REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
PublicaçãoOficialdaSociedadeBrasileiradeAnestesiologiawww.sba.com.br
SCIENTIFIC
ARTICLE
Mucoadhesive
buccal
films
of
tramadol
for
effective
pain
management
Xiao-Qin
Li
a,
Zhao-Ming
Ye
b,
Jian-Bing
Wang
c,
Cai-Rong
Fan
d,
Ai-Wu
Pan
e,
Cong
Li
f,
Ren-Bing
Zhang
g,∗aZhejiangUniversity,UniversityHospital,DepartmentofOrthopedicsNursing,Hangzhou,China
bThe2ndAffiliatedHospitalofMedicalSchoolofZhejiangUniversity,DepartmentofOrthopedics,Hangzhou,China cZhejiangUniversity,SchoolofPublicHealth,DepartmentofEpidemiologyandBiostatistics,Hangzhou,China dHangzhouHospitalofTraditionalChineseMedicine,DepartmentofPharmacy,Hangzhou,China
eZhejiangUniversity,UniversityHospital,DepartmentofInternalMedicine,Hangzhou,China fZhejiangUniversity,UniversityHospital,DepartmentofInformationCenter,Hangzhou,China gZhejiangUniversity,UniversityHospital,DepartmentofOrthopedics,Hangzhou,China
Received28June2015;accepted17August2015 Availableonline7May2016
KEYWORDS
Mucoadhesion;
Buccalfilm;
Tramadol; Analgesia; Swelling;
Orthopedicinjury
Abstract
Backgroundandobjectives: Tramadolhydrochlorideisacentrally-actingsyntheticopioid anal-gesicbindingtospecificopioidreceptors.Itisusedinthemanagementofchronicpainandis recommendedasfirstlinedruginthetreatmentofpostoperativeororthopedicinjuryinduced acutepain.Thepresentworkisdesignedtoprepareandevaluatemucoadhesivebuccalfilm oftramadolhydrochlorideasanovelformofprolongedanalgesiaforpatientswithorthopedic injuries.
Methods:Buccalfilmsoftramadolhydrochloridewerepreparedbysolventcastingmethod.The preparedfilmswereevaluatedforthevariousevaluationparameterslikethickness,surfacepH, weightuniformity,contentuniformity,foldingendurance,swellingindex,invitrodrugrelease study,invitrotestformucoadhesionandinvivostudies(primarymucosalirritancytestand analgesicactivity).
Results:Alltheformulationsexhibitedgoodresultsforphysicochemicalcharacterizations.In invitrodrugreleasestudythefilmsexhibitedcontrolledreleasemorethan12hours.The for-mulationBFT2(containingchitosanandPVPK-90)showednoirritanteffectonbuccalmucosa andelicitthesignificantinvivoanalgesicactivitywith57.14%analgesiaagainstthatofstandard (61.04%).Itwasconcludedthatthemucoadhesivefilmsoftramadolhydrochloridecanbe effec-tivelyusedtoalleviatetheseverepainoforthopedicinjurieswithpromptonsetandprolonged action.
©2016SociedadeBrasileiradeAnestesiologia.Publishedby ElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).
∗Correspondingauthor.
E-mail:[email protected](R.-B.Zhang).
http://dx.doi.org/10.1016/j.bjane.2015.08.016
PALAVRAS-CHAVE
Mucoadesão;
Filmebucal;
Tramadol; Analgesia; Edema;
Lesãoortopédica
Filmesbucaismucoadesivosdetramadolparaocontroleeficazdador
Resumo
Justificativaeobjetivos: Ocloridratodetramadoléumanalgésicoopioidedeac¸ãocentralque seligaareceptoresopioidesespecíficos.Éusadonotratamentodedorcrônicaerecomendado comofármacodeprimeiralinhaparaotratamentonopós-operatórioouemdoragudainduzida porlesão ortopédica. Opresenteestudo visapreparar eavaliaro filmebucalmucoadesivo decloridratodetramadolcomoumanovaformadeanalgesiaprolongadaparapacientescom lesõesortopédicas.
