Research ArticlePREPARATION AND CHARACTERIZATION OF FAMOTIDINE MICROCAPSULEEMPLOYING MUCOADHESIVE POLYMERS IN COMBINATION TO ENHANCEGASTRO RETENTION FOR ORAL DELIVERYBHABANI S NAYAK *1, SUNIL K GHOSH 1 AND K. TRIPATI B PATRO 21Jeypore College of Pharmacy, Faculty of Pharmacy, Rondapalli, Jeypore-764002, Koraput, Orissa, India.2College of Pharmaceutical Sciences,Mohuda, Berhampur – 760002, Ganjam, Orissa, IndiaE.mil: bhabani143@yahoo.co.in, Cell No: +919938860284 (M), Fax no- 06854-246955.Received – 28th May, 2009, Revised and Accepted – 20th July 2009ABSTRACT:A new sustained release microencapsulated drug delivery system employing sustained release polymers incombination has been proposed in this present study. The microcapsules were formulated by orifice ionic gelation technique using famotidine as the model drug and polymers combination forms like (carbopol-934 and hydroxypropyl methyl cellulose, carbopol-934 and sodium carboxy methyl cellulose, carbopol-934 and methyl cellulose,carbopol-934 and guar gum) against carbopol-934 only. Microcapsules were evaluated for particle size, percentageyield, flow properties, drug entrapment efficiency, surface morphology by scanning electron microscopy (SEM),sphericity measurement, percentage moisture loss, wall thickness, swelling property, in vitro drug release profile,drug release kinetic study and mucoadhesion study by in vitro wash off test. The effect of drug and differentpolymer combination on in vitro drug release profile was examined. The famotidine microcapsules with goodstructure and satisfactory yield were produced. Microcapsules employing sustained release polymers used in

combination, exhibited slow release of famotidine over 9 hours with zero order release kinetic fashion. It wasconcluded that the polymer possess substantial release controlling properties used in combination that could be usedfor sustained drug delivery. All data were verified statistically by employing one way ANOVA and found to besignificant at 5 % level of significance.Keyword : Famotidine, Microencapsulation, MucoadhesionINTRODUCTIONSustained release (SR) drug delivery system significantly improve therapeutic efficacy of a drug. Drug release retarding polymers arethe key performer in such systems. Much of the development in SR drug delivery systems Is focusing in the preparation and use ofpolymers with specificity designed macroscopic and microscopic structural and chemical features. Number of natural, semisynthetic and synthetic polymer materials are used in the controlled delivery of drugs. Recent trend towards the use of vegetable andNon toxic products demands the replacement of synthetic additives with natural one. TheNatural materials have been extensively used in the field of drug delivery for their easy availability, cost effectiveness, Eco friendliness,capable of multitude of chemical modifications, potentially degradable and compatible due to natural origin. Past research therefore studied and acknowledged.various natural gum like agar, guar gum,chitosan, xanthium, sodium alginate and lotus bean gum etc. for potential pharmaceuticaland biomedical application. The development of efficient orally delivered mucoadhesivedrug delivery system includes advantageslike, enhanced bioavailability, targetedspecific delivery to specific region of the GItract, maximized absorption rate due toIntimate contact with the absorbing

membrane, improved drug protection bypolymer encapsulation and longer gut transittime resulting in extended periods forabsorption. Famotidine, a potent H2-receoterantagonist was widely used in the treatmentof peptic ulcer in a dose of 20 mg b.i.dassociated with adverse effects like diarrhoea,dizziness, headache and anorexia etc. Theplasma half life of drug was 2.5-3 hour asreported in literature, which may exhibitstoxic effect in prolong use. Hence an attemptwas made in this current study to evaluate theefficacy of combine polymers in designing ofsustained release mucoadhesive famotidinemicrocapsule for oral delivery.MATERIALS AND METHODSMaterialsFamotidine was received as a gift samplefrom Nicholas Piramol India limited,Mumbai. Carbopol-934, Sodiumcarboxy methyl cellulose (SCMC), hydroxylpropyl methyl cellulose (HPMC), methylcellulose and guar gum . All other chemicaland reagents used in this study were ofanalytical grade and procured fromauthorized dealer.Preparation of microcapsules:Mucoadhesive microcapsule were preparedby orifice ionic gelation method withpolymers combinations such as carbopoland HPMC, carbopol and SCMC, carbopoland methyl cellulose, carbopol and guargum, against carbopol only, in the drug polymerratio of 1:3 w/w using famotidine

