Research ArticleFormulation and Evaluation of Multilayered Tablets ofPioglitazone Hydrochloride and Metformin Hydrochloride
Y Ankamma Chowdary1 Ramakrishna Raparla2
and Muramshetty Madhuri2
1 Department of Pharmaceutics NRI College of Pharmacy Pothavarappadu Village Krishna DistrictAndhra Pradesh 521 212 India
2Department of Pharmaceutics Vaageswari Institute of Pharmaceutical Sciences Beside LMD Police StationKarimnagar Andhra Pradesh 505 481 India
Correspondence should be addressed to Ramakrishna Raparla ramakrishnaraparlarediffmailcom
Received 28 November 2013 Revised 15 February 2014 Accepted 2 March 2014 Published 12 May 2014
Academic Editor Fabiana Quaglia
Copyright copy 2014 Y Ankamma Chowdary et alThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited
In the treatment of type 2 diabetes mellitus a continuous therapy is required which is a more complex one As in these patients theremay be a defect in both insulin secretion and insulin action exists Hence the treatment depends on the pathophysiology and thedisease state In the present study multilayered tablets of pioglitazone hydrochloride 15mg and metformin hydrochloride 500mgwere prepared in an attempt for combination therapy for the treatment of type 2 diabetes mellitus PioglitazoneHCl was formulatedas immediate release layer to show immediate action by direct compression method using combination of superdisintegrantsnamely crospovidone and avicel PH 102 Crospovidone at 20 concentration showed good drug release profile at 2 hrs MetforminHCl was formulated as controlled release layer to prolong the drug action by incorporating hydrophilic polymers such as HPMCK4M by direct compression method and guar gum by wet granulation method in order to sustain the drug release from thetablets and maintain its integrity so as to provide a suitable formulation The multilayered tablets were prepared after carryingout the optimization of immediate release layer and were evaluated for various precompression and postcompression parametersFormulation F13 showed 9997 of pioglitazone release at 2 hrs in 01 N HCl and metformin showed 9881 drug release at 10 hrsof dissolution in 68 pH phosphate buffer The developed formulation is equivalent to innovator product in view of in vitro drugrelease profileThe results of all these evaluation tests are within the standardsThe procedure followed for the formulation of thesetablets was found to be reproducible and all the formulations were stable after accelerated stability studies Hence multilayeredtablets of pioglitazone HCl and metformin HCl can be a better alternative way to conventional dosage forms
1 Introduction
A drug delivery system (DDS) is defined as a formulationor a device that enables the introduction of a therapeuticsubstance in the body and improves its efficacy and safetyby controlling the rate time and place of release of drugsin the body The process includes the administration of thetherapeutic product the release of the active ingredient bythe therapeutic product and subsequent transport of theactive ingredients across the biological membranes to the siteof action Oral route for the administration of therapeuticagents is the oldest and most convenient route because oflow cost of therapy and ease of administration which leads to
higher level of patient compliance It has a wide acceptanceup to 50ndash60 of total dosage forms and has been exploredfor systemic delivery of drugs via pharmaceutical productsof different dosage form Approximately 50 of the drugproducts available in themarket are administered orally [1ndash3]
Conventional dosage forms are rapidly absorbed withthe ascending and descending portions of the concentrationsversus time curve reflecting primarily the rate of absorptionand elimination respectively Because of the rapid rate ofabsorption from conventional drug delivery systems drugsare usually administered more than once daily with thefrequency being dependent on biological half-life (t(12)) andduration of pharmacological effect [4ndash6]
Hindawi Publishing CorporationJournal of PharmaceuticsVolume 2014 Article ID 848243 14 pageshttpdxdoiorg1011552014848243
2 Journal of Pharmaceutics
Table 1 Composition of immediate release layer formulations of pioglitazone HCl
An appropriately designed controlled-release drug deliv-ery system (CRDDS) can improve the therapeutic efficacyand safety of a drug by precise temporal and spatial placementin the body thereby reducing both the size and number ofdoses required The main objective of controlledsustainedrelease drug delivery is to make sure of safety and to improveeffectiveness of drugs as well as patient compliance More-over this controlled drug delivery system fails to achieve thestated advantages due to lack of releasing the initial bolus dosedumping and failure to achieve site specific drug deliveryFormulation of layers from different types of polymers allowsmanipulation over more than one rate-controlling polymerthus enabling different kinds of drug delivery of one or moreactive ingredients that is where the drug may be releasedwith a bolus and then at a controlled rate or by targeted drugdelivery in the GI tract using pH dependent polymers [7 8]
Diabetes mellitus is a chronic metabolic disorder charac-terized by a high blood glucose concentration hyperglycemia(fasting plasma glucose gt70mmolL or plasma glucosegt111mmolL two hours after a meal) caused by insulindeficiency often combined with insulin resistance wherecontinuous therapy is required Apart from diet and exercisewhich are fundamental in the treatment of diabetes mellitus(DM) single oral antidiabetic drug sometimes fails to achieveandmaintain glycemic control Consequently a combinationtherapy using agents with complementary mechanism ofaction has become a cornerstone of type 2 diabetes mellitus(T2DM) management [9]
MetforminHCl the only available biguanide remains thefirst line drug therapy for obese patients with T2DM Dailydose of metformin HCl is 05ndash3 gm In monotherapy undercertain conditions metformin at high doses can cause lacticacidosis cataract Pioglitazone HCl is an orally administeredthiazolidinedione agent Daily dose of pioglitazone HCl is15ndash30mg Pioglitazone sensitizes peripheral tissues to insulinand hence may cause hypoglycemia when insulin is usedconcomitantly though hypoglycemia can also occur withmonotherapy Multilayered tablets were formulated to avoidrepetitive dosage form administration Solubility of pioglita-zone decreases with increase in pH and metformin is freelysoluble drug pioglitazone is formulated as immediate releaselayer andmetformin is formulated as controlled release layerThis type of combination will give better compliance [10ndash14]
The release retardant guar gum which was used in thepresent study is one of the most promising dietary fiberswhich is a gel-forming galactomannan obtained by grindingthe endosperm portion of Cyamopsis tetragonolobus L a
leguminous plant All natural fiber diet works with body toachieve a feeling of fullness and to reduce hunger It has alsobeen used as an appetite suppressant [15ndash17]
2 Materials and Methods
21 Materials Pioglitazone and metformin were obtained asa gift samples from Dr Reddyrsquos laboratories Hyderabad andMSN formulations Hyderabad respectively HPMC K4Mand crospovidone were procured from Nihal traders Hyder-abad guar gum is the grounded endosperm of Cyamopsistetragonolobus and all the remaining chemicals are of ana-lytical grade
22 Method221 Preparation of Immediate Release Layer of PioglitazoneHCl (F1ndashF4) Immediate release layer of pioglitazone HClwas prepared by direct compression method (Figure 4)Pioglitazone HCl crospovidone avicel pH-102 and lactosewere accurately weighed and passed through sieve number40 All the above ingredients as shown in Table 1 were mixedin a polybag Talc and magnesium stearate were added afterpassing through sieve number 40 and mixed properly
222 Preparation of Controlled Release Layer of MetforminHCl Formulated with HPMC K4M (F5ndashF8) Controlledrelease layer of metformin HCl containing HPMC K4Mwas prepared by direct compression method MetforminHCl HPMC K4M PVP K30 and dicalcium phosphate werepassed through sieve number 40 All the above ingredientswere mixed in a polybag Talc and magnesium stearate wereadded after passing through sieve number 40 and mixedproperly
