2 Applications of Polymers in Buccal Drug Delivery · PDF fileeffort has been focused on drug...

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Aliasgar Shahiwala

2.1 Introduction

Absorption of drugs through the oral cavity was noted as early as 1847 and systemic studies of oral cavity absorption were first reported in 1935 [1]. Since then, substantial effort has been focused on drug absorption from a drug delivery system in a particular region of the oral cavity [2-5]. As a site for drug delivery, the oral cavity offers many advantages over other routes of drug administration. The mucosal lining of the oral cavity are readily accessible [6], robust, and heal rapidly after local stress or damage [6-8]. Oral mucosal drug delivery systems can be localised easily and are well accepted by patients [9]. The mucosal membranes of the oral cavity can be divided into five regions:

• Floorofthemouth(sublingual)

• Buccalmucosa(cheeks)

• Gums(gingival)

• Palatalmucosaand

• Liningofthelips

These regions are different from each other in terms of anatomy, permeability to drugs, and their ability to retain a delivery system for a desired length of time. The oral cavity has been used for local as well as systemic drug therapy.

Local therapy includes treatment for intraoral conditions such as gingivitis, oralcandidiasis,orallesions,dentalcarries,xerostomia(drynessofmouthduetolackofsaliva),oralcancer,mucositisandneuropathicpain[10-13].

For systemicdrug therapy,buccal and sublingual routesare commonlyuseddueto their transmucosal permeability [14, 15]. Sublingual mucosa is more permeable,

2 Applications of Polymers in Buccal Drug Delivery

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Applications of Polymers in Drug Delivery

thinner with a richer blood supply compared to buccal mucosa, producing a rapid onsetofactionwhichmakesitappropriatefordrugswithashortdeliveryperiod [16, 17]. However, the buccal mucosa is less permeable than the sublingual mucosa and it does not yield a rapid onset of action as seen with sublingual delivery. The mucosa of the buccal area has a large, smooth and relatively immobile surface, which is suitable for the placement of a retentive system and it offers sustained and controlled drug delivery [18, 19].

2.1.1 Advantages of Buccal Drug Delivery [6, 20, 21]

There are various advantages of drug delivery through the buccal route, these are:

• Thebuccalmucosaisrichlyvascularisedandmoreaccessiblefortheadministrationand removal of a dosage form.

• Thereishighpatientacceptabilitycomparedtoothernon-oralroutesofdrugadministration.

• Comparedtotheharshenvironmentalfactorsthatexistintheoraldeliveryofdrugs, the mucosal lining of the buccal tissues provides a much milder environment for drug absorption.

• Thereislowenzymeactivityinthebuccalmucosacomparedtoothermucosalroutes.

• Buccal drug delivery avoids acid hydrolysis in the gastrointestinal tract andbypasses the first-pass effect.

2.1.2 Disadvantages of Buccal Drug Delivery [22-26]

Someofthedrawbacksofthebuccalrouteare:

• Lowpermeabilityofthebuccalmembrane,specificallywhencomparedtothesublingual membrane.

• A smaller surface area.The total surface area of themembranes of the oralcavityavailable fordrugabsorption is170cm2,ofwhich~50cm2 represents non-keratinisedtissues,includingthebuccalmembrane.

• Thecontinuoussecretionofsaliva(0.5–2l/day)leadstosubsequentdilutionofthe drug.

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Applications of Polymers in Buccal Drug Delivery

• Swallowingofsalivacanalsopotentiallyleadtothelossofdissolvedorsuspendeddrug and ultimately the involuntary removal of the dosage form.

• Hazardofchokingbyinvoluntarilyswallowingthedeliverysystem

• Thebuccaldeliverysystemmaybeinconvenientwhileeatingordrinking.

2.2 Factors Affecting Bioadhesion in the Oral Cavity

To administer a pharmaceutical dosage form in the mucosa of the oral cavity, it isnecessary to take intoaccount two importantparameters.First, it isnecessaryto prolong the time of contact between the drug formulation and the mucosal route of administration. Second, the oral mucosa shows a lower permeability to large molecules, which can be problematic for achieving therapeutic levels of such molecules. The ability to maintain a delivery system at a particular location for an extended period of time has a great appeal for both local disease treatments as well as systemic drug bioavailability [26]. There are various factors that contribute towards the bioadhesion to buccal mucosa and these are shown in Table 2.1.

Table 2.1 Factors affecting bioadhesionDrug related

factorsFormulation

related factorsPolymer-related

factorsEnvironmental factors

Hydrophilicity

Acid dissociation constant(pKa)

•Typeofformulation

•Flexibility

•Contactsurfacearea

•Molecularweight

•Flexibility

•Glasstransitiontemperature(Tg)

•Hydrogenbondingcapacity

•Crosslinkingdensity

•Charge

•Concentration

•Hydration(swelling)

•Appliedpressureonapplication

•Contacttime

•Salivaflowrate

•pH

•Mucinturnoverrate

•Movementofthebuccaltissues while eating drinking,andtalking

•Diseasestate

PolymerpropertiesthataffecttheirbioadhesivepropertiesarediscussedinSections 2.2.1-2.2.8.

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2.2.1 Functional Groups

Bioadhesive polymers are generally hydrophilic networks that contain numerouspolar functional groups. The attachment and bonding of bioadhesive polymers to biological substrates occurs mainly through interpenetration followed by secondary non-covalent bondingbetween substrates. Physical entanglements and secondaryinteractions(hydrogenbonds)contributetotheformationofastrengthenednetwork,therefore, polymers with a higher density of available hydrogen bonding groups suchascarboxyl(COOH),hydroxyl(OH),amide(NH2)andsulfategroups(SO4H)would be able to interact more strongly with mucin glycoproteins [27]. In order for bioadhesion to occur, the desired polymers must have functional groups that are capable of forming hydrogen bonds [28].

Theflexibility of the polymer is important in improving this hydrogen bondingpotential. Polymers such as polyvinyl alcohol (PVA), hydroxylatedmethacrylate,and polymethacrylic acid, as well as all their copolymers, are polymers with a good hydrogenbondingcapacity[29].Consequently,suchfunctionalisedpolymersinteractwith the mucus not only through physical entanglements but also through secondary chemicalbonds,thus,resultingintheformationofweaklycrosslinkednetworks[30,31].

2.2.2 Molecular Weight

In general, it has been shown that the bioadhesive strength of a polymer increases withmolecularweight(s)(MW)above100,000[32].ThedirectcorrelationbetweenthebioadhesivestrengthofpolyoxyethylenepolymersandtheirMW,intherangeof200,000to7,000,000hasbeenshownbyTiwariandco-workers[33].Though,alargeMWisessentialforentanglement,excessivelylongpolymerchainslosetheirability to diffuse and interpenetrate mucosal surfaces [34].