as model drug. Famotidine loadedmicrocapsule were prepared by ionicgelation method. Briefly 200 mg of sodiumalginate, 100 mg of polymer (Firstcarbopol-934 alone and then carbopol-934with other polymers in ratio of 1:1 w/w) and100 mg of drug were dispersed in 10 mlwater with a constant stirring at 300 rpm for30 min. The resultant dispersion was addeddrop wise through a syringe (17 gages) intothe CaCl2 solution (10 % w/v). The soformed microcapsules (1:3 w/w ratio) werekept for 30 min for complete reaction andafterwards, microcapsule were recovered byfiltration through a sintered glass filter,under vacuum, dried in hot air oven at 60°Cfor 1 hour.Percentage Yield:The microcapsules were evaluated forpercentage yield and percent drugentrapment. The yield was calculated as perthe equation,Percentage yield = Weight of microcapsule recovered X 100Weight (drug + polymer)Particle size measurement:The size of the prepared microcapsules wasmeasured by the optical microscopy methodusing a calibrated stage micrometer. Particlesize was calculated by using equation,Xg = 10 x [(ni x log Xi) / N], Where, Xg isgeometric mean diameter, ni is number ofparticle in range, Xi is the mid point ofrange and N is the total number of particles.All the experimental units were analyzed intriplicate (n=3).

Flow properties of microcapsules:Flowability of microcapsules wasinvestigated by determining Angle ofrepose, bulk density, Carr’s index andHausner ratio. The angle of repose wasdetermined by fixed funnel method. Themicrocapsules were tapped using bulkdensity apparatus (Excel Enterprises,Kolkata) for 1000 taps in a cylinder and thechange in volume were measured. Carrindex and Hausner ratio were calculated bythe formula,114Carr index (%) = (Df-D0) ×100 ⁄ Df andHausner ratio = Df ⁄ D0, where, Df is poureddensity; D0 is tapped density.Drug entrapment efficiency (DEE):Drug loaded microcapsules (100 mg) werepowdered and suspended in 100 ml watersolvent system. The resultant dispersion waskept for 30 min for complete mixing withcontinuous agitation and filtered through a0.45 μm membrane filter. The drug contentwas determined spectrophotometrically(UV-Visible-1700, Shimadzu, Japanspectrophotometer) at 265 nm using aregression equation derived from the standardgraph (r2 = 0.9978). The drug entrapmentefficiency (DEE) was calculated by theequation, DEE = (Pc / Tc) X 100, Where, Pc ispractical content, Tc is the theoretical content.All the formulations were analyzed intriplicate (n=3).Scanning Electron Microscopy: (SEM)The SEM analysis was carried out using a

scanning electron microscope (LEO, 435 VP,U.K.). Prior to examination, samples weremounted on an aluminium stub using adouble sided adhesive tape and making itelectrically conductive by coating with a thinlayer of gold (approximately 20 nm) invacuum. The scanning electron microscopewas operated at an acceleration voltage of 5kV and resolution of 4000.Percentage moisture loss:The famotidine loaded microcapsules wasevaluated for percentage moisture loss whichsharing an idea about its hydrophilic nature.The microcapsules weighed (W1) initiallykept in desiccator containing calcium chlorideat 37°C for 24 hours. The final weight (W2)was noted when no further change in weightof sample was observed.Moisture loss = [(W1 – W2)/ W2] X 100. Allthe experimental units were studied intriplicate (n=3).Determination of sphericity:The particle shape was measure by computingcirculatory factor (S). The tracing obtainedfrom optical microscopy were used tocalculate Area (A) and perimeter (P).This will indicate the approximate shape ofthe prepared microcapsule calculated by theequation, S = P2/ 12.56 × A. All theexperimental units were studied intriplicate (n=3).Loose surface crystals study:The Famotidine encapsulated microcapsulesprepared by different combination ofpolymers were evaluated by loose surface