223 Preparation of Controlled Release Layer of MetforminHCl Formulated with Guar Gum (F9ndashF12) Metformin HClgranules containing guar gum were prepared by wet granu-lation technique by adding PVP K 30 dissolved in distilledwater as a granulating fluid Required quantities of met-forminHCl guar gum and dicalcium phosphate were passedthrough sieve number 40 and were mixed thoroughly anda sufficient volume of granulating fluid was added slowlyAfter enough cohesiveness was obtained themass was passedthrough sieve number 12 The obtained granules were driedat 50∘C in hot air oven till a constant weight was obtained(until dry) The dried granules were then passed through
Journal of Pharmaceutics 3
sieve number 40 Talc and magnesium stearate were addedafter passing through sieve number 40 and mixed properly
23 Procedure Optimization process is done for immediaterelease layer in order to select the composition to forma multilayered tablet The first layer consists of immediaterelease and the second layer consists of controlled releaseThe first layer was placed in the die cavity which consists ofimmediate release layer and punched with low compressionforce and then the second layer was placed in the die cavitywhich consists of controlled release layer and allowed forpunching and finally barrier layer containing 35mg of ethylcellulose was placed in the die cavity and compressed withmaximum compression force in order to obtain multilayeredtablets by using 12mmpunches of SAIMACHSMD 16 stationtablet compression machine with an average hardness of 6ndash8 kgcm2 Prior to compression the granules were evaluatedfor several tests
The optimized immediate release tablet F3 is formulatedinto multilayer tablet containing metformin HCl as con-trolled release layer with two different polymers
3 Evaluation of Flow Properties
31 Precompression Flow Properties [18ndash20] The granules ofall formulations were evaluated for powder flow propertiesindependently for both immediate and controlled releaselayersThe fixed funnelmethodwas employed tomeasure theangle of repose Bulk and tapped densities were determinedby tapped density apparatus from which compressibilityindex and Hausnerrsquos ratio values were calculated Drugcontent of granules was determined spectrophotometricallyand the granules prepared fromwet granulationmethod (F9ndashF13) were subjected tomoisture content and loss on drying byusing hot air oven
4 Evaluation of Multilayer Tablets [21ndash24]41Thickness The thickness of the tablets was determined byusing vernier calipers Randomly 10 tablets selectedwere usedfor determination of thickness that was expressed in mean plusmnSD and unit is mm
42 Uniformity of Weight The individual weight of 20tablets was taken after selecting them randomly for weightvariation Then their average weight and their mean andstandard deviationwere calculatedand compared with thestandards The weight of the tablet being made is mea-sured to ensure that it contains predetermined amount ofdrug
43 Hardness Hardness is termed as the tablet crushingstrength and it is the force required to break a tablet diametri-cally Hardness of tablets was measured by selecting 5 tabletsrandomly and the hardness of each tablet was measuredwith Monsanto hardness tester The hardness was noted Thehardness is usually measured in terms of kgcm2
44 Friability The tablet friability is a measure of loss due toabrasion The preweighed tablets were exposed to repeatedshocks in Roche Friabilator in which they are initiallyweighed (119882
119900) and kept in a tumbling and rotating apparatus
drum and were subjected to fall from 6 inches height Aftercompletion of 100 rotations the tablets were reweighed (119908)and the percent loss in weight or friability (119891) was calculatedby the formula given below
Friability =Initial weight minus Final weight
Initial weighttimes 100 (1)
45 Disintegration Time The disintegration time was deter-mined at 37plusmn05∘Cusing disintegration test apparatus in 01 NHCl
46 Content Uniformity Twenty tablets were powdered anddose equivalent weight of powder blend was accuratelyweighed and transferred into a 100mL volumetric flaskInitially 5mL of methanol was added and shaken for 10minThen volume was made up to 100mL with the methanolThe solution in the volumetric flask was filtered diluted suit-ably and analyzed spectrophotometrically The drug contentshould be within the range between 90 and 110 of standardamount
Drug content =Drug contentlabel claim
times 100 (2)
47 In Vitro Dissolution Studies In vitro dissolution stud-ies was conducted using USP dissolution apparatus-I at37 plusmn 05∘C temperature and at 50 rpm and the volume ofdissolution media is 900mL 01 N hydrochloric acid wasused as dissolution medium for the first two hours and68 pH phosphate buffer for the remaining time Samplesof 5mL were withdrawn at predetermined time intervalsand replaced with 5mL of fresh dissolution medium Thecollected samples were suitably diluted with dissolution fluidwherever necessary and were analyzed for the pioglitazoneHCl for the first two hours at 269 nm and for metformin HClfor the remaining time at 233 nm by using a double beamUVspectrophotometer
48 Release Kinetics The rate and mechanism of metforminrelease from the prepared multilayer tablets were analyzed byfitting the data in zero order as cumulative amount of drugrelease versus time
119862 = 1198700119905 (3)
where119862 is the amount of drug released at time t and1198700is the
release rate constant first order as log cumulative percent ofdrug remaining versus time
Log 119862 = Log 1198620minus
119870119905
2303
(4)
where1198620is the initial concentration of drug and119870 is the first-
order rate constant Higuchi model as cumulative percentageof drug released versus square root of time
119876 = 11987011990512
(5)
4 Journal of Pharmaceutics
T(
)
98
95
90
85
80
75
70
65
60
55
50
45
4000 3500 3000 2500 2000 1500 1000 650
261212 cmminus1
174190 cmminus1
168303 cmminus1
150953 cmminus1
146139 cmminus1
131275 cmminus1
124284 cmminus1
114851 cmminus1
103801 cmminus1
87262 cmminus1
84932 cmminus1
71182 cmminus1
65927 cmminus1
(cmminus1)
Figure 1 FTIR graph of pure drug pioglitazone HCl
where119876 is the amount of drug released at time 119905 and119870 is thediffusion rate constant Korsmeyer-Peppas model as log timeversus log cumulative percent drug release
Log(119872119905
119872infin
) = Log119870 + 119899 Log 119905 (6)
where 119872119905is the amount of drug released at time 119905 119872
infinis
the amount of drug release after infinite time 119870 is releaserate constant and 119899 is the diffusion exponent indicative of themechanism of drug release
49 Swelling Behavior of Tablets The extent of swelling wasmeasured in terms of weight gain by the tablet Theswelling behaviors of all controlled release formulations werestudied Initially one tablet from each formulationwas kept ina petridish containing 68 pH phosphate buffers The tabletwas removed lightly blotted with tissue paper to removeexcess buffer and reweighed for every 1 h the weights of thetablet were noted Percentage weight gain by the tablet wascalculated by the following formula
S I = (119882119905minus1198820)
1198820
times 100 (7)
where SI is the swelling index119882119905the weight of tablet at time
119905 (h) and1198820the weight of tablet at zero time
410 Stability Studies The tablets were packed in suitablepackaging and the well-sealed tablets were kept in the humid-ity chamber and their stability studies were conducted as per
ICH andWHO guidelines to assess the drug content sampleswhich were collected at the end of the studies and wereevaluated for drug release and its content The conditionsprescribed by ICH guidelines for accelerated studies are 40∘Cplusmn 2∘C75 RH plusmn 5 RH for 3 months
5 Results and Discussion
51 FTIR Studies In order to investigate the possible interac-tions among pioglitazone HCl metformin HCl and differentpolymersdiluents FTIR studies were carried out (Figures 12 and 3) As the identical peaks were observed in all the caseshence it was confirmed that no interaction exists betweendrugs and excipients The characteristic peaks obtained inFTIR studies were shown in Table 3
52 Precompression Flow Properties All the formulationsshowed good flow properties with angle of repose valuesbetween 25∘ and 35∘ and Hausnerrsquos ratio ranged between 110and 119 whereas Carrrsquos index values ranged between 11 and15 and all these values are shown in Tables 4 and 5
53 Evaluation of Prepared Tablets The tablets were visuallyobserved and free from defects such as lamination chippingand capping The prepared tablets passed all the in-processtestsTheweights of the tablets are within the rangeHardnessof the tablets was in the range of 29ndash73 kgcm2 thickness ofthe tablets is within 265ndash520mm and the friability rangesbetween 017 and 081 percent These results are shown inTables 6 and 7
