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ResearchArticle

DESIGNANDEVALUATIONOFCONTROLLEDRELEASEMUCOADHESIVEBUCCALTABLETSOFLISINOPRIL

GUDAADITYA*1,GANESHKUMARGUDAS1,MANASABINGI2,SUBALDEBNATH1,V.V.RAJESHAM11SriKrupaInstituteofPharmaceuticalsSciences,Village:vellkatta,Mondal:Kondapak,Dist:Medak,A.P.502277.2VaagdeviPharmacy

College,Bollikunta,Warangal.Email:subal_2007@yahoo.co.in

Received:09Jun2010,RevisedandAccepted:6July2010

ABSTRACT

Lisinopril,adrugwidelyused in the treatmentofhypertension.However, itsextensive firstpassmetabolismresults inpoor bioavailability.Theobjective of present researchwork is to design and evaluate the controlled release ofmucoadhesive buccal tablets of Lisinoprilwith a goal toincrease the bioavailability, reduce dosing frequency and improve patient compliance. The tabletswere prepared using Carbopol934,Hydroxypropyl methyl cellulose (HPMC), Hydroxy ethyl cellulose (HEC) as mucoadhesive polymers. Six formulations were developed with varyingconcentrationofpolymers.The tabletswereevaluated forhardness,weightvariation, thickness,percentageofdrugcontent,SurfacepH, invitrostudies like swelling,mucoadhesivestrengthanddrug release. Formulation (F4) containingCarbopol934andHPMCK4M in the ratioof (2 :4)showedgoodmucoadhesive strength (36.8) andmaximumdrug releaseof 97.1% in10 hrs. Swelling increasewith increase in concentrationofHPMCK4Mintablets.SwellingpHwasfoundtobe6.10.Formulation(F4)followszeroorderdrugrelease.FTIRstudiedshowednoevidenceoninteractionbetweendrugandpolymers.TheresultsindicatethatthemucoadhesivebuccaltabletsofLisinoprilmaybegoodchoicetobypasstheextensivehepaticfirstpassmetabolismwithanimprovementinthebioavailabilityofLisinoprilthroughbuccalmucosa.

Keywords:Lisinopril,Mucoadhesive,Controlrelease,Swellingindex,HPMC,Carbopol

INTRODUCTION

Mucoadhesive drug delivery systems are delivery systems, whichutilizethepropertyofbioadhesionofcertainpolymers.Bioadhesionisdefinedasanabilityofamaterialtoadhereaparticularregionofthebodyforextendedperiodoftimenotonly for localtargetingofdrugsbutalsoforbettercontrolofsystemicdelivery.Mucoadhesivebuccal drug delivery systems offer many advantages overconventional systems such as ease of administration, rapidterminationof therapyandadministrationtounconsciouspatients.Drugwhicharedestroyedbytheenzymatic/alkalineenvironmentoftheintestinesareunstableintheacidicenvironmentofthestomachcanbeadministeredbythisroute1.

Fromtechnicalpointofview,anidealbuccaldosageformmusthavethreeproperties.Itmustmaintainitspositioninthemouthforafewhours,releasethedruginacontrolledfashionandprovidethedrugreleaseinaunidirectionalwaytowardsthemucosa.Inregardtothefirst requirement, strong adhesive contact to the mucosa inestablished by using mucoadhesive polymers as excipients. If themucoadhesiveexcipientsareabletocontroldrugrelease,thesecondrequirement can be fulfilled by preparing a system have uniformadhesiveness and impermeable backing layer. Variousmucoadhesive devices such as include tablets, film, patches, discs,strips,ointmentsandgelhavebeenrecentlydeveloped2.

Mostof themucoadhesivematerialsareeithersyntheticornaturalhydrophilicorwaterinsolublepolymersandarecapableofformingnumerous hydrogen bonds because of presence of the carboxyl,sulphate or hydroxyl functional groups. Various materials weretestedformucoadhesion.ThesyntheticmaterialsincludeCarbopol934, Hydroxy propyl methyl cellulose (HPMC), Hydroxy ethylcellulose (HEC), Sodium carboxy methyl cellulose, Polymethylmethacrylates and polycarbophil, while natural polymers includexantiumgum, sodiumalginate, gelatin, acacia and tragacanth3. Thebioadhesive polymers can not only cause the adhesion effects butcanalsocontrolthereleaserateofdrug.

