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International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 3, Issue 1, 2011

ResearchArticle

FORMULATIONDEVELOPMENTANDOPTIMIZATIONOFCONTROLLEDPOROSITYOSMOTIC PUMPTABLETSOFDICLOFENACSODIUM

SUDEESHEDAVALATH*,SHIVANANDK,KALYANIPRAKASAM,BPRAKASHRAOANDGOLIDIVAKAR
DepartmentofPharmaceutics,Acharya&B.MReddycollegeofPharmacy,Soldevanahalli,Hesaraghattamainroad,Bangalore560090, IndiaEmail:sudeeshe@gmail.com,sudeeshe@yahoo.com Received:19Sep2010,RevisedandAccepted:22Oct2010 ABSTRACT The porous osmotic pump tablets were designed using DOptimal design and numerical optimization technique was applied to find out the best formulation.OsmoticagentsodiumchlorideandporeformerPEG400wasconsideredasindependentvariables.Drugreleaserateat2h,4h,8h,12 h,T50% andreleaseexponent(n)weretakenasresponses.Theincreaseinconcentrationofporeformerandosmoticagentafteralimit,changesthe releasefromzeroordertoHiguchibasedrelease.Theoptimizedformulation follows nonFickianreleasemechanism.TheFTIRandDSCstudies revealedthatnophysicochemicalinteractionbetweenexcipientsanddrug.TheinfluenceofpHandagitationintensityonthereleaseofdrugwas studiedandthereleasemechanismwasthroughosmosis.Stabilitystudiesrevealedthatoptimizedformulationwasstable.TheresultofDOptimal design and ANOVA studies reveals that osmotic agent and pore former have significant effect on the drug release up to 12 h. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demostrates the feasibility of the optimizationprocedureinsuccessfuldevelopmentofporousosmoticpumptabletscontainingdiclofenacsodiumbyusingsodiumchlorideandPEG 400askeyexcipients. Keywords:Diclofenacsodium,Optimaloptimization,Porousosmoticpump,Polyethyleneglycol400,Sodiumchloride. INTRODUCTION By using oral controlled drug delivery system can provide continuous delivery of drugs at predictable and reproducible kinetics throughout the GI transit. Also the systems that target the drugdeliverytoaspecificregionwithintheGItractforeitherlocal orsystemicaction1. Tomaintaindrugconcentrationwithinthetherapeuticwindowthe drugdoseanddosingintervalareoptimized,thusensuringefficacy while minimizing toxic effects. Oral controlled release system that provides greater effectiveness in the treatment of chronic conditions, reduced side effects, and greater patient convenience duetosimplifieddosingschedule2. Thedrugreleasefromoralcontrolledreleasedosageformsmay be affectedbypH,GImotilityandpresenceoffoodintheGItract.Drugs canbedeliveredinacontrolledpatternoveralongperiodoftimeby the process of osmosis. Drug delivery from this system is not influenced by the different physiological factors within the gut lumen and the release characteristics can be predicted easily from theknownpropertiesofthedrugandthedosageform 3. The oral osmotic pump tablets have many advantages, such as reducing risk of adverse reactions, zeroorder delivery rate, a high degree of in vitroin vivo correlation and improving patient compliance4. Diclofenac sodium is a non steroidal antiinammatory analgesic with potent cyclooxygenase inhibition activity and also commonly usedforpaincontrolandthetreatmentofrheumaticdiseases5. Diclofenac sodium has biological half life of 2 h and it absorbs throughout the intestinal tract. The drug shows linear pharmacokinetics,issuitablefororalcontrolledreleasetabletsand it would be advantageous to slow down its release in GI tract not only to prolong its therapeutic action but also minimize possible sideeffectsofDiclofenac6. MATERIALSANDMETHODS Materials Diclofenac sodium was obtained as gift sample from Novartis pharmaceutical Ltd (Mumbai, India). Cellulose acetate was purchased by S.D Fine Chem. Ltd (Mumbai, India). PEG 400, Microcrystalline cellulose and povidone K30 was received as gift sample from Strides Arco labs LTD (Bangalore, India). Magnesium stearateandtalcwaspurchasedfromS.D.fineChem.LTD(Mumbai, India). Experimentaldesign DOptimal design was applied using the software DesignExpert software (StatEase Inc, Minneapolis,USA).Factors takenasA & B. Aistheosmoticagent(Sodiumchloride),Bistheporeformer7. FourierTransformInfraredSpectroscopy(FTIR) Physicalmixturesofdrugandexcipientswerepreparedtostudythe compatibility. Drug polymer compatibility studies were carried out usingFTIRspectroscopy8. DifferentialScanningCalorimetry(DSC) DSCstudieswerecarriedoutforthepuredrug,physicalmixturesof drugandexcipientsandplacebooftheporousosmoticpumptablets to study the compatibility. The analysis were performed under nitrogen (nitrogen flow rate 50 ml/min) in order to eliminate oxidative and pyrolytic effects at a standard heating rate of 10 C/minoveratemperaturerangeof50C400CusingaUniversal V45ATAinstruments9. Preparationofporousosmoticpumptablet Preparationofcoretablets CoretabletsofDSwerepreparedbywetgranulationmethod.Allthe ingredients (Table 1) except povidone K30, magnesium stearate andtalcwereaccuratelyweightedandmixedinmortarwithapestle for10minutestogettheuniformmix.Thedryblendwasgranulated withsufficientquantityofPVPK30whichwasdissolvedinisopropyl alcohol.Thepowdermasswasdriedat60Cinhotairovenfor6h andpassedthroughsieveno.20.Thedriedgranulesweremixedwith magnesium stearate and talc for 3 min. The blended powder was compressedintoroundtabletsbyusing9mmpunchinRimekmini pressIcompressionmachine9. Coatingofthecoretablets Coating was performed by using spray pan coating machine. The cellulose acetate in acetone containing different levels of pore formers (PEG 400) was used as coating solution (Table 1). Total components in the coating solution were 4% w/v. The coating conditions were as follows: pan, 9 inch circular; speed of pan, 50 rev./min; nozzle diameter,1mm; spray rate, 1 ml/min; spray pressure,40lb/sq.in.;dryingtemperature,5560C.Weightgainof alltheformulationswasmaintainedto3%10.