54 In Vitro Drug Release Profile The drug release from F1composed of 10 crospovidone is 9814plusmn03 F2 composedof 15 crospovidone is 9960 plusmn 01 F3 composed of 20crospovidone is 9989 plusmn 04 and F4 composed of 25crospovidone is 9986 plusmn 02 The concentration of avicelPH 102 was kept at constant in all the formulations that is
15 The drug release at specific time intervals was plottedin a graph and from the drug release profile formulation F3composed of 20 crospovidone showed good drug releaseprofile (9997 plusmn 05) with least disintegration time HenceF3 was selected as the optimized formulation for immediaterelease layer for incorporation with metformin controlled
6 Journal of Pharmaceutics
Table 2 Optimized immediate release layer along with controlled release layer is formulated as bilayer tablets
Pure drugs Optimized multilayer tablet formulated with guar gum (cmminus1)Metformin (cmminus1) Pioglitazone (cmminus1)
NndashH (1∘)3400ndash3250 336823 mdash 337361
NndashH (2∘)3400ndash3250 314815 mdash 328295
C=N1471ndash1689 155980 mdash 156625
C=O1760ndash1665 mdash 174190 167427
CndashO1000ndash1300 mdash 124284 124413
CndashS600ndash700 mdash 65927 68282
C=N1471ndash1689 mdash 150953 153346
release layerThe drug release from crospovidonemay be dueto its capillary activity with the dissolution media [25]
The optimized F3 was formulated into bilayer tabletscontaining metformin controlled release layer along with it(Table 2) The drug release from F11 was better and a barrierlayer was incorporated to it in F13 to release the drug in acontrolled mannerThe drug release profile of the tablets wasshown in Figures 5 and 6
The drug release of pioglitazone HCl from F13 was foundto be 9994plusmn07at 2 hrs of dissolution in 01 NHClThedrugrelease of metformin HCl from F13 was found to be 9881 plusmn05 at 10 hrs of dissolution in 68 pH phosphate buffer
The release of drug not only depends upon the natureof matrix but also depends upon the drug polymer ratio
Due to the differences in the rheological properties of thepolymers they are taken in different concentrations Guargum at low concentrations (F9) can retard the drug releasevery well compared to HPMC K4M (F5) that can retard thedrug release at a slight higher concentration compared to guargum whereas the drug retarding capacity is similar at higherconcentrations for HPMC (F7 and F8) and guar gum (F11 andF12) As HPMC K4M is a semisynthetic polymer by directcompression high binder concentrations are required tomaintain the tablet integrity due to the poor compressibilityproblems of metformin HCl compared to less concentrationsof binder in wet granulation formulated with guar gum thatacts as a good binding agent andmaintains integrity of tabletsup to 8 hrs of dissolution in 68 pHphosphate bufferThe filler
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
An appropriately designed controlled-release drug deliv-ery system (CRDDS) can improve the therapeutic efficacyand safety of a drug by precise temporal and spatial placementin the body thereby reducing both the size and number ofdoses required The main objective of controlledsustainedrelease drug delivery is to make sure of safety and to improveeffectiveness of drugs as well as patient compliance More-over this controlled drug delivery system fails to achieve thestated advantages due to lack of releasing the initial bolus dosedumping and failure to achieve site specific drug deliveryFormulation of layers from different types of polymers allowsmanipulation over more than one rate-controlling polymerthus enabling different kinds of drug delivery of one or moreactive ingredients that is where the drug may be releasedwith a bolus and then at a controlled rate or by targeted drugdelivery in the GI tract using pH dependent polymers [7 8]
Diabetes mellitus is a chronic metabolic disorder charac-terized by a high blood glucose concentration hyperglycemia(fasting plasma glucose gt70mmolL or plasma glucosegt111mmolL two hours after a meal) caused by insulindeficiency often combined with insulin resistance wherecontinuous therapy is required Apart from diet and exercisewhich are fundamental in the treatment of diabetes mellitus(DM) single oral antidiabetic drug sometimes fails to achieveandmaintain glycemic control Consequently a combinationtherapy using agents with complementary mechanism ofaction has become a cornerstone of type 2 diabetes mellitus(T2DM) management [9]
MetforminHCl the only available biguanide remains thefirst line drug therapy for obese patients with T2DM Dailydose of metformin HCl is 05ndash3 gm In monotherapy undercertain conditions metformin at high doses can cause lacticacidosis cataract Pioglitazone HCl is an orally administeredthiazolidinedione agent Daily dose of pioglitazone HCl is15ndash30mg Pioglitazone sensitizes peripheral tissues to insulinand hence may cause hypoglycemia when insulin is usedconcomitantly though hypoglycemia can also occur withmonotherapy Multilayered tablets were formulated to avoidrepetitive dosage form administration Solubility of pioglita-zone decreases with increase in pH and metformin is freelysoluble drug pioglitazone is formulated as immediate releaselayer andmetformin is formulated as controlled release layerThis type of combination will give better compliance [10ndash14]
The release retardant guar gum which was used in thepresent study is one of the most promising dietary fiberswhich is a gel-forming galactomannan obtained by grindingthe endosperm portion of Cyamopsis tetragonolobus L a
leguminous plant All natural fiber diet works with body toachieve a feeling of fullness and to reduce hunger It has alsobeen used as an appetite suppressant [15ndash17]
2 Materials and Methods
21 Materials Pioglitazone and metformin were obtained asa gift samples from Dr Reddyrsquos laboratories Hyderabad andMSN formulations Hyderabad respectively HPMC K4Mand crospovidone were procured from Nihal traders Hyder-abad guar gum is the grounded endosperm of Cyamopsistetragonolobus and all the remaining chemicals are of ana-lytical grade
22 Method221 Preparation of Immediate Release Layer of PioglitazoneHCl (F1ndashF4) Immediate release layer of pioglitazone HClwas prepared by direct compression method (Figure 4)Pioglitazone HCl crospovidone avicel pH-102 and lactosewere accurately weighed and passed through sieve number40 All the above ingredients as shown in Table 1 were mixedin a polybag Talc and magnesium stearate were added afterpassing through sieve number 40 and mixed properly
222 Preparation of Controlled Release Layer of MetforminHCl Formulated with HPMC K4M (F5ndashF8) Controlledrelease layer of metformin HCl containing HPMC K4Mwas prepared by direct compression method MetforminHCl HPMC K4M PVP K30 and dicalcium phosphate werepassed through sieve number 40 All the above ingredientswere mixed in a polybag Talc and magnesium stearate wereadded after passing through sieve number 40 and mixedproperly
223 Preparation of Controlled Release Layer of MetforminHCl Formulated with Guar Gum (F9ndashF12) Metformin HClgranules containing guar gum were prepared by wet granu-lation technique by adding PVP K 30 dissolved in distilledwater as a granulating fluid Required quantities of met-forminHCl guar gum and dicalcium phosphate were passedthrough sieve number 40 and were mixed thoroughly anda sufficient volume of granulating fluid was added slowlyAfter enough cohesiveness was obtained themass was passedthrough sieve number 12 The obtained granules were driedat 50∘C in hot air oven till a constant weight was obtained(until dry) The dried granules were then passed through
Journal of Pharmaceutics 3
sieve number 40 Talc and magnesium stearate were addedafter passing through sieve number 40 and mixed properly
23 Procedure Optimization process is done for immediaterelease layer in order to select the composition to forma multilayered tablet The first layer consists of immediaterelease and the second layer consists of controlled releaseThe first layer was placed in the die cavity which consists ofimmediate release layer and punched with low compressionforce and then the second layer was placed in the die cavitywhich consists of controlled release layer and allowed forpunching and finally barrier layer containing 35mg of ethylcellulose was placed in the die cavity and compressed withmaximum compression force in order to obtain multilayeredtablets by using 12mmpunches of SAIMACHSMD 16 stationtablet compression machine with an average hardness of 6ndash8 kgcm2 Prior to compression the granules were evaluatedfor several tests
The optimized immediate release tablet F3 is formulatedinto multilayer tablet containing metformin HCl as con-trolled release layer with two different polymers
