
Withtheproperformulationdesignofhydrogels,contacttimecanbeextended,especially withsubconjunctivaladministration,wherethedrugcanbypasstheconjunctivalcorneal barrierandenterdirectlyintothetransscleralpathwaytotheposteriorpartoftheeye.
Hydrogelformulationshavebeenusedinavarietyofophthalmicapplicationsbecause theyofferseveraladvantagesoverconventionalmaterials,suchasmildpreparation conditions,highwatercontent,andimportantfeaturesthatmaintaintheactivityof moleculessuchasproteins.Moreover,certaintemperaturesensitiveandinsituhydrogels canbeadministeredinalessinvasivemannerforlongtermimplantationpurposesSome ofthecommerciallyavailablehydrogelbasedproductsonthemarketforoculardrug deliveryarelistedbelow
Table3.Hydrogelsforoculardrugdelivery
Conclusion
HydrogelshavebeenreceivingalotofattentionduetotheiruniquepropertiesAlthough relevanttheoreticalstudieshavebeenconductedtodigdeeperintoit,therearestillmany prescriptionsthathavefailedtoenterthemarket,andhydrogelsarestillpromisinginthe fieldofdrugdelivery
Atpresent,PEGhasbeenwidelyusedashydrogels,anditisexpectedthatfuture applicationprospectswillalsobequitebroadBiopharmaPEGprovidesmultiarmPEG derivatives,including4armand8armPEGproducts,aswellassomeotherPEG productswithspecialstructures,whichcanbeusedtocrosslinkintodegradablePEG hydrogels
4armPEGSuccinimidylCarboxymethylEster
4armPEGAmine
Hydrogel
Hydrogel
4armPEGThiol Hydrogel
8armPEGAmine(tripentaerythritol),HClSalt
Hydrogel
8armPEGAmine,HClSalt Hydrogel
8armPEGThiol(hexaglycerol) Hydrogel
AcrylatePEGNHSEster Hydrogel
MethoxyPEGAmine Hydrogel
References:
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[2]PrausnitzMR,MitragotriS,LangerRCurrentstatusandfuturepotentialof transdermaldrugdelivery[J]NatureReviewsDrugDiscovery,2004,3(2):115
[3]CasconeS,LambertiGHydrogel-basedcommercialproductsforbiomedical
BiopharmaPEG https://wwwbiochempegcom
applications:Areview[J].InternationalJournalofPharmaceutics,2019,573:118803.
[4]Bertens,Christian,J,etalTopicaldrugdeliverydevices:Areview[J]Experimental EyeResearch,2018.
[5]CalóE,KhutoryanskiyVVBiomedicalapplicationsofhydrogels:Areviewofpatents andcommercialproductsScienceDirect[J]EuropeanPolymerJournal, 2015,65:252267
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