Edavalathetal. IntJPharmPharmSci,Vol3,Issue1,8087 Table1:Masterformulaforporousosmoticpumptablets Ingredients(Quantityinmgfor1tablet) Coretablets SodiumChloride Microcrystallinecellulose CoatingComponentsin%w/w Celluloseacetate P.E.G400 OP1 60 105 80% 20% OP2 60 105 70% 30% OP3 60 105 60% 40% OP4 80 85 80% 20% OP5 80 85 70% 30% OP6 80 85 60% 40% OP7 100 65 80% 20% OP8 100 65 70% 30% OP9 100 65 60% 40%

Eachformulaalsocontains:Diclofenacsodium100mg;PovidoneK3015mg;Sodiumlaurylsulphate15mg;Magnesiumstearate2mg;Talc3mg Powderflowproperties Angleofrepose The angle of repose of the mixture of the drug and excipients was determined by fixed funnel method. The values are used in the followingequationtogettheangleofrepose. Tan = h/r Where, h, r and are the height, radius and angle of reposeofthepowderpile. Bulkdensity Accurately weighed 3 g of the sample was transferred to the measuring cylinder of bulk density apparatus. The apparatus was adjusted for 100 tapping and noted the final volume as tapped volume. Weightofthepowder Tappeddensity(t)= Determinationofdrugcontent Ten tablets were accurately weighed and powdered. A quantity of the powder equivalent to 100 mg of Diclofenac sodium was weighed accuratelyandextractedin100mlmethanolbyshakingfor20min.After filtrationthroughwhatmannfilterpaperno.1andsufficientdilutionwith methanol, samples were analyzed spectrophotometrically at 283 nm. Amountof drugpresentwas determined from the calibration curveof Diclofenacsodiuminmethanol12. Invitrodissolutionstudies Drug release studies were carried out using USP dissolution test apparatus (Apparatus I basket type). The dissolution medium was 900mlofphosphatebufferpH7.5.Thereleasewasperformedat37 0.5C, with a rotation speed of 100 rpm. 10 ml samples were withdrawnatpredeterminedtimeintervalsandreplacedwithfresh medium. Thesampleswere filtered through whatmannfilterpaper andanalyzedafterappropriatedilutionbyUVspectrophotometer 3. Porosity Porosityofthepowderwasdeterminedbyusingformula: Porosity=[(Vb Vp)/Vb]100.WhereVb isthebulkvolumeandVp isthetruevolume Carrsindex Thecarrsindexofthepowderwasdeterminedbyusingformula: Carrsindex(%)=[(TBDLBD)100]/TBD Where,TBDisthetotalbulkdensityandLBDistheloosebulkdensity11. EvaluationofPorousosmoticpumpTablets Thickness Thickness ofthe core tabletsand coated tablets were measured by using screw gauge. Ten tablets from each formulation were randomlyselectedandused.Thicknessisexpressedinmillimeters. Hardness The hardness of the core tablets and coated tables were measured using the Pfizer hardness tester. Six tablets from each formulation were randomly selected and used. The average hardness and the standarddeviationwerecalculated.ItisexpressedinKg/cm 2. Friability Friability of the matrix tablets and core tablets of porous osmotic pumptabletswere determined.10tabletswererandomlyselected, weighed and placed in the Roche Friabilator. The apparatus was rotated at 25 rpm for 4 min. After revolutions the tablets were dedusted and weighed again. The percentage friability was measuredusingtheformula, Initialwt.oftabletsFinalwt.oftablets %Friability=x100 Initialwt.oftablets Weightuniformity Ten tablets were randomly selected from each batch and individuallyweighed.Theaverageweightandstandarddeviationof 20tabletswascalculated11. CurvefittingAnalysis For thedeterminationofthe drugrelease kinetics from theporous osmoticpumptablet,theinvitroreleasedatawereanalyzedbyzero order,firstorder,HiguchiandKorsmeyerandPeppasequations. Zeroorderreleasekinetic Tostudythezero orderreleasekineticsthereleasedatawasfitted intothefollowingequation: dQ/dt=K0 Where, Q is the amount of drug release, K0 is the zero order releaserateconstantandtisthereleasetime.Thegraphisplotted percentagecumulativedrugrelease(%CDR)versetime. Firstorderreleasekinetic To study the first order release kinetics the release rate data are fittedintothefollowingequation: dQ/dt=K1Q Where,Qisthefractionofdrugrelease,K 1isthefirstorderrelease rate constantand tisthe releasetime. Thegraphis plottedlog% CDRremainingversetime. Higuchireleasemodel To study the Higuchi release model the release rate data are fitted intothefollowingequation: Q=KHt Where, Q is the fraction of drug release, KH is the release rate constant andt is the release time. The graph is plotted % CDR versessquarerootoftime. KorsmeyerandPeppaskinetics TostudytheKorsmeyerandPeppasreleasekineticsthereleaserate dataarefittedintofollowingequation: Mt/M=KKPtn Where,Mt/Misthefractionofdrugrelease,K KPisthereleaserate constant andt is the release time and n is the diffusion exponent relatedtomechanismofdrugrelease.Thegraphisplottedlog%CDR verseslogtime13. 81