3 Evaluation of Flow Properties
31 Precompression Flow Properties [18ndash20] The granules ofall formulations were evaluated for powder flow propertiesindependently for both immediate and controlled releaselayersThe fixed funnelmethodwas employed tomeasure theangle of repose Bulk and tapped densities were determinedby tapped density apparatus from which compressibilityindex and Hausnerrsquos ratio values were calculated Drugcontent of granules was determined spectrophotometricallyand the granules prepared fromwet granulationmethod (F9ndashF13) were subjected tomoisture content and loss on drying byusing hot air oven
4 Evaluation of Multilayer Tablets [21ndash24]41Thickness The thickness of the tablets was determined byusing vernier calipers Randomly 10 tablets selectedwere usedfor determination of thickness that was expressed in mean plusmnSD and unit is mm
42 Uniformity of Weight The individual weight of 20tablets was taken after selecting them randomly for weightvariation Then their average weight and their mean andstandard deviationwere calculatedand compared with thestandards The weight of the tablet being made is mea-sured to ensure that it contains predetermined amount ofdrug
43 Hardness Hardness is termed as the tablet crushingstrength and it is the force required to break a tablet diametri-cally Hardness of tablets was measured by selecting 5 tabletsrandomly and the hardness of each tablet was measuredwith Monsanto hardness tester The hardness was noted Thehardness is usually measured in terms of kgcm2
44 Friability The tablet friability is a measure of loss due toabrasion The preweighed tablets were exposed to repeatedshocks in Roche Friabilator in which they are initiallyweighed (119882
119900) and kept in a tumbling and rotating apparatus
drum and were subjected to fall from 6 inches height Aftercompletion of 100 rotations the tablets were reweighed (119908)and the percent loss in weight or friability (119891) was calculatedby the formula given below
Friability =Initial weight minus Final weight
Initial weighttimes 100 (1)
45 Disintegration Time The disintegration time was deter-mined at 37plusmn05∘Cusing disintegration test apparatus in 01 NHCl
46 Content Uniformity Twenty tablets were powdered anddose equivalent weight of powder blend was accuratelyweighed and transferred into a 100mL volumetric flaskInitially 5mL of methanol was added and shaken for 10minThen volume was made up to 100mL with the methanolThe solution in the volumetric flask was filtered diluted suit-ably and analyzed spectrophotometrically The drug contentshould be within the range between 90 and 110 of standardamount
Drug content =Drug contentlabel claim
times 100 (2)
47 In Vitro Dissolution Studies In vitro dissolution stud-ies was conducted using USP dissolution apparatus-I at37 plusmn 05∘C temperature and at 50 rpm and the volume ofdissolution media is 900mL 01 N hydrochloric acid wasused as dissolution medium for the first two hours and68 pH phosphate buffer for the remaining time Samplesof 5mL were withdrawn at predetermined time intervalsand replaced with 5mL of fresh dissolution medium Thecollected samples were suitably diluted with dissolution fluidwherever necessary and were analyzed for the pioglitazoneHCl for the first two hours at 269 nm and for metformin HClfor the remaining time at 233 nm by using a double beamUVspectrophotometer
48 Release Kinetics The rate and mechanism of metforminrelease from the prepared multilayer tablets were analyzed byfitting the data in zero order as cumulative amount of drugrelease versus time
119862 = 1198700119905 (3)
where119862 is the amount of drug released at time t and1198700is the
release rate constant first order as log cumulative percent ofdrug remaining versus time
Log 119862 = Log 1198620minus
119870119905
2303
(4)
where1198620is the initial concentration of drug and119870 is the first-
order rate constant Higuchi model as cumulative percentageof drug released versus square root of time
119876 = 11987011990512
(5)
4 Journal of Pharmaceutics
T(
)
98
95
90
85
80
75
70
65
60
55
50
45
4000 3500 3000 2500 2000 1500 1000 650
261212 cmminus1
174190 cmminus1
168303 cmminus1
150953 cmminus1
146139 cmminus1
131275 cmminus1
124284 cmminus1
114851 cmminus1
103801 cmminus1
87262 cmminus1
84932 cmminus1
71182 cmminus1
65927 cmminus1
(cmminus1)
Figure 1 FTIR graph of pure drug pioglitazone HCl
where119876 is the amount of drug released at time 119905 and119870 is thediffusion rate constant Korsmeyer-Peppas model as log timeversus log cumulative percent drug release
Log(119872119905
119872infin
) = Log119870 + 119899 Log 119905 (6)
where 119872119905is the amount of drug released at time 119905 119872
infinis
the amount of drug release after infinite time 119870 is releaserate constant and 119899 is the diffusion exponent indicative of themechanism of drug release
49 Swelling Behavior of Tablets The extent of swelling wasmeasured in terms of weight gain by the tablet Theswelling behaviors of all controlled release formulations werestudied Initially one tablet from each formulationwas kept ina petridish containing 68 pH phosphate buffers The tabletwas removed lightly blotted with tissue paper to removeexcess buffer and reweighed for every 1 h the weights of thetablet were noted Percentage weight gain by the tablet wascalculated by the following formula
S I = (119882119905minus1198820)
1198820
times 100 (7)
where SI is the swelling index119882119905the weight of tablet at time
119905 (h) and1198820the weight of tablet at zero time
410 Stability Studies The tablets were packed in suitablepackaging and the well-sealed tablets were kept in the humid-ity chamber and their stability studies were conducted as per
ICH andWHO guidelines to assess the drug content sampleswhich were collected at the end of the studies and wereevaluated for drug release and its content The conditionsprescribed by ICH guidelines for accelerated studies are 40∘Cplusmn 2∘C75 RH plusmn 5 RH for 3 months
5 Results and Discussion
51 FTIR Studies In order to investigate the possible interac-tions among pioglitazone HCl metformin HCl and differentpolymersdiluents FTIR studies were carried out (Figures 12 and 3) As the identical peaks were observed in all the caseshence it was confirmed that no interaction exists betweendrugs and excipients The characteristic peaks obtained inFTIR studies were shown in Table 3
52 Precompression Flow Properties All the formulationsshowed good flow properties with angle of repose valuesbetween 25∘ and 35∘ and Hausnerrsquos ratio ranged between 110and 119 whereas Carrrsquos index values ranged between 11 and15 and all these values are shown in Tables 4 and 5
53 Evaluation of Prepared Tablets The tablets were visuallyobserved and free from defects such as lamination chippingand capping The prepared tablets passed all the in-processtestsTheweights of the tablets are within the rangeHardnessof the tablets was in the range of 29ndash73 kgcm2 thickness ofthe tablets is within 265ndash520mm and the friability rangesbetween 017 and 081 percent These results are shown inTables 6 and 7
54 In Vitro Drug Release Profile The drug release from F1composed of 10 crospovidone is 9814plusmn03 F2 composedof 15 crospovidone is 9960 plusmn 01 F3 composed of 20crospovidone is 9989 plusmn 04 and F4 composed of 25crospovidone is 9986 plusmn 02 The concentration of avicelPH 102 was kept at constant in all the formulations that is
15 The drug release at specific time intervals was plottedin a graph and from the drug release profile formulation F3composed of 20 crospovidone showed good drug releaseprofile (9997 plusmn 05) with least disintegration time HenceF3 was selected as the optimized formulation for immediaterelease layer for incorporation with metformin controlled
6 Journal of Pharmaceutics
Table 2 Optimized immediate release layer along with controlled release layer is formulated as bilayer tablets
Pure drugs Optimized multilayer tablet formulated with guar gum (cmminus1)Metformin (cmminus1) Pioglitazone (cmminus1)
NndashH (1∘)3400ndash3250 336823 mdash 337361
NndashH (2∘)3400ndash3250 314815 mdash 328295
C=N1471ndash1689 155980 mdash 156625
C=O1760ndash1665 mdash 174190 167427
CndashO1000ndash1300 mdash 124284 124413
CndashS600ndash700 mdash 65927 68282
C=N1471ndash1689 mdash 150953 153346
release layerThe drug release from crospovidonemay be dueto its capillary activity with the dissolution media [25]