Lisinopril iswidelyused in the treatmentofhypertensionwhich isanACEinhibitor.Ithasbiologicalhalflife(4to5hrs).Theobjectiveofpresentstudy is todesignandevaluatethecontrolledreleaseofmucoadhesivebuccaltabletsofLisinoprilwithagoaltoincreasethebioavailability, reduce dosing frequency and improve patientcompliance, employing the mucoadhesive polymers like Carbopol934, Hydroxy propyl methyl cellulose (HPMC), Hydroxy ethylcellulose (HEC). The buccal tablets were evaluated for hardness,

weightvariation,thickness,percentageofdrugcontent,surfacepH,invitro studies like swelling, mucoadhesive strength and drugrelease4.

MATERIALSANDMETHODS

Materials

LisinoprilwasreceivedasgiftsamplefromAlembicLtd.,Vadodara,Gujarat. Carbopol934, Hydroxy Propyl Methyl cellulose (HPMC),Hydroxy ethyl cellulose (HEC)wereprocured as gift samples fromCipla Ltd.,Mumbai, India. All other reagents and chemical used ofanalyticalgrade.

Preparationofmucoadhesivebuccaltablets5

Mucoadhesivebuccaltablets,eachcontaining10mgLisinoprilwereprepared by direct compression method. Composition of variousformulations employing Carbopol 934P, HPMC K4M & HEC areshown in Table 1. All the ingredients of tablets were blended inmortar with a pestle for 15 min to obtain uniform mixture. Theblendedpowderwas then compressed into 150mg tablets (at 57kg/cm2) on a single stoke, 10 station rotary tablet machine(Cadmach Machinery Co. Pvt. Ltd., Ahmedabad, india) with 8mmroundshapedflatpunch.

Evaluationoftablets

Thetabletsfromdifferentformulation(F1toF6)weresubjectedtofollowingtests

Hardness

TabletswereevaluatedfortheirhardnessusingMonsantohardnesstester.

Weightvariation

Tentabletsfromeachformulationwereweighedusinganelectronicdigital balance and the averageweightwas calculated. The resultsareshowninTable2.

Thickness

Tabletswereevaluated for their thicknessusingslidecalipers.TheresultsareshowninTable2.

Contentuniformity

Ten tablets fromeach formulationwere taken, crushedandmixed.From the mixture, 10 mg of Lisinopril equivalent of mixture was

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extractedthoroughlywith100mlofmethanol.Theamountofdrugpresent in extract was determined using UV Spectrometer at 210nm.TheresultspresentedinTable3.

SurfacepH

The surface pH of the buccal tablets was determined in order toinvestigate the possibility of any in vivo side effects. An acidic oralkalinepHmaycause irritation tothebuccalmucosa.ThemethoddevelopedbyBattenbergetalwasused.

A combined glass electrodewasused for this purpose. The tabletswereallowed to swellbykeeping it in contactwithdistilledwater(pH 6.5 0.05) for 2 hrs at room temperature. The pH wasmeasured by bringing the electrode in contactwith the surface ofthe tabletandallowing it toequiliberate for1min.TheresultsareshowninTable3.

Invitroswellingstudies6,7

The degree of swelling of bioadhesive polymers is an importantfactor affecting adhesive. For conducting the study, a tablet wasweighed and placed in a petridish containing 5 ml of phosphatebuffer at pH 6.8 for 12 hrs, the tablets were taken out from thepetridish and excess water was removed carefully by using filterpaper. The swelling Index was calculated using the followingformulaandresultsaresummarizedinTable4.

SwellingIndex(SI)+(WtWo)/WoX100

WhereSI=Swellingindex.

Wt=Weightoftabletsaftertimeatt.

Wo=Weightoftabletbeforeplacinginthebeaker.

InvitromucoadhesiveStudy8

Mucoadhesive strength of the tabletswasmeasured on amodifiedtwoarmphysicalbalanceasdescribedbyQuadnichetal.Therabbitbuccalmucosawasusedasbiologicalmembraneforthestudies.Therabbit mucosa was obtained from the local slaughter house andstored in krebs buffer at 4oC from the time of collection and usedwithin 3 hrs of procurement. The membrane was washed withdistilledwaterandthenwithphosphatebufferpH6.8at37oC.