crystal study to observe the excess drugpresent on the surface of microcapsules. Fromeach batch, 100 mg of microcapsule wasshaken in 20 ml of 0.1N HCl for 5 min andthen filtered through whatman filter paper 41.The amount of drug present in filtrate wasdetermined spectroscopically and calculatedas a percentage of total drug.Determination of swelling properties:The dynamic swelling property ofmicrocapsules in the dissolution medium wasdetermined. Microcapsules of known weightwere placed in dissolution solution for 6 hrand the swollen microcapsules were collectedby a centrifuge and the wet weight of theswollen microcapsules was determined byfirst blotting the particles with filter paper toremove absorbed water on surface and thenweighing immediately on an electronicbalance. The percentage of swelling ofmicrocapsules in the dissolution media was115then calculated by using equation, Sw = [(Wt-Wo)/Wo] ×100, where, Sw= percentage ofswelling of microcapsules, Wt = weight of themicrocapsules at time t, Wo = initial weightof the microcapsules. All the experimentalunits were studied in triplicate (n=3).Determination of wall thickness11,12Wall thickness of microcapsules wasdetermined by method of Luu et al usingequation, h = [r (1-P) d1/3{Pd2+ (1-P) d1}] ×100, where, h= wall thickness, r = arithmeticmean radius of microcapsules, d1 and d2 aredensities of core and coat material respectively,

P is the proportion of medicament inmicrocapsules. All the experimental units werestudied in triplicate (n=3).In vitro drug release13In vitro drug release study was carried out inUSP type-II dissolution test apparatus.Microcapsules were placed in basket ofdissolution vessel containing 900 ml of 0.1NHCl maintained at (37±1) °C and stirred at 50rpm. Aliquots of samples (5 ml) at an intervalof 1 hour were withdrawn and filtered through awhatman filter paper. The samples were analyzedfor famotidine content by UV-Visiblespectrophotometer at 265 nm .All the experimentalunits were analyzed in triplicate (n=3).In vitro drug release kinetic studiesKinetic model had described drugdissolution from solid dosage form wherethe dissolved amount of drug is a functionof test time. In order to study the exactmechanism of drug release from themicrosphere, drug release data wasanalyzed according to zero order14, firstorder15, Higuchi square root16, Korsmeyer-Peppas model17. The criteria for selectingthe most appropriate model were chosen onthe basis of goodness of fit test.Mucoadhesion test by In vitro wash offmethod18A piece of stomach mucosa (5 × 2 cm) wastaken from local slaughter house. It wasmounted on to glass slides with adhesive.About 100 microcapsules were spread on toeach wet rinsed tissue specimen andimmediately thereafter the support was hung

on the arm of a USP tablet disintegrating testmachine. By operating the disintegrating testmachine the tissue specimen was given aslow regular up and down movement in thetest fluid at 37oC taken in the vessel of themachine. At the end of every one hour up to10 hours, the machine was stopped andnumber of microcapsules still adhering ontothe tissue was counted..RESULTS AND DISCUSSIONSThe composition of famotidine loadedmucoadhesive microcapsules using combinedpolymers in ratio of 1:3 w/w of drug polymerwas designed and prepared by orifice ionicgelation method. The obtained microcapsuleswere found to be non aggregated. Thegeneralized microparticulation protocoldepends on, choice of ingredient, successfulpreparation of microcapsules and optimizationat every preparative steps. The percentageyield was found to be in the ranges of 67.7 to87.5 % and the yield was found satisfactoryin all the formulations as reported in Table 1.The formulation F3 is showing maximumyield. The optical microscopy revealed thatall microcapsules thus obtained, were opaque,discrete and spherical particles with smoothsurfaces further confirmed by SEM study.The geometric diameter of the microcapsuleslies in the ranges of 380.1 to 723.4 μm asshown in Table 1. All the formulations havingexcellent flow properties as given in Table 1.The drug entrapment efficiency (DEE) of allthe formulations was reported as high profile