The optimized F3 was formulated into bilayer tabletscontaining metformin controlled release layer along with it(Table 2) The drug release from F11 was better and a barrierlayer was incorporated to it in F13 to release the drug in acontrolled mannerThe drug release profile of the tablets wasshown in Figures 5 and 6
The drug release of pioglitazone HCl from F13 was foundto be 9994plusmn07at 2 hrs of dissolution in 01 NHClThedrugrelease of metformin HCl from F13 was found to be 9881 plusmn05 at 10 hrs of dissolution in 68 pH phosphate buffer
The release of drug not only depends upon the natureof matrix but also depends upon the drug polymer ratio
Due to the differences in the rheological properties of thepolymers they are taken in different concentrations Guargum at low concentrations (F9) can retard the drug releasevery well compared to HPMC K4M (F5) that can retard thedrug release at a slight higher concentration compared to guargum whereas the drug retarding capacity is similar at higherconcentrations for HPMC (F7 and F8) and guar gum (F11 andF12) As HPMC K4M is a semisynthetic polymer by directcompression high binder concentrations are required tomaintain the tablet integrity due to the poor compressibilityproblems of metformin HCl compared to less concentrationsof binder in wet granulation formulated with guar gum thatacts as a good binding agent andmaintains integrity of tabletsup to 8 hrs of dissolution in 68 pHphosphate bufferThe filler
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
sieve number 40 Talc and magnesium stearate were addedafter passing through sieve number 40 and mixed properly
23 Procedure Optimization process is done for immediaterelease layer in order to select the composition to forma multilayered tablet The first layer consists of immediaterelease and the second layer consists of controlled releaseThe first layer was placed in the die cavity which consists ofimmediate release layer and punched with low compressionforce and then the second layer was placed in the die cavitywhich consists of controlled release layer and allowed forpunching and finally barrier layer containing 35mg of ethylcellulose was placed in the die cavity and compressed withmaximum compression force in order to obtain multilayeredtablets by using 12mmpunches of SAIMACHSMD 16 stationtablet compression machine with an average hardness of 6ndash8 kgcm2 Prior to compression the granules were evaluatedfor several tests
The optimized immediate release tablet F3 is formulatedinto multilayer tablet containing metformin HCl as con-trolled release layer with two different polymers
3 Evaluation of Flow Properties
31 Precompression Flow Properties [18ndash20] The granules ofall formulations were evaluated for powder flow propertiesindependently for both immediate and controlled releaselayersThe fixed funnelmethodwas employed tomeasure theangle of repose Bulk and tapped densities were determinedby tapped density apparatus from which compressibilityindex and Hausnerrsquos ratio values were calculated Drugcontent of granules was determined spectrophotometricallyand the granules prepared fromwet granulationmethod (F9ndashF13) were subjected tomoisture content and loss on drying byusing hot air oven
4 Evaluation of Multilayer Tablets [21ndash24]41Thickness The thickness of the tablets was determined byusing vernier calipers Randomly 10 tablets selectedwere usedfor determination of thickness that was expressed in mean plusmnSD and unit is mm
42 Uniformity of Weight The individual weight of 20tablets was taken after selecting them randomly for weightvariation Then their average weight and their mean andstandard deviationwere calculatedand compared with thestandards The weight of the tablet being made is mea-sured to ensure that it contains predetermined amount ofdrug
43 Hardness Hardness is termed as the tablet crushingstrength and it is the force required to break a tablet diametri-cally Hardness of tablets was measured by selecting 5 tabletsrandomly and the hardness of each tablet was measuredwith Monsanto hardness tester The hardness was noted Thehardness is usually measured in terms of kgcm2
44 Friability The tablet friability is a measure of loss due toabrasion The preweighed tablets were exposed to repeatedshocks in Roche Friabilator in which they are initiallyweighed (119882
119900) and kept in a tumbling and rotating apparatus
drum and were subjected to fall from 6 inches height Aftercompletion of 100 rotations the tablets were reweighed (119908)and the percent loss in weight or friability (119891) was calculatedby the formula given below
Friability =Initial weight minus Final weight
Initial weighttimes 100 (1)
45 Disintegration Time The disintegration time was deter-mined at 37plusmn05∘Cusing disintegration test apparatus in 01 NHCl
46 Content Uniformity Twenty tablets were powdered anddose equivalent weight of powder blend was accuratelyweighed and transferred into a 100mL volumetric flaskInitially 5mL of methanol was added and shaken for 10minThen volume was made up to 100mL with the methanolThe solution in the volumetric flask was filtered diluted suit-ably and analyzed spectrophotometrically The drug contentshould be within the range between 90 and 110 of standardamount
Drug content =Drug contentlabel claim
times 100 (2)
47 In Vitro Dissolution Studies In vitro dissolution stud-ies was conducted using USP dissolution apparatus-I at37 plusmn 05∘C temperature and at 50 rpm and the volume ofdissolution media is 900mL 01 N hydrochloric acid wasused as dissolution medium for the first two hours and68 pH phosphate buffer for the remaining time Samplesof 5mL were withdrawn at predetermined time intervalsand replaced with 5mL of fresh dissolution medium Thecollected samples were suitably diluted with dissolution fluidwherever necessary and were analyzed for the pioglitazoneHCl for the first two hours at 269 nm and for metformin HClfor the remaining time at 233 nm by using a double beamUVspectrophotometer
48 Release Kinetics The rate and mechanism of metforminrelease from the prepared multilayer tablets were analyzed byfitting the data in zero order as cumulative amount of drugrelease versus time
119862 = 1198700119905 (3)
where119862 is the amount of drug released at time t and1198700is the
release rate constant first order as log cumulative percent ofdrug remaining versus time
Log 119862 = Log 1198620minus
119870119905
2303
(4)
where1198620is the initial concentration of drug and119870 is the first-
order rate constant Higuchi model as cumulative percentageof drug released versus square root of time
119876 = 11987011990512
(5)
4 Journal of Pharmaceutics
T(
)
98
95
90
85
80
75
70
65
60
55
50
45
4000 3500 3000 2500 2000 1500 1000 650
261212 cmminus1
174190 cmminus1
168303 cmminus1
150953 cmminus1
146139 cmminus1
131275 cmminus1
124284 cmminus1
114851 cmminus1
103801 cmminus1
87262 cmminus1
84932 cmminus1
71182 cmminus1
65927 cmminus1
(cmminus1)
Figure 1 FTIR graph of pure drug pioglitazone HCl
where119876 is the amount of drug released at time 119905 and119870 is thediffusion rate constant Korsmeyer-Peppas model as log timeversus log cumulative percent drug release
Log(119872119905
119872infin
) = Log119870 + 119899 Log 119905 (6)
where 119872119905is the amount of drug released at time 119905 119872
infinis
the amount of drug release after infinite time 119870 is releaserate constant and 119899 is the diffusion exponent indicative of themechanism of drug release
49 Swelling Behavior of Tablets The extent of swelling wasmeasured in terms of weight gain by the tablet Theswelling behaviors of all controlled release formulations werestudied Initially one tablet from each formulationwas kept ina petridish containing 68 pH phosphate buffers The tabletwas removed lightly blotted with tissue paper to removeexcess buffer and reweighed for every 1 h the weights of thetablet were noted Percentage weight gain by the tablet wascalculated by the following formula
S I = (119882119905minus1198820)
1198820
times 100 (7)
where SI is the swelling index119882119905the weight of tablet at time
119905 (h) and1198820the weight of tablet at zero time
410 Stability Studies The tablets were packed in suitablepackaging and the well-sealed tablets were kept in the humid-ity chamber and their stability studies were conducted as per
ICH andWHO guidelines to assess the drug content sampleswhich were collected at the end of the studies and wereevaluated for drug release and its content The conditionsprescribed by ICH guidelines for accelerated studies are 40∘Cplusmn 2∘C75 RH plusmn 5 RH for 3 months
5 Results and Discussion