Método: Filmesbucaisdecloridratodetramadolforampreparadospelométododeevaporac¸ão desolvente.Osfilmespreparadosforamavaliadosparaosváriosparâmetrosdeavaliac¸ãocomo espessura,pH dasuperfície,uniformidadedopeso,uniformidadedoconteúdo,resistênciaa dobras,índicedeintumescimento,estudodeliberac¸ãodadrogainvitro,testeinvitropara mucoadesãoeestudosinvivo(testedeirritac¸ãodamucosaprimáriaeatividadeanalgésica). Resultados: Todasasformulac¸ões apresentaram bonsresultadospara caracterizac¸ões físico-químicas.Emestudodelibertac¸ãodedrogainvitro,osfilmesexibiramliberac¸ãocontrolada maisde12horas.Aformulac¸ãodeBFT2(contendoquitosanaePVPK-90)nãomostrouefeito irri-tantesobreamucosabucaleprovocouumaatividadeanalgésicasignificativainvivocom57,14% deanalgesiaversusadopadrão(61,04%).Concluiu-sequeosfilmesmucoadesivosdecloridrato detramadolpodemserusadoseficazmenteparaaliviaradorintensadelesõesortopédicascom iníciorápidoeac¸ãoprolongada.
©2016SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Este ´eum artigoOpen Accesssobumalicenc¸aCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Buccaldrugadministrationisverywidelyacceptedrouteof administrationfor potentmedicinesfortheclinical condi-tionswhichisassociatedwithseverepainanddiscomfort.1
Generally orthopedic patients suffering from disorders of the skeletal system and associated muscles, joints, and ligaments needs constant and prolonged drug deliv-ery for effective management of therapeutic condition.2
Buccoadhesivedrugdeliveryavoidsthedestructionby gas-trointestinalcontents or hepatic first-pass inactivation of drugandensuresintimatecontactofdrugtothebiological systemforbetterdrugabsorption.3,4
Generallypost-operativepainiseffectivelymanagedby opioid analgesic, semisynthetic opioids, neuroleptic anal-gesicandpotentNSAIDS.Butimmediateaftersurgerymany atime’sevenverystronganalgesicscannoteffectively man-agethepain.Whentheeffectofgeneralanesthesiasubsides (generallyafter6---12haftersurgery)patientsfeelsagreat painwhichmightnotbemanagedbyanymeansandmany times are intolerable. Therefore, the present study was conducted to explore the feasibility and effectiveness of buccalmucoadhesivedrugdeliveryoftramadolasan effec-tive alternative of NSAIDs in relieving pain after surgery or orthopedic injury. In an attempt to reduce the rela-tivelyhigh incidenceofseriousadverse effectsassociated withthesystemicuseofNSAIDs,agrowingnumberof topi-calformulationsofthesedrugshavebecomecommercially available.5 The present work is designed to prepare and
evaluatemucoadhesivebuccalfilmoftramadol hydrochlo-rideasanovelformofprolongedanalgesiaforpatientswith orthopedicinjuries.
Tramadol hydrochloride is a centrally-acting synthetic opioid analgesic binding to specific opioid receptors. It is anon-selective,pureagonistatmu,deltaandkappaopioid receptorswithahigheraffinityforthemureceptor.2,6
Tra-madolHClisfreely solubleinwater,andreadilyabsorbed following oral administration. The systemic bioavailability of tramadolhydrochlorideis approximately68%afteroral administration.TramadolHClisacentrallyactinganalgesic usedin managementofchronic painandis recommended asfirstlinedrugtreatmentoforthopedicinjurytoproduce adequate painrelief.Thehalf-life ofadrugisabout5.5h andtheusualoraldosageregimenis50---100mgevery4---6h withamaximumdosageof400mg·day−1.7
Methods
Chitosan, PVP K-90 and PVP K-70 were purchased from Sigma---Aldrich.Allotherchemicalsusedwereofanalytical grades.
Preparationsofbuccalfilmoftramadol
polymericsolutionandthesolutionwaspouredintoaglass Petridishhaving9.5cmdiameter.ThePetridisheswerekept onflatsurfaceandcoveredbyinvertedfunneltoallow con-trolledevaporationofsolventat40◦Ctillaflexiblefilmwas
formed.Driedfilmswerecarefullyremoved,checkedforany imperfectionsorairbubblesandcutintofilmsof10mmin diameter.8,9
Thicknessandweightuniformity
Astandardscrewgaugewasusedtomeasurethethickness of threerandomlyselectedbuccal films fromeach batch. Weightuniformityoffilmwastestedbytakingweightoffive films ofsizes 10mm diameterfromeach batchandweigh individually onelectronic balanceandtheaverage weight wascalculated.10
Contentuniformity
Drug content uniformity was determined by dissolving the buccal film (10mm in diameter) from each batch by homogenization in 100mL of an isotonic phosphate buffer(pH 6.8)for6hunderoccasional shaking.The drug content was then determined after proper dilution and measured the absorbance at 271nm using a UV---visible spectrophotometer.11
Foldingendurance
Randomlyselectedthreefilmsfromeachbatchweretaken tomeasurethefoldingendurance.The filmswere repeat-edly folded at the same place till it broke. The films folded up to300 timesmanually wasconsidered satisfac-tory value.12 The numberoftimes offilmcouldbefolded
at thesameplacewithoutbreakinggavethe valueof the foldingendurance.