However,eachpolymerdisplaysadifferentoptimumMW.Polyacrylicacid(PAA)hasanoptimalMWofabout750,000,whereaspolyethyleneoxide(PEO)hasanoptimumMWcloserto4,000,000[35].DextranswithMWof19,500,000and200,000possesssimilar bioadhesive strength, which is explained by the helical conformation resulting inshieldingofpotentialbioadhesivesitesinsidecoiledconformersathigherMW[36].

2.2.3 Flexibility

When a polymeric system is applied to the buccalmucosa, polymer chains arediffused in the interfacial region between the polymer and mucosa. Therefore, the

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polymer chains contain a substantial degreeofflexibility inorder to achieve thedesired entanglement with the mucus and bioadhesion to occur. The use of tethered polyethylene glycol (PEG)-PAAhydrogels and their copolymerswith improvedbioadhesive properties was demonstrated [34]. The increased chain interpenetration wasattributedtotheincreasedstructuralflexibilityofthepolymeruponincorporationof PEG. In general,mobility and flexibility of polymers can be related to theirviscositiesanddiffusioncoefficients,wherehigherflexibilityofapolymer causesgreaterdiffusionintothemucusnetwork[36].Whilstacriticallengthisnecessarytoproducebioadhesiveinteractions,thesizeandshapeoftheinterpenetratingpolymericchains must also be considered [37, 38]. The Tg of a polymer can be utilised as a good measurefortheflexibilityofthepolymer.PolymerswithalowTg form films that are moreflexible,withhighpercentageelongation.

2.2.4 Crosslinking Density

Theaverageporesize,thenumberaverageMWofthecrosslinkedpolymers,andthedensityofcrosslinkingarethreeimportantandinterrelatedstructuralparametersofapolymernetwork[34].Therefore,itseemsreasonablethatwithincreasingdensityofcrosslinking,diffusionofwaterintothepolymernetworkoccursatalowerrate,which, in turn, causes an insufficient swelling of the polymer and a decreased rate ofinterpenetrationbetweenthepolymerandthemucin[34].Floryhasreportedthisgeneralpropertyofpolymers,inwhichthedegreeofswellingatequilibriumhasaninverserelationshipwiththedegreeofcrosslinkingofapolymer[39].

Thedegreeofcrosslinkingwithinapolymersystemsignificantly influenceschainmobilityandresistance todissolution.Crosslinkedhydrophilicpolymers swell inthe presence of water allowing them to retain their structure, whereas similar high MWlinearhydrophilicpolymersarecapableofswellingandreadilydispersible.Inbioadhesive terms, swelling is favourable as it not only allows greater control of drug release,but italsoincreasesthesurfaceareaforpolymer/mucusinterpenetration.Ascrosslinkdensityincreases,chainmobilitydecreasesandthus,theeffectivechainlength, which can penetrate into the mucus layer decreases, reducing bioadhesive strength [40].Chain flexibility is critical for interpenetration and entanglementwith the mucus gel. Increased chain mobility leads to increased inter-diffusion and interpenetration of the polymerwithin themucus network [41].Modifyingbioadhesivepolymersurfacewithtethersoflinearandblockcopolymerscontainingneutral or ionisable structures provides increased interdigitation and interpenetration with the mucus [42].

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2.2.5 Charge

Bioadhesivepolymersmaybedivided into threemaingroups in termsofoverallcharge, i.e., anionic, cationic andnon-ionic systems.Non-ionic polymers appeartoundergoasmallerdegreeofadhesioncomparedtoanionicpolymers.Non-ionicpolymersusedinbuccalformulationsincludePEO,starchderivatives,celluloseethers[methylcellulose(MC),hydroxyethylcellulose(HEC),hydroxylpropylcellulose(HPC),hydroxypropylmethylcellulose(HPMC)],andvinylpolymerssuchasPVA,polyvinylpyrrolidone(PVP).Thesepolymersaremostlyusedasaviscosityimparterorbodyformer mostly in combination with anionic polymers.

Anionicpolymer systems such as thePAAmakeup themostof thebioadhesivepolymers used pharmaceutically, since there is the greatest potential for polymer mucus hydrogen bonding with undissociated anionic pendant functional groups. PeppasandBurihavedemonstratedthatstronganionicchargeonthepolymerisoneofthecharacteristicsrequiredforbioadhesion[29].WidelystudiedanionicpolymersinbuccaladhesionincludePAAanditsweaklycrosslinkedderivativesandsodiumcarboxymethylcellulose(NaCMC).PAAandNaCMCpossessexcellentbioadhesivecharacteristics. Other anionic polymers used include sodium alginate, pectin, gelatine (amphiprotic)andgums(acaciagum,karayagum,guargum,tragacanth,xanthangumandsoon).

Ithasbeenalsoshownthatsomecationicpolymerssuchaschitosanarelikelytodemonstratesuperiorbioadhesiveproperties,especiallyinaneutralorslightlyalkalinemedium [43, 44]. Apart from charge, the charge density of a polymer is an important factorforbioadhesion.Polyanionsarepreferredtopolycationsforboththeirlessertoxicity and bioadhesion [45].

MacromolecularchargeisaffectedbythepHofthephysiologicalenvironmentduetothedissociationoffunctionalgroups[46].Forexample,carboxylatedpolymerssuchasPAAandpolymethacrylates,andpHvaluesbelowtheirrespectivepKa values are morefavourable[47].CarboxylicgroupsinPAAareonlyeffectiveasinteractionsitesintheiracidicform[40].ParkandRobinson[28]havesuggestedthatapproximately80%protonationofcarboxylgroupsisnecessaryforbioadhesionwithinPAAsystems.Although bioadhesion processes are optimised in low pH environments, bioadhesion may not be completely lost at higher pH values [48]. At higher pH levels repulsion of‘like’COO-functionalgroupschangesthespatialconformationofthepolymersfromacoiledstateintoa‘rod-like’structuremakingthemmorereadilyavailableforinter-diffusionandinterpenetration[12].OntheotherhandabovethepKa of mucin, a net negative charge may result in the repulsion of anionic species observed inionisedPAAsystems.AtsuchelevatedpHvalues,positivelychargedpolymers,

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such as chitosan, may form polyelectrolyte complexes with negatively charged mucins and exhibit strong bioadhesion [49].

The effect of polymer charge of modified chitosan on its bioadhesive properties was demonstratedbySolomonidouandco-workers[50].Ethylenediaminetetraaceticacid(EDTA)anddiethylenetriaminepentaaceticacid (DTPA)were covalentlyattachedto chitosan by the formation of amide bonds between the primary amino group of the polymer and the carboxylic acid groups of the complexing agents [51]. Almost everyprimaryaminogroupof chitosan couldbemodifiedbyEDTAresulting inincreasedbioadhesivestrength(81.7±9.9mN).WhileDTPAwasboundtoonly63.8 ±5.8%oftheaminogroupsofchitosan,theremainingprimaryaminogroupsofthechitosan-DTPAconjugateleadtostronglyreducedadhesiveproperties,withamaximumdetachmentforceof3.0±1.3mN.