The rabbit buccal mucosa was cut into pieces and washed withphosphate bufferpH6.8.Apiece of buccalmucosawas tied to theglassvial,whichwasfilledwithphosphatebuffer.Theglassvialwastightlyfittedintoaglassbeaker(filledwithphosphatebufferpH6.8at 37o C 0.5oC), so that it just touches the mucosal surface. Thebuccaltabletsweresucktolowersideofarubberstopper.Thetwosideofthebalanceweremadeequalbeforethestudy,bykeepinga5gms,wasremovedfromtherighthandpan,whichloweredthepanalongwiththetabletoverthemucosa.Thebalancewaskeptin the

position for 1 min contact time. Mucoadhesive strength wasassessedintermsofweight(gms)requiredtodetachthetabletfromthe membrane. Mucoadhesive strength which was measured asforceofadhesioninNewtonsbyusingfollowingformulawasused(Table3),

Forceofadhesion(N)=Mucoadhesivestrength/100X9.81

Invitrodrugreleaseprofile9,10

The United States of Pharmacopoeia (USP) XXIV rotating paddlemethodwasusedtostudythedrugreleasefromthebuccaltablets.Thedissolutionmediumconsistedof900mlofphosphatebuffer(pH6.8).Thereleasewasperformedat37oC0.5oC,withrotationspeedof 50 rpm. Samples (5ml)werewithdrawn at predetermined timeintervals (1, 2, and 310 hrs) and volumewas replacedwith thefresh medium. The samples were filtered through Whatman filterpaper and analyzed after appropriate dilution by UVspectrophotometry at 210 nm. The experiments for differentformulations (F1 to F6) were conducted in triplicate and averagevalues were recorded and found the release kinetics such as zeroorder, first order, Higuche and Hixconcrowell were determined &thedataareshowninTable5.

RESULTSANDDISCUSSION

Before designing various formulations, the drug polymerexcipientcompatibilitystudieswereconductedbyFTIRspectroscopyandtheresultsarepresentedinFig.1&Fig.2.Theresultsindicatethattheywereno chemical incompatibilitybetweendrugpolymer,polymerpolymerandpolymerexcipients.

Totalsixdifferentformulations(F1toF6)ofLisinoprilbuccaltabletswere prepared by direct compression techniques using variousproportions ofpolymersandexcipients. Inorder to select the bestformulations, various evaluation parameters were checked andsubjectedtoinvitrodissolutionstudiesandtheirreleaseprofiles.

Hardness

The hardness of tablets of different formulation (F1 to F6) wasdetermined as per standard procedure. The average hardness oftablets was found to be 5 to 7 kg/cm. None of the formulationsshoweddeviationforanyofthetabletstested

Thicknessoftablets

Theaveragethicknessof tablets(F1 toF6)determinedandresultsare presented in Table 2. The maximum and minimum averagethickness of tablet was found to 3 mm and 2.5 mm respectively.None of the formulation (F1 to F6) deviated from the standards.

Table1:Compositionofmucodhesivebuccaltablets

IngredientsFormulations

F1 F2 F3 F4 F5 F6Lisinopril 10 10 10 10 10 10Carbopol934p 25 42.5 60 25 42.5 60HEC 60 42.5 60 HPMCK4M 60 42.5 25Sprayeddriedlactose

35 35 35 35 35 35

Mannitol 17 17 17 17 17 17Magnesiumstearate

5 5 5 5 5 5

Table2:WeightvariationandthicknessofLisinoprilbuccaltablets

Formulationcode Averageweightoftablet(mg) ThicknessinmmF1 152.4 2.7F2 152.1 2.5F3 153.3 3F4 1515 2.5F5 15.4 2.7F6 150.5 2.5

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Contentuniformity

Thecontentuniformityoftheentiretablet(F1toF6)wasevaluatedandtheresultsarepresentedinTable3.Themaximumpercentageof drug content from the different formulations was found to be100.12 andminimumpercentage of drug contentwas found to be98.6%. Hence it is concluded that all the formulations are fallingwithinthepharmacopoeiallimits.

SurfacepH

ThesurfacepHoftabletsofeachformulation(F1toF6)wastestedandtheresultsareprovidedintable3.ThemaximumandminimumpH values of the formulations were found to be 6.10 and 5.59respectively.TheacceptablepHofsaliva is in therangeof57andthesurfacepHofalltabletsiswithinlimits.Hence,theformulationsmaynotproduceanyirritationtothebuccalmucosa.