Tappedvolumeofthe powder

Edavalathetal. IntJPharmPharmSci,Vol3,Issue1,8087 Optimization In the numerical optimization techniques, the desirability approch wasusedtogeneratetheoptimumsettingsfortheformulation. For the optimized formulation, the drug release at 2 h, 4 h, 8 h, 12 h, T50%, release exponent(n) were kept in target. The drug release targetwaskeptaccordingtotheUSPstandards(Table10). EffectofpHondrugrelease Theoptimizedformulationofporousosmoticpumptabletsistested for the effect of pH on drug release. The best formulations are undergonedissolutionstudiesin0.1NHCl,6.8pHphosphatebuffer, 7.5pHphosphatebufferanddistilledwaterinrotationspeedof100 rpm and 37 0.5C using USP dissolution test apparatus (type 1) andcompared9. Effectofagitationintensityondrugrelease The optimized formulation of matrix and porous osmotic pump tablesaretestedfortheeffectofagitationintensityondrugrelease. The best formulations are undergone dissolution studies by maintainingdifferentrotationspeedof50,100,150rpmandat37 0.5Cin7.5pHphosphatebufferfor8husingUSPdissolutiontest apparatus(type1)andcompared9. Effectofosmoticpressure Thereleasestudiesoftheoptimizedformulationwereconductedin media of different osmotic pressure for confirming the mechanism of drug release. To increase the osmotic pressure of the release mediaosmoticagentmannitolwasaddedin7.5pHphosphatebuffer at37C1C).Releasestudieswereperformedin900mLofmedia using USPI dissolution apparatus (100 rpm). To avoid any interferenceintheanalysisbymannitol,thesampleswereanalyzed todeterminetheresidualamountremainingineachformulation.At the end of 8 h formulations were withdrawn from each vessel and cut open, and the contents were dissolved in sufficient volume of phosphatebuffer.Theresultsafterdirectmeasurementofdruginto the release media were similar to the results of residual drug analysis method. The osmotic pressure of the medium was determinedusingVantHoffandMorseequation9. V=nRT Were, Osmotic pressure, V Volume of the solution in liter, n Numberofmolesofsolute,TAbsolutetemperature,RGasconstant whichisequalto0.082litatm/moldeg. Membranemorphologyofporousosmoticpumptablet ScanningElectronMicroscopy Coating membranes of formulation obtained before and after complete dissolution of core contents were examined for their porous morphology by scanning electron microscope (JEOL JSM 6300,Japan).Membranesweredriedat45Cfor12handstored between sheets of wax paper in a dessicator until examination. The membrane were coated under an argon atmosphere with goldpalladium, and observed with a scanning electron microscope14. Stability Thepurposeofstabilitystudyistoprovideevidenceonthequality of a drug substance or drug product which varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. The formulation was subjected to accelerated stability studies as per ICH (The International Conference of Harmonization) guidelines. The most satisfactory formulationwassealedinanaluminumfoilandstoredat302C, 65 5% RH and at 40 2 C, 75 5% RH for 6 months. Tablets were periodically removed and evaluated for physical characteristics,invitrodrugrelease9. RESULTANDDISCUSSION DrugpolymercompatibilitystudiesusingFTIR In order to investigate the possible chemical interaction between drug and selected polymers, FTIR studies were carried out. IR spectrum for pure drug and physical mixture of drug polymers were obtained and analyzed for principle peaks at 3380 cm 1 (NH stretch), 1647 cm1 (C=O), 3081 cm1 (Aromatic CH), 750 cm1 (Cl stretch), 1453 cm1 (CH bend), 1564 cm1 (NH bend). The FTIR characteristicofDiclofenacsodiumwithpolymersresemblesalmost with the spectra of authentic sample of Diclofenac sodium. The studies suggest that there is no incompatibility between drug and polymer.ResultsaregiveninTable2.