2.2.6 Concentration

The importance of concentration can be explained by the polymer chain length available for penetration into the mucus layer in the development of a strong adhesivebondwiththemucus.Whentheconcentrationofthepolymeristoolow,the number of penetrating polymer chains per unit volume of the mucus is small, and the interaction between polymer and mucus is unstable [33]. In general, the more concentrated polymer would result in a longer penetrating chain length and better adhesion. However, for each polymer, there is a critical concentration, above which thepolymerproducesan‘unperturbed’stateduetoasignificantlycoiledstructure.Asa result, the accessibility of the solvent to the polymer decreases, and chain penetration of the polymer is drastically reduced. Therefore, higher concentrations of polymers do not necessarily improve and, in some cases, actually diminish bioadhesive properties. Itwasdemonstratedthathighconcentrationsoffilm-formingpolymers,PVPorPVAinflexiblepolymericfilmsdidnotfurtherenhancethebioadhesivepropertiesofthefilms and on the contrary, they decreased the desired strength of bioadhesion [35].

Optimal polymer concentration is dependent on the physical state of the delivery system, with observational differences between semi-solid and solid dosage forms. In the semi-solid state, an optimum concentration exists for each polymer beyond which reduced adhesion occurs because a lower number of polymer chains are available for interpenetration with mucus. On the other hand, solid dosage forms such as tablets exhibit increased adhesive strength as the bioadhesive polymer concentration increases [52].

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2.2.7 Hydration (Swelling)

Another important factor affecting the bioadhesive strength of polymeric components isthedegreeofhydration.Hydrationisrequiredforabioadhesivepolymertoexpandandcreateaproper‘macromolecularmesh’[53]ofsufficientsize,andalsotoinducemobility in the polymer chains in order to enhance the interpenetration process betweenthepolymerandmucin.Polymerswellingpermitsamechanicalentanglementbyexposingthebioadhesivesitesforhydrogenbondingand/orelectrostaticinteractionbetweenthepolymerandthemucousnetwork[53].However,acriticaldegreeofhydration of the bioadhesive polymer exists where optimum swelling and bioadhesion occurs[42].Excesshydrationmayleadtodecreasedbioadhesionand/orretentionduetotheformationofslipperymucilage[54].Therefore,crosslinkedpolymerswithoptimum hydration may be advantageous for providing a prolonged bioadhesive effect.

Manypolymersexhibitadhesivepropertiesunderconditionswheretheamountofwater is limited. In such conditions, adhesion is thought to be a result of a combination of capillary attraction and osmotic forces between the dry polymer and the wet mucosal surface which act to dehydrate and strengthen the mucus layer [55]. Although thiskindofstickinghasbeenreferredtoasbioadhesion,itisimportanttoclearlydistinguish such processes from wet-on-wet adhesion in which swollen bioadhesive polymers attach to mucosal surfaces [56].

2.2.8 Environmental Factors

The bioadhesion of a polymer not only depends on its molecular properties, but also ontheenvironmentalfactorsadjacenttothepolymer.Saliva,asadissolutionmedium,affects the behaviour of the polymer.

Dependingonthesalivaflowrateandmethodofdetermination,thepHofthismediumhas been estimated to be between 6.5 and 7.5 [11]. The pH of the microenvironment surrounding the bioadhesive polymer can alter the ionisation state and, therefore, theadhesionpropertiesofapolymer.Mucinturnoverrateisanotherenvironmentalfactor. The residence time of dosage forms is limited by the mucin turnover time, whichhasbeencalculatedtorangebetween47and270mininrats[57]and12–24h in humans [35].

Movement of the buccal tissueswhile eating, drinking, and talking, is anotherconcern, which should be considered when designing a dosage form for the oral cavity. Movementswithintheoralcavitycontinueevenduringsleep,andcanpotentiallylead to the detachment of the dosage form. Therefore, an optimum time span for the

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administration of the dosage form is necessary to avoid many of these interfering factors [58].

The ionic strength of the surrounding medium may also have a significant role in defining the bioadhesive bond force. In general bioadhesion strength is decreased in the presence of ions due to shielding of functional sites that are pertinent for adhesionprocessesandimportantly,gelnetworkexpansion[56-60].However,thisgeneralisation is not always applicable, and indeed certain polymeric systems such as gellan are dependent upon the presence of divalent cations for in situ gelation [61].

2.3 Buccal Polymeric Dosage Forms

Buccalpolymericsystemsmainlyusedaremostlysemi-solids(e.g.,ointmentandgels)andsolids(e.g.,tablets,filmsandpatches).

2.3.1 Semi-solids

Bioadhesiveointmentsorgelsaremostlyusedforlocaliseddrugtherapywithintheoral cavity. Orabase®–ERSquibbisafirst-generationbioadhesivepaste,andhasbeen used for a long time as a barrier system for mouth ulcers. It consists of finely groundpectin,gelatinandsodiumCMCdispersedinapolyethyleneandamineraloilgelbase,whichcanbemaintainedatitssiteofapplicationfor15-150min[62].Neutralisedpolymethacrylicacidmethylesterwasusedtoavoidirritationcausedby conventional adhesive ointments to deliver tretinoin to treat lichen planus [63]. Ahighviscositygel-ointmentcontainingcarbopol(CP)(12.5%)showedsustaineddrugabsorptionfor5hwhenappliedtoahamstercheekpouch[64].CP-containingointment with a white petrolatum base for the delivery of prednisolone was also described by the same authors [65].

Thehydrogelsofpoly(2-hydroxyethylmethacrylate),sincetheirdiscoverybyWichterleandLimin1960[66],havebeenofgreatinterestindrugdeliveryresearch.Hydrogelsarethreedimensionalhydrophilicpolymernetworkscapableofswellinginwaterorbiologicalfluids,andretainingalargeamountoffluidintheswollenstate[67].Theirability to absorb water is due to the presence of hydrophilic groups such as -OH, -CONH-,-CONH2,-COOH,and–SO3H[68].Factorssuchaspolymercomposition,watercontent,crosslinkingdensity,andcrystallinity,canbeusedtocontrolthereleaserate and releasemechanism fromhydrogels [69].Chitosan glutamate, a solublesalt of chitosan, was also utilised in hydrogel dosage form for buccal delivery of an anaesthetic drug, lidocaine hydrochloride and found to be effective for symptom reliefofaphthosisandotherpainfulmouthdiseases[70].

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Theeffectofrecombinanthumanepidermalgrowthfactor(rhEGF)onbuccalmucosalulcerhealingwascheckedusingtwodifferentformulations:Eudisperthvhydrogelandpolycarbophil(PCP)974Phydrogel[71].ThebioadhesiveforceofEudisperthvwassignificantlygreaterthanthatofPCP974P.TheulcerhealingeffectofrhEGFonan acetic acid induced ulcer in golden hamsters was more at 24 h after administration ofrhEGF/EudisperthvhydrogelcomparedtothatwithrhEGFsolutionalone.Withtheadditionofsodiumlaurylsulfate(0.5%)toEudisperthvhydrogel,thecurativeratio was further increased 1.5 times. The authors proposed that the healing effect is a combination of protection of the drug against proteases present in the mucosa andprolongationofthereleaseofrhEGFfromtheformulationatthesiteofaction.

