Prof. Chakka Gopinath

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Future Journal of Pharmaceutical Sciences xxx (2017) 1e8

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Design expert supported mathematical optimization of repaglinidegastroretentive floating tablets: In vitro and in vivo evaluation

N. Raghavendra Naveen a, *, Chakka Gopinath a, D. Subba Rao b

a Annamacharya College of Pharmacy, New Boyanapalli, Rajampet 516126, Y.S.R. Cuddapah Dist, Andhra Pradesh, Indiab Dept. of Chemical Engineering, JNTUA, Anantapur 515002, Andhra Pradesh, India

a r t i c l e i n f o

Article history:Received 10 September 2016Received in revised form31 March 2017Accepted 20 May 2017Available online xxx

1. Introduction

The majority of the traditional oral drug delivery systems havefew impediments which are mainly associated to gastric residenceof dosage form [1]. Control drug delivery systems aimed not just toextend the release of drug but also to lengthen its retention in itsabsorption site [2]. This can be achieved by designing several gastroretentive dosage forms like mucoadhesion [3], expandable systems[4], low density and high density systems etc [5,6].

Repaglinide is an oral anti-hyperglycemic agent belonging tomeglitinide class, which requires frequent dosing before meals dueto short half-life (1hr) and there by imposing side effects such asskeletal muscles pain, headache and GIT effects [7]. Floating drugdelivery system increases the effectiveness of dosage forms byreleasing the drug in control manner and thus maintaining itsconcentration for longer duration [8]. Due to short lasting action,fast clearance, enzymatic stability and absorption window in upperGIT (stomach), makes repaglinide a suitable target for developinggastroretentive dosage form.

The utilization of plant based gums andmucilage turns out to beimperative as pharmaceutical excipient, especially in designing ofcontrol drug delivery system [9]. Physico-chemical properties suchkind of material can be altered to meet the necessities of drugdelivery systems [10].

Abelmoschus esculentus (L.) Moench., known as ‘Okra’, belongingto mallow family [11] which is cultivated widely throughout the

* Corresponding author. Tel.: þ917799559585.E-mail address: [email protected] (N.R. Naveen).Peer review under responsibility of Future University.

http://dx.doi.org/10.1016/j.fjps.2017.05.0032314-7245/© 2017 Future University. Production and hosting by Elsevier B.V. This is anlicenses/by-nc-nd/4.0/).

Please cite this article in press as: N.R. Naveen, et al., Design expert supportablets: In vitro and in vivo evaluation, Future Journal of Pharmaceutical

tropical and subtropical regions of the world [12]. This study aimedto demonstrate the utilization of OG in development of stomachspecific drug delivery system. Floating tablets of repaglinide wereformulated using 3-full level factorial design by considering con-centrations of OG, HPMC K15M and xanthan gum as independentvariables.

2. Materials and methods

Repaglinide was kindly gifted by K.P.Labs, Hyderabad, India.HPMC K 15M and xanthan gumwere purchased from Loba ChemiePvt Ltd; Mumbai (Maharashtra, India), India. Fresh immature fruitsof Abelmoschus esculentus were purchased from local market ofRajampet (Andhra Pradesh, India) and gumwas extracted. All othersolvents and chemicals are of analytical grade.

2.1. Method of isolation and extraction of Okra gum (OG) [12]

The extraction of OG was changed in view of the methodologyby Sunitha Reddy et al. [12]. Unripe fruits of Abelmoschus esculentswere acquired from local market of Rajampet, Andhra Pradesh,India. The fruits were washed thoroughly and sliced daintily. Theseeds were expelled as they don't contain any mucilage. The slicedmass was soaked in double distilled water for about 24 h to extortout the mucilage. Ensuing to dousing, a white muslin cloth wasused to extract the viscous gum by squeezing the swollen slices andthe gum was precipitated by adding twice the volume of alcohol(90%). Then, precipitated gum was washed with diethyl ether andpetroleum ether to remove any fat soluble impurities then washedwith alcohol. This was repeated for about 2e3 times. Final precip-itation was carried out with acetone. The precipitated gum wasdried in hot air oven at 40 �C and milled using steel grinder. Finalproduct was screened under sieve #60 and stored in desiccator.