51 FTIR Studies In order to investigate the possible interac-tions among pioglitazone HCl metformin HCl and differentpolymersdiluents FTIR studies were carried out (Figures 12 and 3) As the identical peaks were observed in all the caseshence it was confirmed that no interaction exists betweendrugs and excipients The characteristic peaks obtained inFTIR studies were shown in Table 3
52 Precompression Flow Properties All the formulationsshowed good flow properties with angle of repose valuesbetween 25∘ and 35∘ and Hausnerrsquos ratio ranged between 110and 119 whereas Carrrsquos index values ranged between 11 and15 and all these values are shown in Tables 4 and 5
53 Evaluation of Prepared Tablets The tablets were visuallyobserved and free from defects such as lamination chippingand capping The prepared tablets passed all the in-processtestsTheweights of the tablets are within the rangeHardnessof the tablets was in the range of 29ndash73 kgcm2 thickness ofthe tablets is within 265ndash520mm and the friability rangesbetween 017 and 081 percent These results are shown inTables 6 and 7
54 In Vitro Drug Release Profile The drug release from F1composed of 10 crospovidone is 9814plusmn03 F2 composedof 15 crospovidone is 9960 plusmn 01 F3 composed of 20crospovidone is 9989 plusmn 04 and F4 composed of 25crospovidone is 9986 plusmn 02 The concentration of avicelPH 102 was kept at constant in all the formulations that is
15 The drug release at specific time intervals was plottedin a graph and from the drug release profile formulation F3composed of 20 crospovidone showed good drug releaseprofile (9997 plusmn 05) with least disintegration time HenceF3 was selected as the optimized formulation for immediaterelease layer for incorporation with metformin controlled
6 Journal of Pharmaceutics
Table 2 Optimized immediate release layer along with controlled release layer is formulated as bilayer tablets
Pure drugs Optimized multilayer tablet formulated with guar gum (cmminus1)Metformin (cmminus1) Pioglitazone (cmminus1)
NndashH (1∘)3400ndash3250 336823 mdash 337361
NndashH (2∘)3400ndash3250 314815 mdash 328295
C=N1471ndash1689 155980 mdash 156625
C=O1760ndash1665 mdash 174190 167427
CndashO1000ndash1300 mdash 124284 124413
CndashS600ndash700 mdash 65927 68282
C=N1471ndash1689 mdash 150953 153346
release layerThe drug release from crospovidonemay be dueto its capillary activity with the dissolution media [25]
The optimized F3 was formulated into bilayer tabletscontaining metformin controlled release layer along with it(Table 2) The drug release from F11 was better and a barrierlayer was incorporated to it in F13 to release the drug in acontrolled mannerThe drug release profile of the tablets wasshown in Figures 5 and 6
The drug release of pioglitazone HCl from F13 was foundto be 9994plusmn07at 2 hrs of dissolution in 01 NHClThedrugrelease of metformin HCl from F13 was found to be 9881 plusmn05 at 10 hrs of dissolution in 68 pH phosphate buffer
The release of drug not only depends upon the natureof matrix but also depends upon the drug polymer ratio
Due to the differences in the rheological properties of thepolymers they are taken in different concentrations Guargum at low concentrations (F9) can retard the drug releasevery well compared to HPMC K4M (F5) that can retard thedrug release at a slight higher concentration compared to guargum whereas the drug retarding capacity is similar at higherconcentrations for HPMC (F7 and F8) and guar gum (F11 andF12) As HPMC K4M is a semisynthetic polymer by directcompression high binder concentrations are required tomaintain the tablet integrity due to the poor compressibilityproblems of metformin HCl compared to less concentrationsof binder in wet granulation formulated with guar gum thatacts as a good binding agent andmaintains integrity of tabletsup to 8 hrs of dissolution in 68 pHphosphate bufferThe filler
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
where119876 is the amount of drug released at time 119905 and119870 is thediffusion rate constant Korsmeyer-Peppas model as log timeversus log cumulative percent drug release
Log(119872119905
119872infin
) = Log119870 + 119899 Log 119905 (6)
where 119872119905is the amount of drug released at time 119905 119872
infinis
the amount of drug release after infinite time 119870 is releaserate constant and 119899 is the diffusion exponent indicative of themechanism of drug release
49 Swelling Behavior of Tablets The extent of swelling wasmeasured in terms of weight gain by the tablet Theswelling behaviors of all controlled release formulations werestudied Initially one tablet from each formulationwas kept ina petridish containing 68 pH phosphate buffers The tabletwas removed lightly blotted with tissue paper to removeexcess buffer and reweighed for every 1 h the weights of thetablet were noted Percentage weight gain by the tablet wascalculated by the following formula
S I = (119882119905minus1198820)
1198820
times 100 (7)
where SI is the swelling index119882119905the weight of tablet at time
119905 (h) and1198820the weight of tablet at zero time
410 Stability Studies The tablets were packed in suitablepackaging and the well-sealed tablets were kept in the humid-ity chamber and their stability studies were conducted as per
ICH andWHO guidelines to assess the drug content sampleswhich were collected at the end of the studies and wereevaluated for drug release and its content The conditionsprescribed by ICH guidelines for accelerated studies are 40∘Cplusmn 2∘C75 RH plusmn 5 RH for 3 months
5 Results and Discussion
51 FTIR Studies In order to investigate the possible interac-tions among pioglitazone HCl metformin HCl and differentpolymersdiluents FTIR studies were carried out (Figures 12 and 3) As the identical peaks were observed in all the caseshence it was confirmed that no interaction exists betweendrugs and excipients The characteristic peaks obtained inFTIR studies were shown in Table 3
52 Precompression Flow Properties All the formulationsshowed good flow properties with angle of repose valuesbetween 25∘ and 35∘ and Hausnerrsquos ratio ranged between 110and 119 whereas Carrrsquos index values ranged between 11 and15 and all these values are shown in Tables 4 and 5
53 Evaluation of Prepared Tablets The tablets were visuallyobserved and free from defects such as lamination chippingand capping The prepared tablets passed all the in-processtestsTheweights of the tablets are within the rangeHardnessof the tablets was in the range of 29ndash73 kgcm2 thickness ofthe tablets is within 265ndash520mm and the friability rangesbetween 017 and 081 percent These results are shown inTables 6 and 7
54 In Vitro Drug Release Profile The drug release from F1composed of 10 crospovidone is 9814plusmn03 F2 composedof 15 crospovidone is 9960 plusmn 01 F3 composed of 20crospovidone is 9989 plusmn 04 and F4 composed of 25crospovidone is 9986 plusmn 02 The concentration of avicelPH 102 was kept at constant in all the formulations that is
15 The drug release at specific time intervals was plottedin a graph and from the drug release profile formulation F3composed of 20 crospovidone showed good drug releaseprofile (9997 plusmn 05) with least disintegration time HenceF3 was selected as the optimized formulation for immediaterelease layer for incorporation with metformin controlled
6 Journal of Pharmaceutics
Table 2 Optimized immediate release layer along with controlled release layer is formulated as bilayer tablets
Pure drugs Optimized multilayer tablet formulated with guar gum (cmminus1)Metformin (cmminus1) Pioglitazone (cmminus1)
NndashH (1∘)3400ndash3250 336823 mdash 337361
NndashH (2∘)3400ndash3250 314815 mdash 328295
C=N1471ndash1689 155980 mdash 156625
C=O1760ndash1665 mdash 174190 167427
CndashO1000ndash1300 mdash 124284 124413
CndashS600ndash700 mdash 65927 68282
C=N1471ndash1689 mdash 150953 153346
release layerThe drug release from crospovidonemay be dueto its capillary activity with the dissolution media [25]
The optimized F3 was formulated into bilayer tabletscontaining metformin controlled release layer along with it(Table 2) The drug release from F11 was better and a barrierlayer was incorporated to it in F13 to release the drug in acontrolled mannerThe drug release profile of the tablets wasshown in Figures 5 and 6
The drug release of pioglitazone HCl from F13 was foundto be 9994plusmn07at 2 hrs of dissolution in 01 NHClThedrugrelease of metformin HCl from F13 was found to be 9881 plusmn05 at 10 hrs of dissolution in 68 pH phosphate buffer
The release of drug not only depends upon the natureof matrix but also depends upon the drug polymer ratio