A randomised crossover design clinical study was carried out to compare the buccal deliveryofdiclofenacsodiumfromaprototypehydrogel(Voltaren®)withthatofintravenous(IV)infusion[72].Followingbuccaldeliverynearlysteady-statelevelsof100ng/mlwasachievedby3hwitha30mindelaycomparedtotheIVinfusion.Meansteady-statefluxofdiclofenacsodiumof2.1±0.6mg/cm2-h across human buccal mucosawasobtainedwithatimelagof1.0±0.5h.Theauthorshaveconcludedthatthe traditional lipoidal model of buccal permeation based on the partition coefficient is inadequateinexplainingsuchalargefluxofioniseddrug(diclofenacsodium).However,thedrugismostlyinatun-ionisedformatthebuccalmucosa(pH=6.85)becauseofthepKaoftheweaklybasicdiclofenacsodium(4±0.2at25ºC)andthisexplainsthehighfluxofionicspeciesbasedonpH-partitionphenomena.

In order to develop a bioadhesive hydrogel for buccal drug delivery, the understanding of the properties such as Tg, water contact angles and the peel and shear detachment forces which determine the adhesiveness is an absolute necessity [73]. The contact angle measurement of acrylic acid and butyl acrylate copolymers with porcine oral mucosarevealedthatthecontactanglemaximisesat50%butylacrylatecontent,whereas, the Tgdecreasesfrom0%to100%butylacrylate.Theauthorsfoundthata certain combination of the contact angle and Tg, which are directly related to the polarity of the polymer surface and the molecular mobility of the polymer groups is requiredtoobtainproperadhesiveness.

Pilobuc™isamodifiedreleasehydrogelpolymerbuccalinsertcontainingpilocarpinefor the treatment of symptoms associatedwith primary and secondary Sjögren’ssyndromedevelopedbyCytokinePharmaSciences Inc., [74].Thebuccal insert isplacedbetweenthebuccalmucosaandgingivatowardsthebackofthemouth.

Littleattentionhasbeenpaidtodeliveryofhydrophobicdrugsusinghydrogelsandthis was usually accomplished using polymer mixtures such as polyisobutylene, polyisopreneandCP934P[75].Onlyafewstudiesdescribetheuseofhydrogelsin the delivery of hydrophobic drugs and these are: vephylline in both polymalic

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acidPEGgelsandhydrophobicPEG-basedhydrogels [76], ibuprofen inpoly(N-isopropylacrylamide)(PNIPAAm)basedgels[77],progesteroneinPNIPAAm-basedgels [78], cyclosporine inPVP-polyhydroxyethylmethacrylatehydrogels [79],anddenbufyllineinphysicallycrosslinkedpalmitoylglycolchitosanhydrogels[80].

2.3.2 Solids

Although semi-solid systems offer ease of administration and comfort, tablets and patches typically offer greater active ingredient stability (typically solid state),improved residence time, and thus, may provide longer periods of therapeutic druglevelsatdiseasesites.Commonlyengineeredtabletandpatchplatformshaveincludedmatrixdevicesand/ormulti-layersystems,containinganadhesivelayerandother drug functional layers [81-83]. A drug impermeable layer is often included in such systems, to encourage unidirectional drug release, thus avoiding salivary gland clearance mechanisms. A common approach to avoid clearance of a tablet from the buccalcavityistoplacethedosageformundertheupperlip.Buccastem® an adhesive anti-emetictabletcontainingprochlorperazinemaleateisadministeredinthisway.Despitetheadvantagesofbioadhesivetablets,theoscillatoryactionoftalkingandmastication can mean that some patients may find the use of such drug delivery platforms uncomfortable. This is one of the principal factors for the dominance of semi-solidandflexiblepatch-basedsystemsinbuccaldrugdelivery.

2.3.2.1 Powder Dosage Forms

Buccalbioadhesivepowderdosageformsareeitheraphysicalmixture,matrixorreservoir system of drug with bioadhesive polymer to be sprayed onto the buccal mucosa.Yamamotoandco-workershavedescribedapowdercontainingHPCandbeclomethasone diproprionate that was sprayed onto the oral mucosa of rats. A significant increase in the residence time relative to an oral solution was seen, and 2.5%ofthebeclomethasonewasretainedonthebuccalmucosaforover4h[84].

2.3.2.2 Tablets

Buccalbioadhesivetabletsaredrydosageformsthatmayhavetobemoistenedpriorto their application on the buccal mucosa and are the most investigated dosage form forbuccaldrugdeliverytodate.Thesizeofthetabletthatcanbecomfortablyretainedinplaceforprolongedperiodsisamajorconstraintforthisdosageform.Therefore,theyareusuallykeptsmall,flat,andoval,withadiameterofapproximately5–8mm[85] and can be applied to different sites in the oral cavity, including the palate, the

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mucosaliningthecheek,aswellasbetweenthelipandthegum.Theysoftenorswell,adheretothemucosa,andareretainedinpositionuntildissolutionand/orreleaseiscomplete.Themajordrawbackofbuccalbioadhesivetabletsistheirlackofphysicalflexibility,leadingtopoorpatientcomplianceforlong-termandrepeateduse[86].

Variouspolymersfromdifferentsourcesareusedtoachievebioadhesionandsustaineddrug release. Tablets are usually prepared by direct compression, with sufficient pressuretogiveahardtablet,whichcanwithstandmechanicalshocksduringeatinganddrinkingfortheirlong-termstayintheoralcavity.Largenumbersofbioadhesivetablets have been studied and are presented in Table 2.2.

Table 2.2 List of buccal mucoadhesive tablets investigatedActive ingredient Polymers used Investigators

Acitretin CP934PandHPMC Gaetaandco-workers[87]

Baclofen SodiumCMC,sodiumalginate,andMethocelk15M

Gavaskarandco-workers[88]

Buprenorphine HEMAcopolymerisedwithPolymeg®(polytetramethyleneetherglycol)

Cassidyandco-workers[89]

Buspironehydrochloride CP974PandHPMCK4M Duandco-workers[90]

Carbamazepine HPMCandCP Ikinciandco-workers[91]

Carbenoxolone Pectin Wattanakornandco-workers[92]

Carvedilol Sodiumalginate,PVPK30,CP974P,andHPMC

Tamilvananandco-workers[93]

Carvedilol HPMCK4M,HPMCK15MandCP934

Yamsaniandco-workers[94]

Cetylpyridiniumchloride SCMCandHPMC Aliandco-workers[95]

Cetylpyridiniumchloride HMPC,PCP,orCP974P Minghettiandco-workers[96]

Cetylpyridiniumchloride HPCandCP934 CollinsandDeasy[97]

Chlorhexidinediacetate Chitosanandsodiumalginate Giunchediandco-workers[98]