Table2:FTIRspectrumofDSaloneandexcipients IRabsorptionbands Diclofenacsodium Drug+MCC Drug+CA Drug+PVP Drug+SC DrugpolymercompatibilitystudiesusingDSC In order to investigate the possible physical interaction between drug and excipients, DSC studies were carried out. The drug exhibited a sharp melting endotherm at 281.35C. The DSC thermogramsofDiclofenacsodium,porousosmoticpumptabletand placebo of porous osmotic pump tablets are depicted in Fig. 1. No changeintheendothermofthedrugwasobservedincoatedporous osmotic pump tablets. From this it was inferred that there was no interactionbetweenthedrugandexcipients. Interpretation NHstretch(cm1) 3380 3339 3350 3397 3231 C=O(cm1) 1647 1637 1645 1648 1650 AromaticCH(cm1) 3081 3080 3085 3080 3085 Clstretch(cm1) 750 756 757 756 752 CHbend(cm1) 1453 1456 1457 1455 1456 NHbend(cm1) 1564 1550 1550 1558 1562

Fig.1:DSCspectraofdrugandexcipients Diclofenacsodium(DS),Placeboofporousosmoticpumptablets,Physicalmixtureofdrugandexcipients 82

Edavalathetal. IntJPharmPharmSci,Vol3,Issue1,8087 Powderflowproperties The results of preformulation parameters for formulated physical mixtures of all batches are shown in table 3. The flowability of the polymers was found to be quite good according to the flow properties. Angle of repose ranges from 26.89 to 28.50, bulk densityrangesfrom0.353to0.361g/cm3,%Compressibilityranges from13.21to14.54%. Table3:Powderflowpropertiesforformulatedphysicalmixtures FormulationCode OP1,OP2,OP3 OP4,OP5,OP6 OP7,OP8,OP9 AngleofRepose* () 26.890.23 27.180.53 28.500.49 BulkDensity*(g/cm3) 0.3580.002 0.3530.004 0.3610.005 TappedDensity* (g/cm3) 0.4130.003 0.4110.006 0.4230.006 Porosity* (%) 13.150.09 14.010.10 14.470.17 Compressibility*(%) 13.210.16 14.110.28 14.540.15 Physicochemicalproperties The mean values of hardness, friability, thickness, weight and drug contentofpreparedmatrixtabletsandcoretabletofporousosmotic pump tablets is recorded in the table 4. The thickness, diameter, hardness, weight of the coated porous osmotic pump tablets is recordedinthetable5.