Due to the differences in the rheological properties of thepolymers they are taken in different concentrations Guargum at low concentrations (F9) can retard the drug releasevery well compared to HPMC K4M (F5) that can retard thedrug release at a slight higher concentration compared to guargum whereas the drug retarding capacity is similar at higherconcentrations for HPMC (F7 and F8) and guar gum (F11 andF12) As HPMC K4M is a semisynthetic polymer by directcompression high binder concentrations are required tomaintain the tablet integrity due to the poor compressibilityproblems of metformin HCl compared to less concentrationsof binder in wet granulation formulated with guar gum thatacts as a good binding agent andmaintains integrity of tabletsup to 8 hrs of dissolution in 68 pHphosphate bufferThe filler
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
54 In Vitro Drug Release Profile The drug release from F1composed of 10 crospovidone is 9814plusmn03 F2 composedof 15 crospovidone is 9960 plusmn 01 F3 composed of 20crospovidone is 9989 plusmn 04 and F4 composed of 25crospovidone is 9986 plusmn 02 The concentration of avicelPH 102 was kept at constant in all the formulations that is
15 The drug release at specific time intervals was plottedin a graph and from the drug release profile formulation F3composed of 20 crospovidone showed good drug releaseprofile (9997 plusmn 05) with least disintegration time HenceF3 was selected as the optimized formulation for immediaterelease layer for incorporation with metformin controlled
6 Journal of Pharmaceutics
Table 2 Optimized immediate release layer along with controlled release layer is formulated as bilayer tablets
Pure drugs Optimized multilayer tablet formulated with guar gum (cmminus1)Metformin (cmminus1) Pioglitazone (cmminus1)
NndashH (1∘)3400ndash3250 336823 mdash 337361
NndashH (2∘)3400ndash3250 314815 mdash 328295
C=N1471ndash1689 155980 mdash 156625
C=O1760ndash1665 mdash 174190 167427
CndashO1000ndash1300 mdash 124284 124413
CndashS600ndash700 mdash 65927 68282
C=N1471ndash1689 mdash 150953 153346
release layerThe drug release from crospovidonemay be dueto its capillary activity with the dissolution media [25]
The optimized F3 was formulated into bilayer tabletscontaining metformin controlled release layer along with it(Table 2) The drug release from F11 was better and a barrierlayer was incorporated to it in F13 to release the drug in acontrolled mannerThe drug release profile of the tablets wasshown in Figures 5 and 6
The drug release of pioglitazone HCl from F13 was foundto be 9994plusmn07at 2 hrs of dissolution in 01 NHClThedrugrelease of metformin HCl from F13 was found to be 9881 plusmn05 at 10 hrs of dissolution in 68 pH phosphate buffer
The release of drug not only depends upon the natureof matrix but also depends upon the drug polymer ratio
Due to the differences in the rheological properties of thepolymers they are taken in different concentrations Guargum at low concentrations (F9) can retard the drug releasevery well compared to HPMC K4M (F5) that can retard thedrug release at a slight higher concentration compared to guargum whereas the drug retarding capacity is similar at higherconcentrations for HPMC (F7 and F8) and guar gum (F11 andF12) As HPMC K4M is a semisynthetic polymer by directcompression high binder concentrations are required tomaintain the tablet integrity due to the poor compressibilityproblems of metformin HCl compared to less concentrationsof binder in wet granulation formulated with guar gum thatacts as a good binding agent andmaintains integrity of tabletsup to 8 hrs of dissolution in 68 pHphosphate bufferThe filler
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Pure drugs Optimized multilayer tablet formulated with guar gum (cmminus1)Metformin (cmminus1) Pioglitazone (cmminus1)
NndashH (1∘)3400ndash3250 336823 mdash 337361
NndashH (2∘)3400ndash3250 314815 mdash 328295
C=N1471ndash1689 155980 mdash 156625
C=O1760ndash1665 mdash 174190 167427
CndashO1000ndash1300 mdash 124284 124413
CndashS600ndash700 mdash 65927 68282
C=N1471ndash1689 mdash 150953 153346
release layerThe drug release from crospovidonemay be dueto its capillary activity with the dissolution media [25]
The optimized F3 was formulated into bilayer tabletscontaining metformin controlled release layer along with it(Table 2) The drug release from F11 was better and a barrierlayer was incorporated to it in F13 to release the drug in acontrolled mannerThe drug release profile of the tablets wasshown in Figures 5 and 6
The drug release of pioglitazone HCl from F13 was foundto be 9994plusmn07at 2 hrs of dissolution in 01 NHClThedrugrelease of metformin HCl from F13 was found to be 9881 plusmn05 at 10 hrs of dissolution in 68 pH phosphate buffer
The release of drug not only depends upon the natureof matrix but also depends upon the drug polymer ratio
Due to the differences in the rheological properties of thepolymers they are taken in different concentrations Guargum at low concentrations (F9) can retard the drug releasevery well compared to HPMC K4M (F5) that can retard thedrug release at a slight higher concentration compared to guargum whereas the drug retarding capacity is similar at higherconcentrations for HPMC (F7 and F8) and guar gum (F11 andF12) As HPMC K4M is a semisynthetic polymer by directcompression high binder concentrations are required tomaintain the tablet integrity due to the poor compressibilityproblems of metformin HCl compared to less concentrationsof binder in wet granulation formulated with guar gum thatacts as a good binding agent andmaintains integrity of tabletsup to 8 hrs of dissolution in 68 pHphosphate bufferThe filler
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 4 Dissolution graph of pioglitazone HCl immediate releasetablets (F1ndashF4)
dicalcium phosphate employed in the formulations (F5ndashF13)is insoluble and nonswelling and also slows the drug releasefrom the matrix [26 27]
HPMC forms low density hydrocolloid system and ahydrogel layer would be formed which acts as a gel boundaryfor the delivery system that retards the drug release Thetablets swelled radially and axially during the in vitro swellingstudies of HPMC and the dissolution of drug can be diffusioncontrolled by the formation of gel that forms a viscous layeracting as a protective barrier to both the influx of water andthe efflux of the drug in solution from the polymer matrixas water uptake increases with increase in concentrationof polymer whereas the penetration of water into tabletsformulatedwith guar gum (F9ndashF13) was rather slowThe guargum formulations showed an initial burst of drug releasefrom the matrix-embedded system diffusion coupled witherosion might be the mechanism of the drug release at lowconcentrations and the slow drug release was observed withincrease in the concentration of the polymer this might
be due to the formation of thick gel layer with increasingviscosity around the tablets and this gel further inhibits theentry of release medium into the matrix and control releaseof the drugThe reason behind this is due to the slow erosionof the gelled layer backbone mechanism for the drug releasefrom the tablets containing higher amounts of guar gum[28 29]
55 Release Kinetics The data suggested that the releasekinetics of the drug follow zero order drug release asthe values of regression coefficient obtained for zero orderdrug release profiles (1199032 = 08524 to 09932) are higheras compared to first-order drug release profiles (1199032 =00098ndash04866) The in vitro release profiles of drug fromall these formulations could be best expressed by Higuchirsquosequation as the plots showed the highest linearity (1199032 =09422 to 09966) This indicates that the drug release fromthe tablets was diffusion method To confirm the exactmechanism of drug release further the data was fitted inKorsmeyer-Peppas equation and the results showed that thedrug release follows diffusion mediated Fickian model fromthe 119899 value (119899 lt 045) (Table 8)
56 Swelling Studies The swelling index was found to beincreasedwith the polymer concentrationThe swelling indexwas found to be increased with polymer concentrationTherewas a good correlation between the swelling index and in vitrodrug release (Figure 7)
57 Stability Studies Accelerated stability studies were per-formed as per ICH guidelines for optimized formulationThe tablets showed no significant changes in the physicalappearance and colorThe tablets were evaluated at initial 1stmonth 2nd month and 3rd month for in vitro drug releaseThe in vitro release profile was the same as that of the initialone and the results were shown in Figure 8 indicating thatthe formulation was quite suitable