Chlorhexidine HPMCandcarbomer Carloandco-workers[99]

Chlorpheniraminemaleate HakeagumfromHakea gibbosa Alurandco-workers[100,101]

Chlorpheniraminemaleate Polyoxyethylene Tiwariandco-workers[33]

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Clotrimazole CP974P,HPMCK4M Rajeshandco-workers[102]

Cyanocobalamin Polyoxyethylene Tiwariandco-workers[103]

Danazol(danocrine) PCPorHPMC Jainandco-workers[104]

DiltiazemHCl CP934PandHPMC SinghandAhuja[105]

DiltiazemHCl CP934witheitherHPC,HPMCorPVPK30

Ahujaandco-workers[106]

DiltiazemHCl CP934P,HPMC,PCP,SCMC,PAA

Nafeeandco-workers[107]

DiltiazemHCl CP934PandPVPK30 Gannuandco-workers[108]

Domperidone CP934P,MethocelK4M,MethocelE15LVandchitosan

Balamurugan[109]

Ergotaminetartrate CarboxyvinylpolymerandHPC Tsutsumiandco-workers[110]

Fluoride Notmentionedinthearticle(subjecttoapatent)

Bottenbergandco-workers[111]

Fluoride CP,HPMC,andgelatin Vivien-Castioniandco-workers[112]

Flurbiprofen Hydrotalcite Perioli[113]

Glucagon-likepeptide-1 PEOandCP Gutniakandco-workers[114, 115]

HydralazineHCl CP934PandCMC Dinsheetandco-workers[116]

Hydrocortisone acetate HPMC,CP974PorPCP Ceschelandco-workers[117]

Insulin CP934withHPCorHPMC Hosnyandco-workers[118]

Insulin CP934andHPC Ishidaandco-workers[119]

Itraconazole Eudragit®E100,CP934P,HPMCK4M

Madgulkarandco-workers[120]

Ketoprofen Chitosanandsodiumalginate Miyazaki[121]

Lactoferrin Sodium alginate Kuipersandco-workers[122]

Lercanidipine PEO,HPMC Chardeandco-workers[123]

Leu-enkephalin ThiolatedPCP Langothandco-workers[124]

LignocaineHCl CP934P,sodiumCMCandPVPK30

Parvezandco-workers[125]

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Luteinisinghormone-releasing hormone

PVPK30,PVPK90,CP934P Nakaneandco-workers[126]

Metoprololtartarate CP934P,HPMC,HEC,SCMC Ramanaandco-workers[127]

Metoclopramide CP934P,HPMC,PCP,sodiumCMC,PAA

Garcia-Gonzalezandco-workers[128]

Metronidazole HPMC,sodiumCMCandCP934P

Ahujaandco-workers[129]

Metronidazoleorbenzydamine

Gelatin/HPC,gelatin/HPMCandgelatin/sodiumCMC

Parodiandco-workers[130]

Metronidazole HEC,HPC,HPMC,orsodiumCMCcombinedwithCP940,CP971,orPCP

Perioliandco-workers[131]

Miconazolenitrate MixturesofHPMC,SCMC,CP934P,andsodiumalginate

MohammedandKhedr[132]

Miconazolenitrate Thermallymodifiedmaizestarch(drumdriedwaxymaize)/PAAmixtures

Bouckaertandco-workers[133–136]

Miconazolenitrate Notmentionedinthearticle VanRoeyandco-workers[137]

Morphine Notmentionedinthearticle Beyssacandco-workers[138]

Morphinesulfate HPMCwithCP Anlarandco-workers[139]

Nalbuphine CP934andHPC Hanandco-workers[140]

Nicotine CP934andHPC ParkandMunday[141]

Nicotine CP974P,sodiumalginate,andHPMC

Ikinciandco-workers[142]

Nifedipine CMCandCP VarshosazandDehghan[143]

Nifedipine Sodiumalginate,PVP,andPEG Saveandco-workers[144]

NifedipineorpropranololHCl

Chitosanwithorwithoutananioniccrosslinkingpolymer(PCP,sodiumalginate,gellangum)

Remuñán-Lópezandco-workers[85]

Nimesulide Carbomer Ceschelandco-workers[145]

Nystatin Carbomer,HPMC Labotandco-workers[146]

Omeprazole Sodiumalginate,HPMC Choiandco-workers[147],ChoiandKim[148],Yongandco-workers[149]

Ondansetron SodiumCMC,HPMC,CP934P Hassanandco-workers[150]

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Oxytocin Dillenia indica fruit mucilage MetiaandBandyopadhyay[151, 152]

Pentazocine CP974PandHPMC AgarwalandMishra[153]

Pindolol CP934andsodiumCMC(bioadhesivepolymers),HPMCandHPC(matrix-formingpolymers)

Dortuncandco-workers[154]

Piroxicam HPMCandCP940 JugandBecirevic-Lacan[155]

Pravastatinsodium Carageenan,PVPK30,Pluronic® F127

Shidhayeandco-workers[156]

Prednisolone PCPandCP934P Rafiee-Tehraniandco-workers[157]

Propranolol PAA,HPMC,andHPC CelebiandKislal[158]

PropranololHCl HPMCandPCP Akbariandco-workers[159]

PropranololHCl CP934P,HPMC,PCP,sodiumCMC,PAA

Taylanandco-workers[160]

PropranololHCl SodiumCMC,CP934P,EC Patelandco-workers[161]

PropranololHCl HPMC,CP934P Desaiandco-workers[162]

Prosidol N/A(articleinRussian) Osipovaandco-workers[163]

Salbutamol sulfate Carbopol934P,HPMCK4M,andxanthan gum

Chaudhariandco-workers[164]

Salmon calcitonin HakeagumfromHakea gibbosa Alurandco-workers[165]

Sodiumfluoride Eudragit® Rand/orEC Diarraandco-workers[166]

Terbutaline sulfate CP934P,MethocelK4M,MethocelK15M,sodiumCMC,EC

Nakhatandco-workers[167]

Testosterone Starch-g-PAAcopolymersorstarch/PAAmixtures

Ameyeandco-workers[168]

Testosterone DrumdriedwaxymaizeandCP974P

Voorspoelsandco-workers[169]

Testosterone Notmentionedinthearticle Rossandco-workers[170]

Theophylline Starch–acrylicacidgraftcopolymers

Gereshandco-workers[171]

Triamcinolone acetonide CP934PandSCMC Aliandco-workers[172]

Zinc sulfate ECandEudragit®R Diarraandco-workers[173]

EC:Ethylcellulose

SCMC:Sodiumcarboxymethylcellulose

ReproducedwithpermissionfromN.Salamat-Miller,M.ChittchangandT.P.Johnston,Advanced Drug Delivery Reviews2005,57,11,1666.©2012,Elsevier[86](Newstudieshavebeenincludedtobringtheinformationup-to-date)

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Timololmaleatebioadhesivebuccaltabletswereformulatedusingthedrug,CP934PandHPMCK4Mwiththeratiosof1:2.5:10bydirectcompressionandsustainedzero-orderdrugreleasewereobservedfor7h[174].Inasimilarstudy,formulationscontainingCP-934andHPMCK4Mintheratioof(2:4)showedgoodbioadhesivestrength(36.8)withzero-orderdrugreleaseoflisinoprilfor10h[175].