ranges from 30.3 to 96.7 % may be due to useof polymers in combination, as abridged inTable 1. The maximum DEE was shown byformulation F3. The shape of famotidinemicrocapsule as evidenced from the scanningelectron photomicrograph was spherical anduniformly distributed shown in Fig 1. Thepercentage of moisture loss was found in arange 2.24 to13.26 % tabularized in Table 2.The minimum moisture content was observedwith formulation F3. The results ensure thepresence of diminutive water content whichcan be due to the involvement of water inprocess method and hydrophilic property ofmucoadhesive polymers. But the lessenproportion of water obtained indicates itsproper drying and instant hardening ofmicrocapsule due to quick gelation occurredbetween calcium chloride and sodiumalginate facilitate the storage behavior of theformulations. The famotidine loadedmucoadhesive microcapsules obtained havingcircularity factor very close to 1.00, whichconfirm their sphericity, as represented inTable 2. These loose surface crystal studieslend a hand to estimate the excess amount ofdrug attached on the surface of microcapsulesafter a successful drug entrapment. The studywas executed with various preparedformulations and the results were tabularizedin Table 2. The swelling indexes ofmicrocapsules were found satisfactory andshown in Table 2, indicates thehydrophlilicity property of the polymers withestablishing the fundamentals that the

increase in swelling index may depends onthe use of polymers in combination informulations. The wall thickness was foundto be highest 3.888μm for F2 in comparisonto other formulations as shown in Table 2.The wall thickness of the microcapsulesmainly built up with polymer content informulations. The in vitro famotidine releasesfrom microcapsules prepared by combinationof polymers were studied. All the formulationswere found to be release famotidine in acontrolled manner for a prolonged period over9 hours which is represented graphically in Fig2. Among all the formulations, F3 was found torelease famotidine in a controlled manner withconstant fashion over extended period of time.To illustrate the kinetic of drug release frommicrocapsules, release data was analyzedaccording to different kinetic equationsdepicted in Table 3. Release data of allformulations except F1 and F5 following zeroorder kinetic showing a constant release profile,independent of formulation variations. The drugrelease of the formulations F1 and F5, have adiffusion controlled release pattern which isdependent on concentration of release retardingpolymer as they are best fit in Higuchi squareroot kinetic model. The Table 3 showed that allthe formulations release the drug by diffusionfollowing Fickian (n<0.5) transport mechanismexcept the formulation F5, which follow non-Fickian (n>0.5) transport mechanism. Statisticalverification with one way ANOVA methodattested the fact that the drug release data werefound significant at 5 % level of significance (p

< 0.05). The order of mucoadhesion propertyamong all the formulations was found asF1>F2>F3>F4>F5, as shown in Fig 3. Theformulations F1, F2 and F3, are showing goodbioadhesion..

Fig. 1 : Scanning electron photomicrograph of prepared microcapsules (f3) under lowerresolution :CONCLUSIONThe formulation F3 containing drug: polymerratio 1:3 with polymer combination ofcarbopol-934 and SCMC was found to be thebest microcapsule formulation, regarding allthe properties evaluated in order to achieveobjective of this study. The novel formulationdesign facilitated the optimization andsuccessful development of famotidinemicrocapsule formulations. Our dataconcluded that choice of combination ofpolymers instead of single polymer may be aneffective strategy for the designing anddevelopment of famotidine mucoadhesivemicrocapsule for easy, reproducible and costeffective method to prove its potential for

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