Note:(*)Allvaluesarethemeanofthreereadings Table4:Physicochemicalparametersofdevelopedcoretabletsofporousosmoticpump Formulationcode OP1,OP2,OP3 OP4,OP5,OP6 OP7,OP8,OP9 Hardness* (kg/cm2) 8.130.15 8.230.137 8.2670.07 Friability (%) 0.389 0.521 0.445 Thickness* (mm) 3.910.009 3.780.007 3.670.012 Weight* (mg) 300.61.855 301.72.099 3011.66 Drugcontent*(%) 99.110.615 98.540.735 99.190.372

Note:(*)Allvaluesarethemeanofthreereadings

Table5:Physicochemicalparametersofdevelopedporousosmoticpumptablets FormulationCode OP1 OP2 OP3 OP4 OP5 OP6 OP7 OP8 OP9 Thickness* (mm) 4.0110.13 4.0100.02 4.0060.017 3.8960.019 3.890.015 3.8890.013 3.7800.017 3.7700.015 3.7700.016 Diameter* (mm) 9.1090.014 9.1060.017 9.1080.018 9.1030.015 9.1120.015 9.1170.011 9.1030.022 9.1280.014 9.1220.015 Hardness* (kg/cm2) 8.50.11 8.470.16 8.430.15 8.40.126 8.470.10 8.50.11 8.430.15 8.430.234 8.470.16 Weight* (mg) 310.21.03 309.81.03 310.40.966 310.31.49 309.71.337 309.61.174 309.71.159 310.51.08 3111.247

Note:(*)Allvaluesarethemeanofthreereadings Invitrodissolutionstudy Inporousosmoticpumptabletsthedrugreleaserateisdependson the concentration of the osmotic agent and the pore former used. The osmotic agent concentration increases then the osmotic pressure created inside the tablet also increases, the core compartment imbibes aqueous fluids from the surrounding environment across the membrane and dissolves the drug so the releaseofthedrugalsowillincrease.Theporeformerconcentration increases then the number of pore formed or the pore size also increases it will cause easy leaching out of the drug from the formulation. The concentration of the pore former or the osmotic agentonincreasebeyondalimit,itwillcausethereleaseofthedrug inadiffusionmanner.ResultsareshowninFig.2A,2B,2C.

Fig.2A

Fig.2B

Fig.2C

Fig.2:Dissolutionprofileofporousosmoticpumptablets 83

Edavalathetal. IntJPharmPharmSci,Vol3,Issue1,8087 Invitrodrugreleasestudyafter2hour(h) Total amount of Diclofenac sodium released from all formulations ranges from 18.68% to 39.42% in 2 h (Table 6). Increased rate of drug release was observed after 2 h with increase of the concentration of osmogent and pore former. When the tablets contact with dissolution media the pore formation on membrane will takes place. The porous membrane and concentration of osmogentinthecoretabletactsasratecontrollingforthereleaseof drug. In this case, effect of both osmogent and pore former can be explainedbymathematicalequationintermsofactualfactors: R1=+26.97+6.42*A+4.63*B The linear model is selected for this response with Model Fvalue 15.92andpvalueis0.0101.pvaluelessthan0.0500indicatemodel termsaresignificant.InthiscaseA,sodiumchlorideandB,PEG400 aresignificantmodelterms.BoththefactorA,sodiumchlorideand B,PEG400increasesdrugreleasefromthetablets(positiveeffect). TheeffectofAand Bcanbefurtherelucidatedwiththehelpof3D surfaceplot(Fig.3A).HigherreleaseofDiclofenacsodiumwasfound after2hinhigherconcentrationsofbothfactors.AthighlevelofA andBpercentagereleasehashighvaluewhichindicatesfactorAand Bhelpsmorereleaseofdrug. Invitrodrugreleasestudyafter8hour Total amount of Diclofenac sodium released from all formulations ranges from 46.07% to 80.69% in 8 h (Table 6). Increased rate of drug release was observed after 8 h with increase of the concentration of osmogent and pore former (positive effect). The effect of both osmogent and pore former can be explained by mathematicalequationintermsofactualfactors: R3=+64.56+9.97*A+7.56*B The linear model is selected for this response with Model Fvalue 156.75andpvalueis0.0001indicatethemodelissignificant.The effect of A and B can be further elucidated with the help of 3D surfaceplot(Fig.3C).

Fig.3C:3DsurfaceplotshowingtheeffectoffactorAandfactor Bondrugreleaseafter8h Invitrodrugreleasestudyafter12hour Total amount of Diclofenac sodium released from all formulations rangesfrom61.06%to99.87%in12h(Table6).Increasedrate of drug release was observed with increase of the concentration of osmogent and pore former (Positive effect). The effect of both osmogent and pore former can be explained by mathematical equationintermsofactualfactors: R4=+85.38+12.36*A+8.42*B The linear model is selected for this response with Model Fvalue 21.81 and p value is 0.0056 indicate the model is significant. The effect of A and B can be further elucidated with the help of 3D surfaceplot(Fig.3D).