2.2. Physico chemical characterization of OG

Extracted gum was assessed for different physico chemicalproperties like solubility, viscosity, swelling index, total ash, pH,moisture content, flow properties and test for arsenic.

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2.3. Phytochemical screening of OG

Chemical tests that were conducted are: Ruthenium red test,Molisch test, test for reducing sugars, Ninhydrin test and so forth toaffirm the nature of OG.

2.4. Toxicity studies [13,14]

Toxicity studies were performed as described by Knudsen andCurtis. The animals utilized were endorsed by institutional ethicalcommittee (IEC ANCP). The male albino rats (Wistar strain)weighing 160e200 g were alienated into different groupscomprising of six animals each (one control group and five testgroups). The control group received normal saline 20 ml/kg i.p. Theother groups received 500,1000, 2000, 3000 and 4000mg/kg of OGsuspension orally. The animals were watched constantly forbehavioural changes for the initial 4 h and then observed formortality if any for 48 h.

2.5. Drug excipient compatibility studies [15]

Pure drug along with excipients were subjected to FTIR spec-troscopic studies (Shimadzu digital IR Spectrometer, Japan) inrange of 400e4000 cm�1 to analyze for major interactions.

2.6. Formulation of gastro retentive floating tablets

Repaglinide floating tablets were prepared by wet granulationtechnique by utilizing 8%PVP K30 in 80% ethanol solution asgranulating medium [16]. Subsequent to being grinded and sifted,required amounts of repaglinide, OG, HPMC K 15M, Xanthan gumand all other excipients were blended thoroughly, consequentlypassed through sieve #80. Required proportions of granulatingmedium was added to the powder blend and screened under #30mesh to obtain wet granules. These granules were dried at55e60 �C for about 120 min and dampness was maintained be-tween 3% and 5%. The dried granules which were retained on sieve#30, lubricated by adding prescribed amount of magnesium stea-rate and talc. Finally, the tablets were compressed by using concavefaced 8-mm punches in Rotary tablet punching machine (Cha-munda pilot press, Ahmedabad, Gujarat, India.) and compressionforce was adjusted to control the hardness within 5e8 kg/cm2.

2.7. Optimization of concentrations of OG, HPMC K15 M andXanthan gum by 3-full level factorial design1 [17,18]

The present study consisted three full level factorial design (33:total 27runs) for optimization. Statistical experimental design wasperformed by making use of DESIGN EXPERT (Stat-Ease Inc., Min-neapolis, USA). Response surface graphs were used to evaluate thefactor interaction between the variables. Selected independentvariables studied were the concentration of OG (X1); HPMC K15M(X2); and Xanthan gum (X3) and the three factorial levels for these

Table 133 full factorial design of Repaglinide floating tablets.a

Coded values Actual Values

X1 (%) X2 (%) X3 (%)

High (þ1) 35 15 15Medium (0) 22.5 7.5 7.5Low (�1) 10 0 0

a Each formulation contains 2 mg of repaglinide, Sodium bicarbonate (10%), Citricacid (5%), Ethyl cellulose (7%), Magnesium stearate (2%), Talc (1%) and Lactose(quantity sufficient to produce 200 mg tablet).


variables are coded as�1, 0 andþ1 for low,medium and high levelsrespectively (Table 1). Floating lag time (Y1) and swelling index (Y2)were selected as dependent variables.

A total of 27 experimental runs were required for analyzing theinteraction of each level on formulation characters and to optimize.Multiple factorial regression analysis (quadratic model) was carriedout to measure the response (Yi) in each trail.

Yi ¼ b0 þ b1X1 þ b2X2 þ b3X3 þ b4X1X2 þ b5X1X3 þ b6X2X3

þ b7X21 þ b8X

22 þ b9X

23

Where Yi - Dependent variable;

b0 - Arithmetic mean response of all trials;bi - Estimated coefficient for factor Xi,X1, X2 and X3 (Main effects) - Average value of changing factorone at a timeX1X2 and X1X3 and X2X3 - Represent the interaction terms andX12, X2

2 and X32 - The polynomial terms

2.8. Evaluation of Repaglinide floating tablets [5]

2.8.1. In vitro buoyancy studiesPrepared tablet matrices were placed in 900 ml of stimulated

gastric fluid (SGF-prepared by dissolving 2.0 g of NaCl, 3.2 g ofpurified pepsin in 7.0 mL of Hcl and water up to 1000 mL. This testsolution has a pH of about 1.2) and the time required for the tabletsto rise to the surface of SGF was noted as floating lag time.