SurfacepH
Buccalfilmswerelefttoswellfor1honthesurfaceofthe agarplate,preparedbydissolving2%(w/v)agarinwarmed isotonicphosphatebufferofpH6.8understirringandthen pouredthesolutionintothepetridishallowedtostandtill gellingatroomtemperature.ThesurfacepHwasmeasured bymeansofpHpaperplacedonthesurfaceoftheswollen film.13,14
Swellingindex
Thewateruptakewasdeterminedgravimetrically.Thedried films fixed to stainless steel support were immersed in a beaker containing25mLdistilledwater at room tempera-ture.Atspecificintervalsupto3h,theswollensamplewith thepre-weighedmeshwereweighedafterremovalofexcess surfacewaterbylightblottingwithafilterpaper.The exper-imentwasdiscontinuedwhenthefilmsbegintodisintegrate
ordissolve.15 Toquantifytheswellingprocess,theswelling
indexpercentagewascalculatedasfollows:
Swellingindex%=
W s−Wd
Wd
×100
whereWdistheweightofthedriedpolymerfilmandWsis theweightafterswelling.
Invitroreleasestudy
Invitrodrugreleasestudywascarriedoutbyusingmodified dissolutiontest apparatustype1 (eight-stationdissolution apparatus). The dissolution medium, 50mL IPB, pH 6.8, weremaintainedat 37±0.50◦Candit waskeptinaglass
beaker placed inside the dissolution flask. The film was attachedtoendoftheshaft(withoutbasket)withthehelp ofcyanoacrylateadhesive,whichwasrotatedat50rpm.16
Aliquotsofsamples(2mL)werewithdrawnattheintervals of1, 2,3,4, 5,6 and7h andfiltered usingWhatman fil-terpaperNo.1.Thewithdrawalswerecompensatedusing equalvolumes of IPB keptat the same temperature. The concentrationofdrugreleasedinthemediumwasmeasured spectrophotometrically at 271nm after suitable dilution withthedissolutionmedium.
Invitromucoadhesiontest
Theinvitromucoadhesiontimewasdeterminedbyusinga modifiedUSPdisintegrationapparatus.800mLofphosphate bufferofpH6.8(IPB)maintainedat37±0.50◦Cwereused
asdisintegrationmedium.Apieceofporcinebuccalmucosa, 3cmlengthwastakenforthestudy.Thebuccalmucosawas attachedtoa rectangular glasspiece usingcyanoacrylate adhesivefromnon-mucosalsurface.Themucoadhesivefilm washydratedfromonesurfaceusingpH6.8IPBandthenthe hydratedsurfacewasbroughtincontactwiththemucosal membrane.Theglassslabwasverticallyfixedtothe appa-ratusandallowedtomoveupanddownsothatthefilmwas completelyimmersed in thebuffer solutionat the lowest pointandwasoutatthe highestpoint.17 Thetime
neces-saryforcompletedetachmentofthefilmfromthemucosal surfacewasobservedandrecorded(n=3).
Invivostudy
ThehealthymaleWistarrats(200---250g)wereusedforthe study. The rats were kept in cages in standard environ-mentalconditionsoflightandtemperature.The ratswere allowed free accessto drinking water and standard diet. The protocols of the animal study were approved by the Institutional Animal Care and Use Committee of Zhejiang University,Hangzhou (approval refno. 109. 10/08/2014); andwascarriedoutincompliancewiththeDirective.
Primarymucosalirritancystudies
Table1 Formulationsofbuccalfilmsoftramadolhydrochloride.