Fig.3A:3DsurfaceplotshowingtheeffectoffactorAandfactor Bondrugreleaseafter2h Invitrodrugreleasestudyafter4hour Total amount of Diclofenac sodium released from all formulations ranges from 26.71% to 53.68% in 4 h (Table 6). Increased rate of drug release was observed after 4 h with increase of the concentration of osmogent and pore former. The effect of both osmogent and pore former can be explained by mathematical equationintermsofactualfactors: R2=+40.77+10.19*A+6.10*B The linear model is selected for this response with Model Fvalue 12.46 and p value is 0.0157 indicate the model is significant. The EquationshowsbothfactorsAandBhavesignificantpositiveeffect ontheresponse.TheeffectofAandBcanbefurtherelucidatedwith thehelpof3Dsurfaceplot(Fig.3B).

Fig.3D:3DsurfaceplotshowingtheeffectoffactorAandfactor Bondrugreleaseafter12h EffectofformulationvariablesonT50% The value of T50% ranges from the 3.7 to 8.6 h (Table 6). The increasedT50%wasobservedatlowconcentrationsofosmogentand poreformer(negativeeffect).Theeffectofbothosmogentand pore formercanbeexplainedbymathematicalequationintermsofactual factors: R5=+5.691.45*A1.20*B 84

Fig.3B:3DsurfaceplotshowingtheeffectoffactorAandfactor Bondrugreleaseafter4h

Edavalathetal. IntJPharmPharmSci,Vol3,Issue1,8087 Thelinearmodelwasfoundtobesignificantforthetimefor50%of drugrelease.TheModelFvalueof34.79andvalueofpislessthan 0.0023indicatethemodelissignificant.Theequationindicatesthat T50%increaseasfactorsdecreases(negativeeffect). Effectofformulationvariableonreleaseexponent The linear model was found to be not significant for release exponentwiththemodelFvalue0.52andpvalue0.7267(Table6).

Inthisresponse,factorAandBwasfoundtobenotsignificant.So, themodelequationisasfollows: R6=+0.640.026*A0.023*B

Thenvalueofoptimizedformulafoundtobe0.695whichindicates themechanismofreleaseisnonFickian.

Table6:ResultofreleaseparameterobtainedforformulationsbyDOptimaldesign Run OP1 OP2 OP3 OP4 OP5 OP6 OP7 OP8 OP9

Sodiumchloride 60 80 100 60 80 100 60 80 100

PEG400 20 30 40 20 30 40 20 30 40

Drugreleaseafter 2h 4h 8h 18.68 26.71 46.07 21.39 31.32 56.08 23.54 35.66 63.48 21.09 31.62 54.93 25.08 38.44 65.46 30.87 48.32 69.53 26.31 42.74 67.32 36.37 51.79 77.44 39.42 53.68 80.69

12h 61.04 72.06 83.51 76.73 87.76 96.58 91.66 99.25 99.87

nvalue 0.606 0.678 0.689 0.690 0.665 0.612 0.695 0.568 0.552

T50% 8.6 7.1 5.8 7.1 5.5 4.3 5.3 3.8 3.7

Curvefittinganalysis The in vitro release data was fitted to various kinetic models like Higuchi, First order, Zero order and Peppas. In porous osmotic pump tablets OP1, OP2 follows first order kinetics, OP3 to OP7 follows zero order kinetics, OP8 and OP9 follows Higuchi release model.Resultsaregiveninthetable7.Whenthedatawereplotted according to the firstorder equation, the formulations showed a

comparatively poor linearity, with regression value of 0.945; whereas the regression value for zeroorder equation was 0.982, which indicated that drug release from optimized formulation (OP7) was independent of drug concentration. In matrix tablets and porous osmotic pump tablets the n value for Peppas model wasfoundtobeinbetween0.45and0.89,indicatesthatthedrug released from the formulation by anomalous (nonFickians) mechanism.