BuccaltabletsoflisinoprilwerealsopreparedusingdifferenthydrophilicpolymerssuchasHPMC,sodiumCMCandCP[176].Alltheformulationswerebestfittedtothe Higuchi model and according to this model the drug releases from these tablets may becontrolledbydiffusion.AnincreaseintheamountofCP934PcausesincreasesinswellingindexalongwiththedecreasingamountofHPMCK4MandsodiumCMC.

A buccal matrix tablet formulation for the delivery of a model, poorly water-solubledrug,omeprazolewasdeveloped[177].Thematrixwasdesignedusingtwopolymers,Polyox™andsodiumCMC,asabioadhesivesustainedreleaseplatform,andcyclodextrins(CD)asmodulatorsofdrugreleaseandpermeationenhancers.The bioadhesive profiles of the matrices formulated were evaluated to determine the influenceofCDonthebioadhesion.TheeffectofCDinthedrugreleasefeaturesfrom the loaded matrices was also studied, and mathematical models were applied todeterminethemechanismofdrugreleasefromthematrices.Finally,thepotentialofcomplexedomeprazoleloadedmatricestoobtainabuccaldeliverysystemwasassessed by permeation studies in the porcine buccal mucosa. Some very interesting conclusions were drawn from this study:

• Thepresenceofhydrophobicdruginthematrixdecreasesbioadhesionduetoitshydrophobic character. The drug shows low capacity to absorb water, necessary tohydratethebioadhesivematrixandconsequentlytodevelopabioadhesivebond.

• CD,largeMWoligosaccharides,canformhydrogenbondswithsomepolymers,interferingintheformationofbioadhesivebonds.Whendrugwascomplexedwith β-cyclodextrin(βCD),adecreaseintheworkandforceofbioadhesionwasobserved compared to the tablet containing the drug alone. The authors suggested that βCDisanaturalCDwithhydroxylgroupsavailabletoestablishhydrogenbondswiththepolymericchains,consequently,whenthisCDwasaddedtotheformulation, a large reduction in the bioadhesion was observed. However, when methylated βCD(MβCD)wasused,itshowedimprovedbioadhesiveperformancedue to its higher capacity to absorb water from the mucosa, which is necessary for thehydrationofthepolymer,thusincreasingtheflexibilityandinterpenetrationof the moieties available for bonding to the mucus. Availability of additional methoxy groups onMβCD interactswith themucus layer contributing to astronger bioadhesive behaviour.

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• Inthepresenceofthealkaliagent,L-arginine(ARG),usedtostabilisethedrug,thebioadhesionperformanceincreaseswhenomeprazoleiscomplexedwithβCD.ARGformshydrogenbondswiththeβCDhydroxylgroupsandthepolymericchains remain free for bioadhesion resulting in improved bioadhesion. However, incaseofMβCD,thepresenceofARGverymuchincreasestheabsorbanceofwater,causinganexaggeratedhydrationofpolymersandconsequentlyreducingthe bioadhesion [28, 178]. Authors have carried out substantial mathematical modelling of dissolution curves, indicating that the release of the drug, in free or in complex state, from the bioadhesive matrices followed a super case II transportmechanismestablishedonthebasisoftheKorsmeyer-Peppasfunction.The permeation experiments were performed on porcine buccal mucosa. The cumulativeamountofomeprazolepermeatedover8hthroughtheepitheliumwas16.1μg/cm2 of pig buccal mucosa which was increased by 2.4 times and 3.3 times in the presence of βCDandMβCD, respectively.Thiswas furtherincreased to3.8-and5.9-fold, respectively, inpresenceofARG.Theauthorsfinally concluded that the system containing the selected polymer mixture and thedrugcomplexwithMβCDinpresenceofARGshowedagreatpotentialasa buccal drug delivery formulation.

Bioadhesive tablets for buccal administration of nicotinewere prepared as analternative to the available nicotine dosage forms [179]. Three types of tablets with three different ratios for each type were developed, each containing two bioadhesive components(HPMCK4Mandsodiumalginate,HPMCK4MandCP,andchitosanand sodium alginate. All the tablets were prepared by direct compression having adiameterof9.5mmandathicknessintherangeof1.20to1.50mmwithgoodmechanicalpropertiessuchashardnessandfriability.Formulationwith30%HPMCand10%CPpolymer showedhigherbioadhesionand retardeddrug releaseduetotheirhighMWandhighviscosity.ThereleaserateofnicotinefrombioadhesivetabletsdecreasedwithincreasingconcentrationofHPMCduetothehigherswellingandslowerosionofthepolymer.SodiumalginateandCParemorehydrophilicthanHPMC,swells rapidlywith fastererosion, thus is lesseffective incontrolling therateofdrugreleaseatlatertimes.Whenpharmacokineticstudiesof5mgnicotinetabletswith20%HPMCand10%CPwereconductedinsmokers,apeakplasmaconcentration of nicotine of 16.78 ±2.27ng/mlwasobtainedin2h,withanareaundertheconcentration-timecurve(AUC(0-24)) of 82.4 ±24.0ng/ml.Theseresultssuggested that the bioadhesive tablet developed for buccal administration was a potentialapplicationinnicotinereplacementtherapyforsmokingcessation.

Bioadhesive buccal tablets containing ondansetron hydrochloride (ODH)wereprepared using polymers such as gelatin, chitosan, xanthan gum in varying concentrationsof5,10or15%w/wandHPMCK4M40%w/w, having a diameter of3-3.2mmbythedirectcompressiontechnique[180].Theformulationscontaining

76


xanthan gum gave better bioadhesion and sustained drug release up to 8 h compared to those containing gelatin and chitosan. In vitro releasefromalltheODHbuccaltabletsfollowed supercase II transport mechanism due to polymer chain disentanglement and relaxation.

One of the addition features in the buccal drug delivery system is that it should provide the drug release in a unidirectional way toward the mucosa, in order to avoid drug loss resulting from wash out with saliva and maximise buccal drug delivery. This can beachievedbyusinganimpermeablebackinglayer[85,162].Usingthistechnique,various scientists have prepared bilayer and multi-layer tablets.

Patelandco-workershavedevelopedbilayeredandmulti-layeredbuccaladhesivetablets of propranolol hydrochloride [81]. The tablets were prepared using sodium CMCandCP934asbioadhesivepolymerstoimpartbioadhesionandECtoactasanimpermeablebackinglayer.Comparedtobilayeredtablets,multi-layeredtabletsshowed a slow rate of release of the drug with improved ex vivo bioadhesive strength and enhanced ex vivo bioadhesion time. The mechanism of drug release was found tobenon-Fickiandiffusionforboththebuccaldevices.