Formulationcode Chitosan% (w/w)
PVPK-90 (mg)
PVPK-70 (mg)
Propyleneglycol (%)
Tramadol (mg)
BFT1 1 50 --- 5 500
BFT2 1 100 --- 5 500
BFT3 1.5 50 --- 5 500
BFT4 1.5 100 --- 5 500
BFT5 1 --- 50 5 500
BFT6 1.5 --- 100 5 500
wasappliedtooralmucosa(ofurethaneanesthetizedrats)
tothegroupI(control)usinganadhesivetapeUSP.Tothe
groupII (test) transmucosal patch formulationBFT2
(con-tainingchitosanandPVPK-90)wasapplied.TothegroupIII
(standard)0.8%v/vaqueoussolutionofformaldehyde
(irri-tant)wasapplied.Theapplicationsiteswereobservedfor
anyerythemaandedemaonthemucosalsurfacefor2days
afterapplicationandthescoringwasdone(Table1).
Invivoanalgesicactivity
Mal albino rats were divided in three groups of six rats each.Thefirstgroupservedascontrolanditreceived non-medicatedbuccalfilms. The test group II receivedbuccal films(BFT2,50g·kg−1bodymass).Thethirdgroupreceived
standard (transmucosal gelof fentanyl citrate,10g·kg−1
bodymass).Threehoursaftertreatment,0.6%(V/V)acetic acid solution (10mL·kg−1) was injected to rats intraperi-toneally.Totalnumberofwrithes, whichwasaparameter ofchemicallyinducedpain(i.e.,constrictionofabdomen, turningof trunkand extensionofhind legs), wascounted for 20min The analgesic effectwas expressedas percent reductionofwrithesincomparisonwiththecontrol.
Statisticalanalysis
Results were expressed as mean values±standard devia-tions.Statisticalanalysiswascarriedoutusingtheanalysis of variance (ANOVA). A probability value less than 0.05 (p<0.05)wasconsideredtobeasignificantvalue.
Results
Buccal films of tramadolhydrochloride were prepared by solvent casting method by using Chitosan PVP K-70 and
PVP K-90 as mucoadhesive polymers. The prepared films wereevaluatedforthevariousphysicochemicalevaluation parameters like thickness, surface pH, weight unifor-mity, content uniformity, folding endurance and swelling index (Table 2). Thickness of all six formulations was found tobein therangeof 0.24±0.04to0.54±0.02mm The all prepared formulation of tramadol hydrochloride buccal film showed the pH range within the range of salivary pH i.e. 6.32---6.82. The observed surface pH of the formulation BFT1, BFT2, BFT3, BFT4, BFT5and BFT6 are 6.82±0.28, 6.40±0.16, 6.44±0.09, 6.59±0.12, 6.52±0.44, 6.53±0.23 respectively. The result of film thicknessshowed that therewasnosignificant difference ofsurfacepHinalltheformulation.Thefoldingendurance wasmeasured manually,by foldingthefilm repeatedlyat apointtillitbroke.The numberoftimesof filmcouldbe folded atthesameplacewithout breakinggavethe value of the folding endurance. Hence the breaking time was taken astheend point. The foldingendurancewasfound to be highest for formulation BFT6(298±5.211) and the lowestforformulationBFT1(238±4.211).Itwasfoundthat the foldingendurance wasincreasedwith theaddition of PVPwithincreasedconcentrationofchitosan.18,19 Percent
swellingof buccal films werefound to bein therange of 17.40±0.28 to24.66±1.50. It was concluded that more hydrophilicnatureofpolymerinBFT2resultedinmaximum swellingascomparedtotheotherformulations.
Invitrodrugreleasestudywascarriedoutbyusing mod-ifieddissolutiontestapparatus(Fig.1).Thestudyrevealed that the drug release was dependent on the concentra-tionanddifferentgradesofpolymers used.Among allthe formulationsofbuccalfilmsformulationBFT2showed max-imumdrugreleaseattheendof12h.Invitromucoadhesion test wasperformed byusingmodified disintegrating appa-ratus. Results of in vitro mucoadhesion test showed that
Table2 PhysicochemicalcharacteristicsofpreparedbuccalfilmsoftramadolHCl.
Buccalfilm code
Thickness(mm) SurfacepH Weight uniformity
(mg)
Folding endurance
Drug content
(%)
Swelling% after6h
Table3 Primarymucosalirritationtestoftransmucosalmucoadhesivebuccalfilmsoftramadol.
Ratno. ControlgroupI Test(BFT2)groupII StandardirritantgroupIII
Erythemaa Edemab Erythemaa Edemab Erythemaa Edemab
1 1 0 1 1 3 2
2 0 1 0 1 3 2
3 0 1 0 0 3 1
Average±S.D 0.34±0.58c 0.67±0.58c 0.34±0.58c 0.67±0.58c 3±0 1.67±0.50 a Erythemascale:0,none;1,slight;2,welldefined;3,moderate;and4,scarformation.
b Edemascale:0,none;1,slight;2,welldefined;3,moderate;and4,severe;n=3. c p<0.05,significantcomparedwithformalin.