Table7:Summaryofdrugreleasekineticsofformulations Kineticprofileof KorsmeyerPeppas formulation n KKP Porousosmoticpumptablets OP1 0.606 13.00 OP2 0.678 13.21 OP3 0.689 15.10 OP4 0.690 13.30 OP5 0.665 16.63 OP6 0.612 20.37 OP7 0.695 16.33 OP8 0.568 23.88 OP9 0.552 25.59 R2 0.965 0.989 0.990 0.990 0.984 0.994 0.997 0.995 0.999 Zeroorder K0 R2 4.796 5.807 6.760 6.045 7.056 7.317 7.334 7.477 7.584 0.978 0.983 0.982 0.987 0.982 0.972 0.982 0.959 0.948 Firstorder K 0.076 0.106 0.147 0.115 0.173 0.237 0.196 0.322 0.348 R2 0.989 0.989 0.979 0.981 0.961 0.875 0.945 0.812 0.865 Higuchi KH 18.43 22.24 25.95 23.09 27.07 28.40 28.19 29.35 29.99 R2 0.967 0.967 0.969 0.965 0.968 0.981 0.972 0.990 0.993

Drug release exponents(n), Korsmeyer Peppas release constant(K KP), Correlation coefficient(R2) of different models, Zero order release rate constants(K0),Firstorderreleaserateconstant(K),
}

Table8:SummaryofANOVAtableforporousosmoticpumptabletsfromDOptimaldesign Source OPreleaseat2h A B Model OPreleaseat4h A B Model OPreleaseat8h A B Model OPrelaseat12h A B Model T50% A B Model nvalue A B Model d.f 2 2 4 2 2 4 2 2 4 2 2 4 2 2 4 2 2 4 Sumsquare 254.43 130.19 384.62 630.70 240.37 871.07 603.42 357.34 960.76 928.95 429.80 1358.75 12.63 8.86 21.49 5.345E003 3.201E003 8.546E003 Meansquare 127.21 65.10 96.16 315.35 120.18 217.77 301.71 178.67 240.19 464.48 214.90 339.69 6.31 4.43 5.37 2.672E003 1.600E003 2.136E003 Fvalue 21.06 10.78 15.92 18.04 6.88 12.46 196.89 116.60 156.75 29.82 29.82 21.81 40.88 28.69 34.79 0.66 0.39 0.52 pvalue 0.0075 0.0245 0.0101* 0.0100 0.0508 0.0157* 0.0001 0.0003 0.0001* 0.0040 0.0160 0.0056* 0.0022 0.0042 0.0023* 0.5674 0.6989 0.7267ns

Note:(*)significant(p<0.05),ns:notsignificant 85

Edavalathetal. IntJPharmPharmSci,Vol3,Issue1,8087 ANOVA InporousosmoticpumptabletstheresultofANOVAdemostrateall theindependentvariables(Factors)werefoundtobesignificantfor response R1, R2, R3, R4, R5 but not significant for response R6 (Table 8). The linear model were found to be significant for all responsesexceptR6.So,aboveresultindicatethat boththefactors play an important role in the formulation of porous osmotic pump tabletcontainingDiclofenacsodium. Optimization It was concluded that the formulation OP7 is the most satisfactory formulaion for the physiologically independent controlled delivery ofDiclofenacsodium.

A good releationship between the experimental and predicted values (Table 11), which confirms the practicability and validity of themodel. Membranemorphologyofporousosmoticpumptablets Membranesobtainedbeforedissolutionclearlyshowednonporous region(Fig.4A).After12hdissolution,clearlyshowedporesformed inrangeof1to25mowingtodissolutionofPEG400(Fig.4B).The leachingofPEG400fromthemembraneleadstoformationofpores, andthusthereleaseofdrugtakesplace.InformulationOP7contains 20% PEG which produces less pores compare to OP8 (30% PEG 400)andOP9(40%PEG400).

Fig.4A:Beforedissolution EffectofpHondrugrelease When formulation OP7 was subjected to in vitro release studies in buffers with different pH and distilled water, no signicant difference in the release proles were seen compared to that in phosphate buffer pH 7.5. Thus the uid in different parts of the GI tractwillscarcelyaffectdrugreleasefromtheosmoticsystem. Effectofagitationintensityondrugrelease The release profile of Diclofenac sodium from the optimized formulationOP7wasindependentoftheagitationalintensityofthe releasemedia. EffectofOsmoticPressure Thedrugreleaseratedecreasedwithincreaseinosmoticpressureinthe media;however,thelagtimewasprolonged.Thedrugreleaseprofiles with varying osmotic pressure are shown in table 9. This finding confirmsthatthemechanismofdrugreleaseisbytheosmoticpressure.