Bilaminatedfilmswere preparedby a casting/solvent evaporation technique andbilayered tablets prepared by direct compression containing a bioadhesive layer with adrugandadrug-freebackinglayer[85].Thebioadhesivelayerwascomposedofamixtureofdrugandchitosan,withorwithoutananioniccrosslinkingpolymer(PCP,sodiumalginate,gellangum),andthebacking layerwasmadeofEC.Theuncrosslinked chitosan-containing devices absorbed a large quantity ofwater,gelled and then eroded, allowingdrug release.Usingnifedipine andpropranololhydrochloride as slightly and highly water-soluble model drugs, respectively, it was demonstrated that these new devices show promising potential for use in controlled delivery of drugs to the oral cavity. The bilaminated films showed a sustained drug release inaphosphatebuffer (pH6.4).Tabletsdisplayedcontrolledswellinganddrugreleaseandadequateadhesionwereproducedby in situ crosslinkingof thechitosanwithPCP.

Solid dispersions as well as hydrogels loaded with dexamethasone sodium phosphate (DSP)werepreparedusingchitosan[181].Binarysoliddispersionsatvariousdrug-to-polymerweightratioswerepreparedbyfreeze-dryingandthencompressedintotablets.Simultaneously,DSP-loadedhydrogelcomposedofchitosanandglycerinwasalso prepared. A slow and prolonged release of the drug was observed in vitro from bothkindsofsystems.AprolongedreleaseofDSPwasachievedafterin vivo buccal application of both the systems, as compared with a glycerin solution of the drug.

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2.3.2.3 Polymeric Films and Patches

Though polymeric films were extensively used in pharmaceutical tablet coating formulations, the use of polymeric films for buccal delivery was not attempted until late1980sor early1990s.Buccalfilmmaybepreferredoveradhesive tablets intermsofflexibilityandcomfort.Inaddition,theycancircumventtherelativelyshortresidence time of oral gels on the mucosa, which is easily washed away and removed by saliva [97, 182]. In addition, the buccal film is able to protect the wound surface and thus, reduce pain.

Anidealbuccalfilmshouldbeflexible,elastic,softyetadequatelystrongtowithstandbreakageduetostressfrommouthactivity.Inaddition,itmustalsopossessgoodbioadhesive strength so that it can be retained in the mouth for the desired time. Swelling of film, if it happens, should not be too extensive in order to prevent discomfort. As such, the mechanical, bioadhesive, and swelling properties of buccal filmarecriticalanditisessentialthattheyareevaluated[183].SodiumCMC(sodiumCMC/PEG400/CP934P)andanHPMC/PEG400/CP934Pfilmwerecomparedasadrugvehicle forbuccaldelivery.HPMCfilmswere tougher,moreelastic,morebioadhesive in vivo and swelled in a more tolerable manner in the oral cavity than thesodiumCMCfilms.

Buccalbioadhesivepatchesontheotherhand,arelaminatedormulti-layeredthinfilms, round or oval in shape, consisting of a bioadhesive drug reservoir polymeric layerandanimpermeablebackinglayertoprovideunidirectionalflowofdrugacrossthebuccalmucosa[182].Theirsizesareusuallyinrangeof1-3cm2 so that they areconvenientandcomfortableforthepatient.Theymustalsobeflexibleandmaybe ellipsoid in shape to fit comfortably onto the centre of the buccal mucosa [184]. Variousstudiesdescribetheuseoffilmsandpatchesforbuccaldrugdeliveryandare presented in Table 2.3.

A buccal bioadhesive system for systemic delivery of acyclovir was prepared using an adhesive,acopolymerofacrylicacidandPEGmonomethylethermonomethacrylate,and an impermeable membrane to prevent excessive washout by saliva and to attain unidirectional release [188]. This bioadhesive system was shown to be a good candidate for controlled oral mucosal delivery of acyclovir for up to 22 h.

Aporous,flexiblebilaminatedfilmconsistingofabioadhesivelayer(chitosan-EDTAacidhydrogelfilm)withan impermeableprotective layermadeofEC forbuccalprotein administration was produced by a simple and mild casting procedure [215]. Rheologyresultsshowedthatachitosan-EDTAhydrogel(10:2)possessedthegreatestdegree of visco-elasticity and was well-structured compared with other hydrogels. The in vitro bioadhesion studies suggested that the bioadhesive force of the hydrogel

78


remainedover17,000N/m2 during 4 h in the simulated oral cavity. A pronounced hypoglycaemic effect following buccal administration of insulin loaded bilaminated film in healthy rats showed a 17%pharmacological availability comparedwithsubcutaneousinsulininjection.

Table 2.3 List of the buccal mucoadhesive films and patches investigatedActive ingredient Polymers used Investigators

Acyclovir CopolymersofacrylicacidandPEGmonomethylethermonomethacrylate

Shojaeiandco-workers[185,186]

Acyclovir ChitosanHClandPAAsodiumsalt

Rossiandco-workers[187]

Buprenorphine CP934P,polyisobutylene,andpolyisoprene

Guo[75],GuoandCooklock[188]

Cetylpyridiniumchloride PVA,HEC,orchitosan Nafeeandco-workers[189]

Chitosan Chitosan Ikinciandco-workers[190]

Chlorhexidinediacetate EC JonesandMedlicott[191]

Chlorhexidinedigluconate Chitosan Senelandco-workers[192]

Chlorpheniraminemaleate Polyoxyethylene Tiwariandco-workers[33]

CMVh-galplasmidDNAor h-gal protein

PCPandEudragit®RS100 CuiandMumper[193]

Dipotassiumglycyrrhizate PCP,HPC,andEC Rheeandco-workers[194]

Glibenclamide ChitosanandPVP Ilangoandco-workers[195]

Insulin GelatinandCP934P Ritschelandco-workers[196]

Ipriflavone Polylactide-co-glycolide, chitosan

Peruginiandco-workers[197]

Isosorbide dinitrate HPC,HPMCphthalate Danjoandco-workers[198]

Lidocaine HPC Okamotoandco-workers[199,200]

Lignocaine Proprietarymucoadhesivesupport system

Brookandco-workers[201]

Melatonin CP934Pandpolyisobutylene Bénèsandco-workers[202]

Metoprololtartrate Eudragit® NE40DwithHPMC,sodiumCMCorCP

Wongandco-workers[203]

Miconazolenitrate SodiumCMC,chitosan,PVA,HEC,HPMC

Nafeeandco-workers[83]

79


Nifedipine Sodiumalginate,MC,PVP,andPEG

Saveandco-workers[144]

NifedipineorpropranololHCl

Chitosanwithorwithoutananioniccrosslinkingpolymer(PCP,sodiumalginate,gellangum)

Remuñán-Lópezandco-workers[85]

Oxytocin CP974P Liandco-workers[204,205]

PlasmidDNA Noveon,Eudragit®S100 CuiandMumper[193]

Protirelin(TRH) HEC,HPC,PVP,orPVA AndersandMerkle[182]