0 20 40 60 80 100
12 10
8 6
4 2
0
Cumulative,
%
drug
released
Time (h)
BFT1 BFT2 BFT3 BFT4 BFT5 BFT6
Figure1 In vitrodrug releasestudy ofbuccalfilmsof tra-madolhydrochlorideinphosphatebufferofpH6.8.
formulation BFT6 with higher concentration of chitosan showedthemaximummucoadhesionpropertyascompared to others.20,21 Whereas BFT2 had the least mucoadhesion
property,whichmightbeduetohydrophilicnatureofPVP K-90 which loosen the bond strength from the mucosal area.
FormulationBFT2wassubjectedtoinvivostudiesfor pri-marymucosalirritancytestandanalgesicactivity.TheBFT2 filmswerefoundtobenon-irritantintheprimarymucosal irritationtest(Table3).TheformulationBFT2showed signif-icantlygoodinvivoanalgesicactivitywith57.14%analgesia against that of standard which showed 61.04% analgesia (Table4).
Discussion
Mucoadhesion is one of the most widely investigated approachesindeliveringthedrugsforquickonsetofaction andimprovedbioavailability.Thebuccalmucosabeingrich invasculatureprovidesaverygoodplatformfordelivering thedrug directly tothe systemic circulation. The dosage requirementis verylessascomparedtothat oforal drug delivery.In orthopedic patients the acute pain is many a timesistobedealtimmediatelywithhighefficacy.Andfor thesamebuccalmucoadhesivepatchesareconsideredtobe thebestapproach.21---24Themucoadhesivebuccalpatchesof
analgesicshavebeeninvestigatedinclusiveoftramadol.25---27
Oral Transmucosal Fentanyl Citrate (OTFC) provides the rapid-onsetopioidsandashortdurationofanalgesia. Exten-siveresearches have been doneonthe transmucosaldrug deliverysystemoffentanylforbuccal,sublingualandnasal mucosaldelivery.28---31
The various alternative dosage forms of tramadol have been investigated for improving the efficacy of the treatment.32---34 Insome previous studiesalsothe
mucoad-hesivedosageformshavebeendevelopedfortramadol.27,34
Inthepresentstudy,ascomparedtootherformulations BFT2(containingchitosanandPVPK-90)showedincreased surface wetting and water penetration which resulted in good dissolution profile. On the other hand, formulation BFT6(containingchitosan andPVPK-70)showedminimum drugrelease;might bedue tomoreconcentration of chi-tosan which being less water soluble retarded the drug release.Resultsofinvitroreleasestudyindicatedthat vary-ingconcentrationofchitosandidnotaffectthedrugrelease significantly.
Table4 Invivoanalgesicactivityoftransmucosalmucoadhesivebuccalfilmsoffilmsoftramadol.
Drug Oraldosea
(g·kg−1)
Analgesicactivity
N◦ofwrithesb Analgesia%
Control(blankfilms) --- 77±4 ---Fentanylcitrate(standard) 10 30±1c 61.04
BFT2 20 33±2c 57.14
a Doseequimolartotheparentdrugcalculatedonthebasisofdrugcontents. b Mean±SEM,n=6.
BFT2 showed excellent analgesic activity with no irritation on the mucosa.The analgesic activity wasvery muchcomparabletothe standard oral mucoadhesive for-mulation of fentanyl citrate which is a very well known analgesic opioid with rapid-onset anda shortduration of analgesia. Sonot only the rapid onset of action but also theprolongedrelease(asindicatedbyinvitroreleasedata) (Fig.1) can be achieved with the present formulation of tramadol.
Summary
Theresultsofthestudyshowthattherapeuticlevelsof tra-madolcanbedeliveredthroughbuccalroute.The present study concludes that these erodiblemucoadhesive buccal filmscontainingtramadolcanbeverypromising for effec-tivedosestosystemiccirculationinpatientsoforthopedic injuries.Filmsexhibitedcontrolledreleaseovermorethan 10hwithnoirritationonmucosa.Thefilmsshowed compa-rableanalgesic effectinvivostudies.Thusthesefilmscan beselectedforthedevelopmentofbuccalfilmforeffective therapeuticuses.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgement
This work was supported by study on technology for the detectionofserumlowmolecular-massbiomarkersof min-istryofS&TofZhejiangProvince(no.2013C37083).
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