Invitrodrugreleaseprofile

Thedrugreleasepatternwasstudiedforallformulations(F1toF6)for 10 hrs following standard procedure and the results areprovidedinFig.5.Thedrugreleasepatternofbuccalmucoadhesivetablets varied according to their type and ratio of polymers. Themostimportantfactoraffectingtherateofreleasefrombuccaltablet

isthedrugandpolymerratio.TheformulationF1,F2,F3containedthedrug,Carbopol934pandHECpolymersintheratioof1:2:4,1:3.4 : 3.4 and 1 : 4 : 2 respectively. The in vitro cumulative drugreleaseprofileofformulationsF1,F2,F3at10hrsshowed86.54%,85.48%and84.1%drugreleaserespectively.

Similarly the formulations F4, F5, and F6 contained drugCarbopol934pandHPMCK4Mpolymersintheratioof1 :2 :4,1 :3.4 :4.3and1:4:2respectively.TheinvitrocumulativedrugreleaseprofileofformulationsF4,F5andF6at10hrsshowed97.1%,95.41%and93.17drugreleaserespectively.Itwasconcludedthatbyincreasingthe concentrationof carbopol934p in the formulations (F1 to F6),thedrugreleaseratefromthetabletwasfoundtobedecreased,butwhentheconcentrationofsecondarypolymersHECandHPMCK4Mis increase, the drug release rate was found to be increased. Thismay be attributed to increased hydration followed by increasedswellingofpolymerswithincreaseinconcentration.

Theoveralldataontheinvitrodissolutionstudiescloselyindicatedthatamongthesixformulations,theformulationF4wasfoundtobethebestwithhighpercentageofdrugrelease(97.1).Thecumulativedrug release of formulations containing carbopol 934p withsecondary polymers was found to be in order ofF4>F5>F6>F1>F2>F3.

Table3:Contentuniformity,surfacepH,mucoadhesivestrength,mucoadhesiveforceofLisinoprilbuccaltablets

Formulation Percentagehydration1h 2h 4h 8h 12h

F1 48.5 58.8 17.0 88.10 90.1F2 47.1 57.7 70.3 86.9 89.5F3 48.5 56.6 69.1 86.5 93.5F4 50.2 61.7 73.6 90 93.5F5 48.6 47.2 88.6 89.7 89.7F6 47.5 57.7 71.2 86.9 89.2

Table4:InvitroswellingstudyofLisinoprilbuccaltablets

Formulationcode %Drugcontent SurfacepH Mucoadhesivestrength(g)

Mucoadhesiveforce(N)

F1 99.2 5.9 28.8 2.79F2 98.6 5.8 29.2 2.86F3 99.13 6.0 32.4 3.17F4 100.12 6.10 36.5 3.58F5 99.2 5.59 34.5 3.38F6 98.8 5.9 30.5 2.99

Table5:DrugreleasekineticsstudiesofLisinoprilbuccaltablets

Formulation Zeroorder(R2)

Firstorder(R2)

Higuchi(R2)

HixonCrowell(R2)

F1 0.9911 0.9091 0.8171 0.9249F2 0.9860 0.8950 0.7940 0.9090F3 0.9920 0.8990 0.8310 0.9450F4 0.9940 0.7840 0.9260 0.9030F5 0.9831 0.8184 0.8490 0.8810F6 0.9870 0.8150 0.8980 0.9010

Fig.1

Fig.2

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Kinetictreatmenttodissolutiondata

Kinetic studies i.e. zeroorder, first order andHiguchi andHixconCrowellwereconducted forall formulationsand thedata isshowninTable6.Thevalueof regression correlation coefficient (R2)wasevaluated for all the formulations which value was close to 0.99.Hence it is conducted that all the formulations are following thezeroorderdrugrelease.

CONCLUSION

Theoverallstudies indicatedthat thepolymersCarbopol934pandHPMCK4Mintheratioof2:4showedsatisfactorymucoadhesiveproperties. Among the 6 formulations, the formulation F4 usingthese polymers in the above ratio with drug exhibited significantswelling properties with optimum release profile. Hence it can beconcluded that the formulation F4 will be useful for buccaladministration for the treatment of antihypertensive. So, themucoadhesive buccal tablets ot Lisinoprilmay be a good choice tobypass the extensive hepatic first pass metabolism with animprovement in the bioavailability of Lisinopril through Buccalmucosa.

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