Fig.4B:Afterdissolution

Fig.4:MembranemorphologyofformulationOP7byscanningelectronmicroscopy Table9:Dissolutionparametersofoptimizedformulationwith varyingosmoticpressure Osmotic (atm) 7.753 31.009

Pressure

Lag (h) 1.45 1.95

time

Dissolution (%/h) 7.68 6.71

rate

Stabilitystudies After the 6 months storage of formulation OP7, values of all parameters like hardness, diameter, thickness, % drug content, friability were checked periodically and found to be almost similar totheinitialvalues.Thedrugdissolutionanddiffusionprofilewere similartotheinitialprofile.Therewasnotanysignificantchangein anyvalueandalsonochangesinthephysicalappearance.Soitcan besaidthatformulationisstable.

Table10:ComparisonofreleaseprofileofUSPDiclofenacsodiumextendedreleasetabletswithoptimizedCPOPformulation Time (h) 2 4 8 16

ReleaseprofileofDiclofenacsodiumextendedreleasetabletslabelledfor12hdosing( USPtolerancelimit)(%) Between22%and42% Between34%and61% Between52%and82% Notlessthan73%

Release profile of formulationOP7(%) 26.31 42.74 67.32 91.66in12h

optimized

Table11:Comparisonofexperimentedandpredictedvaluesofoptimizedformulation Optimizedformula OP7 Predicted Experimental Dependablevariables Drug release at 2 Drug release at 4 h h 29.0878 44.5333 26.31 42.74 Drug release at 8 h 66.7011 67.32

Drugreleaseat12 h 88.0189 91.66

T50% 5.57778 5.3

Releaseexponent 0.629222 0.695

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Edavalathetal. IntJPharmPharmSci,Vol3,Issue1,8087 CONCLUSION Theobservedindependentvariableswerefoundtobeveryclose to predicted values of optimized formulation which demostrates the feasibility ofthe optimizationprocedureinsuccessful development ofporousosmoticpumptablets containingDiclofenacsodium(100 mg) by using sodium chloride (100mg) as osmotic agent and 20% w/w(with80%w/wcelluloseacetate)ofPEG400asporeformer. Stabilitystudiesrevealedthatoptimizedformulationisstable. REFERENCES 1. 2. ChienYW. Novel drug delivery systems. 2nd ed. New York: MarcelDekker;2005.p.13996. Sharma S. Osmotic controlled drug delivery system. [Online]. [2008 Oct 20]; [1]. Available from: URL:http://www.pharmainfo.net/reviews/osmoticcontrolled drugdeliverysystem. MakhijaSN,VaviaPR.Controlledporosityosmoticpumpbased controlled release systems of pseudoephedrine I. Cellulose acetate as a semi permeable membrane. J Control Release 2003;89:518. MehramiziA,AsgariME,PourfarzibM,BayatiKH,DorkooshFA, Rafiee T M. Influence of cyclodextrin complexation on lovastatin release from osmotic pump tablets (OPT). DARU 2007;15(2):718. ShengFangS,ChenHisC,ChaoFengK,JindingH.Invitroand invivocomparisonoftwodiclofenacsodiumsustainedrelease oralformulations.IntJPharm2003;260:3946. 10. 11. 6. 7. 8. 9. Chowdary KPR, Mohapatra P, Krishna MN. Evaluation of olibanumanditsresinasratecontrollingmatrixforcontrolled releaseofdiclofenac.IndianJPharmSci2006;68(4):497500. James S. Encyclopedia of pharmaceutical technology. 3rd ed. NewYork:Informahealthcare;2007,p.245266. Punna RR, Sindhura G, Ranendra NS. Design and study of lamivudine oral controlled release tablets. AAPS Pharm Sci Tech2007;8(4):E1E9. KanagaleP,LohrayBB,MisraA,DavadraP,KiniR.Formulation and optimization of porous osmotic pumpbased controlled release system of oxybutynin. AAPS Pharm Sci Tech 2007; 8(3):E1E7. WenJenL,HongGuannL.Designofamicroporouscontrolled delivery system for theophylline tablets. J Control Release 2003;89:17987. Hamdy A, Ossama Y A, Hesham S. Formulation of controlled release baclofen matrix tablets: Influence of some hydrophilic polymers on the release rate and in vitro evaluation.AAPSPharmSciTech2007;8(4):E1E11. Ayhan S, Yalcin O, Askin I Imer. Preparation and in vitro evaluation of sustained release tablet formulations of diclofenacsodium.Farmaco2005;60:17177. Donald LW. Hand book of Pharmaceutical Controlled Release Technology.NewYork:MarcelDekker;2000,p.1838,22554, 4316. PrakashRB,GeethaM,PurushothamaN,UtpalS.Optimization and development of swellable controlled porosity osmotic pump tablet for theophylline. Trop J Pharm Research 2009; 8(3):24755.

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