58 Comparison of Optimized Formulation with MarketedFormulation The in vitro drug release profile of optimizedformulation (F13) was compared with that of the marketed
Journal of Pharmaceutics 11
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F5F6
F7F8
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)Time (min)
F9F10
F11F12
(b)
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 5 Dissolution graph of optimized immediate release layer formulated with metformin controlled release layer containing (a) HPMCK4M (F5ndashF8) and (b) guar gum (F9ndashF12)
0
20
40
60
80
100
120
0 100 200 300 400 500 600 700Time (min)
F13
Dru
g re
leas
e (
)
(a)
0
20
40
60
80
100
120
0 200 400 600 800
Dru
g re
leas
e (
)
Time (min)
F13Innovator
(b)
Figure 6 Dissolution graph of optimized guar gum formulation (F13) (a) individually and (b) compared with innovator
formulation (PIO-FIXMF 15)The drug release of pioglita-zone frommarketed formulationwas found to be 5657plusmn03at 5min and 9997 plusmn 05 at 2 hrs whereas the drug releasefrom the optimized formulation was found to be 6057 plusmn08 at 5min and 9994 plusmn 07 at 2 hrs indicating that thedrug release from the optimized formulation of immediate
release layer of pioglitazone HCl showed better drug releasecompared to the innovator The drug release of metforminHCl from marketed formulation was found to be 975 plusmn08 and from F13 was 9881 plusmn 05 at 10 hrs Hence thedrug release from optimized formulation was better whencompared to marketed formulation
12 Journal of Pharmaceutics
86
88
90
92
94
96
98
100
0 50 100 150Swelling index
Dru
g re
leas
e (
)
(a)
86
88
90
92
94
96
98
100
0 50 100 150 200Swelling index
Dru
g re
leas
e (
)(b)
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 7 Graph of swelling index versus drug release of tablets formulated with (a) HPMC K4M and (b) guar gum
0
20
40
60
80
100
120
0 200 400 600 800Time (min)
Initial25 c1 month25 c2 month25 c3 month
40 c1 month40 c2 month40 c3 month
Dru
g re
leas
e (
)
Figure 8 Stability studies graph of optimized multilayered tablets
6 Conclusion
From the experimental results the following was concludedPioglitazone HCl and metformin HCl along with the
polymers and other excipients which are selected were com-patible and were confirmed from the FTIR studies A barrierlayer is incorporated in F13 to release the drug in a controlledmanner such that the drug is to be eliminated before theadministration of next dosage form and in night times the
metabolic processes are slow and the plasma drug concen-tration levels decline slowly due to the reduced eliminationrate The drug release rate from immediate layer was foundto be dependent on the concentration of superdisintegrantsemployed whereas the controlled release layer was foundto be dependent on the type of and polymer concentrationemployed in the tablet formulation This may be due to thevariations in the viscosity swelling index and type of releasemechanism involved The formulation F13 formulated with
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
crospovidone-20 avicel PH 102-15 in immediate releaselayer guar gum-225 and PVPK30-2 in controlled releaselayer along with the barrier layer showed the required drugrelease profile
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
[2] S Aggarwal N Syan and P Mathur ldquoBi-layer tablet techno-logymdashopening new ways in drug delivery systems an over-viewrdquo International Journal of Research in Pharmaceutical andBiomedical Sciences vol 4 pp 2229ndash3701 2013
[3] T R Dash and P Verma ldquoMatrix tablets an approach towardsoral extended release drug deliveryrdquo International Journal ofPharmaceutical Sciences Review vol 2 pp 12ndash24 2013
[4] P Bhateja P Kumar S P Gautam Hitesh S Dogra and NDogra ldquoFormulation development and evaluation of Sustainedrelease tablets of AceclofenacrdquoWorld Journal of PharmaceuticalResearch vol 1 pp 1394ndash1423 2012
[5] H Gopinath R Sowjanya V Chakravarthi A Shaheda K NSudha and R Kola ldquoFormulation and evaluation of ofloxacinfloating tablets by using hydroxyl propyl methyl cellulose aspolymerrdquo Journal of Chemical and Pharmaceutical Sciences vol5 pp 974ndash2115 2012
[6] S Pandey Niraj M M Gupta and B S Chauhan ldquoBilayertablets recent trends in oral drug delivery with present andfuture prospectsrdquo International Journal of Pharma and BioSciences vol 2 pp 2319ndash8141 2013
[7] D M Brahmankar and S B Jaiswal Biopharmaceutics ampPharmacokinetics a Treatise Vallabh Prakashan 2nd edition
[8] I Ahmed Syed and YM Rao ldquoAmodified release drug deliveryDevice multilayered matrix tabletsrdquo The American Journal ofPharmTech Research vol 2 pp 2249ndash3387 2012
[9] R Simo and C Hernandez ldquoTreatment of diabetes melli-tus general goals and clinical practice managementrdquo RevistaEspanola de Cardiologia vol 55 no 8 pp 845ndash860 2002
[10] S A Sadiq A Chatterjee and S A Vernon ldquoProgression ofdiabetic retinopathy and rubeotic glaucoma following cataractsurgeryrdquo Eye vol 9 no 6 pp 728ndash732 1995
[11] M Bouchoucha B Uzzan and R Cohen ldquoMetformin anddigestive disordersrdquo Diabetes and Metabolism vol 37 no 2 pp90ndash96 2011
[12] I Gabriely and H Shamoon ldquoHypoglycemia in diabetes com-mon often unrecognizedrdquo Cleveland Clinic Journal of Medicinevol 71 no 4 pp 335ndash342 2004
[13] M Stolar ldquoSafety and efficacy of PioglitazoneMetformin com-bination therapy in treatment of type 2 diabetes a rationale forearlier userdquo Clinical Medicine Therapeutics vol 1 pp 289ndash3032009
[14] Indian Pharmacopoeia Volume 2 page No 740 15 2007[15] httpwwwsatgumcomapplicationphp[16] S-J Yoon D-C Chu and L R Juneja ldquoChemical and physical
properties safety and application of partially hydrolized guargum as dietary fiberrdquo Journal of Clinical Biochemistry andNutrition vol 42 no 1 pp 1ndash7 2008
[18] J Cooper and C Gunn ldquoPowder flow and compactionrdquo inTutorial Pharmacy S J Carter Ed pp 211ndash233 CBS Publishersand Distributors 1986
[19] J R Patel B A Patel D G Patel D S Patel and V B PatelldquoFormulation and evaluation of oral controlled drug deliverysystem for a model anti diabetic drugmetforminrdquo InternationalJournal of Current Pharmaceutical Research vol 3 pp 37ndash392011
[20] M Rangapriya VManigandan R Natarajan andKMohanku-mar ldquoFormulation and evaluation of floating tablets of Piogli-tazone hydrochloriderdquo International Journal of Pharmaceuticaland Chemical Sciences vol 1 pp 1048ndash1054 2012
[21] D Rohini S Alexandar and M J N Chandrasekar ldquoPrepara-tion and in vitro evaluation of sustained release tablet formula-tions of metformin HCLrdquo Asian Journal of Pharmaceutical andClinical Research vol 5 no 1 pp 45ndash48 2012
[22] K Venkateswarlu and A Shanthi ldquoFormulation and evaluationof sustained release glipizidematrixrdquo IOSR Journal of Pharmacyand Biological Sciences (IOSRJPBS) vol 2 no 5 pp 17ndash23 2012
[23] P Shirse ldquoFormulation and evaluation of bilayered tablets ofHP-120573-cyclodextrin complexed Glimepiride with Metforminhydrochloride for immediate and sustain releaserdquo InternationalJournal of Pharmacy and Biological Sciences vol 3 pp 148ndash1602012
14 Journal of Pharmaceutics
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
[24] A Chime Salome C Onunkwo Godswill and I OnyishiIkechukwu ldquoKinetics and mechanisms of drug release fromswellable and non swellablematrices a reviewrdquoResearch Journalof Pharmaceutical Biological and Chemical Sciences vol 4 pp97ndash103 2013
[25] Md Mofizur Rahman S Roy S Hasan et al ldquoEffect of modeof addition of disintegrants on dissolution of model drug fromwet granulation tabletsrdquo International Journal of PharmaceuticalSciences Review and Research vol 2 pp 84ndash92 2011
[26] G Abhilash B Baby B P Rao S Raja Rajan K Rameshand G R Kumar ldquoComparative study on the efficiency ofvarious binder combinations for metformin tabletsrdquo Journal ofPharmacy and Pharmaceutical Science Research andReview vol2 pp 20ndash24 2013
[27] P M Husen P A Kumar S V Kulkarni and B SomeshwaraRao ldquoFormulation and in vitro evaluation of controlled releasematrix tablets of metoclopramide hydrochloride influence offillers on hydrophilic natural gumsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 pp 181ndash187 2012
[28] S Verma N Narang G Upmanyu and J Sharma ldquoPreparationand in vitro evaluation of gastroretentive tablets of anti retrovi-ral drug using different polymersrdquo Current Pharma Researchvol 3 pp 245ndash249 2011
[29] A Singh P K Sharma and R Malviya ldquoRelease behavior ofdrugs from various natural gums and polymersrdquo Polimery wMedycynie vol 41 no 4 pp 73ndash80 2011
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