Salmon calcitonin PCPandEudragit®S100 CuiandMumper[206]

Terbutaline sulfate CP934,CP971,HPMC,HEC,orSCMC

MohamedandMortada[207]

Testosterone PCPandEudragit®S100(polymethacrylicacid-co-methyl methacrylate)

Jayandco-workers[208]

Tetracaine,ofloxacin,miconazole,guaiazuleneand triacetin

HPC Oguchiandco-workers[209]

Tetracycline Atelocollagen Minabeandco-workers[210]

Thiocolchicoside GelatinandCMC Artusiandco-workers[211]

TRH Organic polymers Liandco-workers[212]

TRH Notmentionedinthearticle Schurrandco-workers[213]

Triamcinolone acetonide CP,PoloxamerandHPMC Chunandco-workers[214]

CMV:Cytomegalovirus

TRH:Thyrotropin-releasinghormone

ReproducedwithpermissionfromN.Salamat-Miller,M.ChittchangandT.P.Johnston,Advanced Drug Delivery Reviews,2005,57,11,1666.©2012,Elsevier[86](Newstudieshavebeenincludedtobringtheinformationup-to-date)

A comparison of the buccal bioadhesive performance of different polymeric films was carriedoutusingthetextureanalyserTA-XT2i(StableMicroSystems,Godalming,UK) [216]. Swelling index and tensile strengthweremeasured as parametersof bioadhesive interaction. These two parameters gave two opposite orders of performancebetweenCMCandcarrageenan-λ after a contact time of 15 min. The ranking order of bioadhesive performance based on visco-elasticmoduli of thehydrogelswereintheorderofCP971P>PCP>carrageenan-λ>sodiumCMC.

BilayerfilmswerepreparedusingdifferentratiosofNoveon®andEudragit®S100asthebioadhesivelayerandapharmaceuticalwaxastheimpermeablebackinglayerand

80


werepost-loadedwith100μgofplasmidDNAofcytomegalovirusβ-galactosidase adenovirous or β-galactosidase protein [193]. The antigens remained stable after beingreleasedfromthebilayerfilms(releaseof60-80%in2hforboth).BuccalimmunisationusingbilayerfilmscontainingplasmidDNAledtocomparableantigen-specificimmunoglobulinGtitretothatobtainedusingsubcutaneousproteininjection.

Bioadhesivebuccal filmsof losartanpotassiumwerepreparedby solvent castingusingECorEudragit®RSPOastheretardantpolymerandHPMCasthebioadhesivepolymerwithpropyleneglycolasaplasticiser[217].Maximumswellingofthefilmswas observed in the formulations containing the higher proportions of hydrophilic polymer, i.e.,HPMC.The least swellingwasobserved infilmscontaininghigherproportionsofEudragit®RSPOandEudragit® ECwhicharewaterinsolubleandlesshydrophilicandthereforesubjecttolessswellinguponhydration.Thepresenceofthehydrophilicpolymer,HPMCseemstoincreasethesurfacewettabilityandswellingofthefilmsand,therefore,filmscontainingHPMCshowedfasterdisintegration.Thebioadhesive force was found to be higher for film formulations containing higher proportionsofthebioadhesivepolymer,HPMC.Inaddition,HPMChydratesfastachieving maximum swelling at shorter periods, which could promote interpenetration ofthepolymerchainwiththetissue.AsthepercentageofHPMCintheformulationsincreased, the tensile strengthandpercentageelongationatbreakalso increased.HigherproportionsofECorEudragit®RSPOinfilmsmakethemmorebrittleandweak. Thefilmscomposedoflargeramountsofthebioadhesivepolymer,HPMC,showed the greatest bioadhesion time of nearly 6 h, while a comparatively shorter bioadhesion time was observed with films containing higher amounts of the retardant polymers. In vitro drug release studies reveal that all films exhibited sustained release up to 6 h. Ex vivo permeation studies through porcine buccal mucosa showed that filmscontainingahigherpercentageoftheHPMCshowedslowerpermeationofthedrug for 6-7 h.

2.4 Novel Carriers

Bioadhesivemicro/nanoparticlesoffermoreadvantagescomparedtoconventionalbuccal tablets because their high surface area enables them tomake intimatecontact with a larger mucosal surface area. Also, being relatively small they can be incorporatedinalmostanykindofdosageform,andaremorelikelytobeacceptablebythepatients.Also,beingsmallinsize,microparticlesarelesslikelytocauselocalirritationatthesiteofadhesionandtheuncomfortablesensationofaforeignobjectwithin the oral cavity compared to tablets [41].

A comparative study was made between the bioadhesiveness of polymeric microparticles ofCP, PCP, chitosan orGantrez®with particle sizes in the range

81


23-38 μm to porcine oesophageal mucosa and it was found that microparticles preparedfromthePAAexhibitedgreaterbioadhesivestrengththanthoseconstructedfromchitosanorGantrez®. However, in elution experiments involving a challenge with artificialsaliva,particlesofchitosanorGantrez® were retained onto mucosal tissue for longer time periods compared to microspheres of the polyacrylic acids [218, 219].

Microspheres based on Poloxamer 407, alone or in amixturewithGelucire® 50/13weredevelopedasapossiblebuccaldeliverysystemforatenolol[220].Themicrospheres were tested as they were or were directly compacted to obtain tablets and the formulation was evaluated in vivo in rabbits against amarketed tabletformulation as a reference. After administration of the microsphere formulations, the atenolol concentration remained higher than that of the reference tablet during the entire elimination phase showing a sustained release profile from the microspheres. In addition, the absolute bioavailability of microsphere formulations was higher than that of the reference tablets even though a lower drug dose was used, suggesting a possible dose reduction by atenolol microparticles via oral trans-mucosal administration.

Nanoparticlescanpenetratethroughtheepitheliumandbasementmembraneintothe underlying connective tissue suggesting the possibility of oral trans-mucosal nanoparticle delivery for systemic therapeutics. The proof of this principle was demonstrated by internalisation of solid lipid nanoparticles incorporating model fluorescentprobesinmonolayer-culturedhumanoralsquamouscellcarcinomacelllines [221].

2.5 Conclusions

Drugdeliverythroughbuccalmucosaposevariousbarrierssuchassmallsurfacearea,less permeable mucosa, rapid salivary clearance with swallowing and involuntary removal of drug.With advantages such as increase in the residence time of thepolymer,site-specificadhesion,penetrationenhancement,andenzymicinhibition,itis not exaggerated to say that it is polymers, which have made buccal drug delivery possible. Site-specific bioadhesive polymers have been utilised for the buccal delivery of a wide variety of therapeutic compounds. These days, pharmaceutical companies rely heavily on novel drug delivery technologies to combat, with soaring research and development costs, an impending onslaught of patent expirations, mega-merger mania, increasing consumer demands for improved medications, and to transform products and extend product lifecycles. The authors believe that with recent advances in the field of polymer science and biotechnology, many macromolecule drugs utilising a polymeric platform for buccal drug delivery will be available in the near future.

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