2.8.2. Swelling indexPre weighed (M0) tablet formulations were kept in 100 ml of

SGF. At the end of 6 h the tablet waswithdrawn and reweighed (Mt).The degree of swelling was calculated in terms of percentageweight gain.

SI ¼ fðMt�M0Þ=M0g � 100

2.9. Preparation of check point batch for validation of experimentaldesign [19]

By using optimized concentrations of OG, HPMC K15M andxanthan gum, formulation ORF-1 was prepared and evaluated fordifferent post-compression parameters (hardness, friability,swelling index and In vitro floatability). Validation of experimentaldesign was done by calculating relative error using the followingEq. (1).

Relative error ð%Þ ¼ Predicted values� Practical valuesPredicted value

� 100

(1)

2.9.1. In vitro dissolution studiesDrug release from ORF-1 was performed as indicated by ChP

paddle strategy [20]. Studies were done at 50 rpm in 900 ml of SGFat 37± 0.5 �C. 10 ml of samples were withdrawn at various timeintervals and filtered through 0.45mm millipore filter. The filtratewas diluted accordingly and analysed for drug content by UVspectrophotometer (UV-1800, Shimadzu, Japan) at 223 nm. Thedepiction of the in vitro dissolution profiles was investigated byutilizing the subsequent kinetic models (Table 2) [21].

tedmathematical optimization of repaglinide gastroretentive floatingSciences (2017), http://dx.doi.org/10.1016/j.fjps.2017.05.003

Table 2Kinetic models.

Model Equation Abbreviations

Zero order Q ¼ Q0 e K0t Q is the amount of drug released at time tQ0 is the amount of drug remaining in theformulationK0 is zero-order release rate constantK1 is first-order rate constantK2 is Higuchi rate constantQ/Q0 is fraction of drug release at time, tK is a constant andn is diffusion exponent indicating themechanism of drug release.

First order In Q ¼ In Q0 e K1 tHiguchi model Q ¼ K2t1/2

Peppas model Q/Q0 ¼ K tn

Table 3Physico chemical characterization of okra mucilage.

Physico chemical parameter Result

Description Powder: Light brown coloured granularpowder

Solubility In water- slightly soluble (forms thick gel)In ethanol, acetone, ether and chloroform -practically insoluble

Viscosityi) 0.5% conc 62.32 cPii) 1% conc 228.78 cP

Swelling ratio 28Total ash 5.65%i) Acid insoluble 0.25%

pH (1% w/v solution) 5.6Moisture content 15.09%Flow propertiesi) Bulk density (g/cc) 0.62ii) Tapped density (g/cc) 0.72iii) Carr's index 15.05%iv) Angle of repose 32�

v) Hausner's ratio 1.16Test for foreign matter <0.1%Test for arsenic <0.1 ppm

Table 4Phytochemical screening of mucilage.

Tests Observations

Molisch's test (Test for carbohydrate) PositiveRuthenium test (Test for mucilage) PositiveTest for saponins PositiveFerric chloride test (Test for tannins) NegativeNinhydrin test (Test for proteins) NegativeWagner's test (Test for alkaloids) NegativeKeller-killaini test (Test for glycosides) NegativeShinoda test (Test for flavonoids) NegativeFehling's test (Test for reducing sugar) NegativeSilver nitrate test (Test for chlorides) NegativeBarium chloride test (Test for sulphates) Negative

N.R. Naveen et al. / Future Journal of Pharmaceutical Sciences xxx (2017) 1e8 3

2.10. In vivo evaluation studies

All the in vivo studies were approved by Institutional Ethicalcommittee of Annamacharya College of Pharmacy, Rajmapet,Andhra Pradesh, India (IEC-ANCP/2016).

2.10.1. Buoyancy studies in rabbits using X-ray imaging [22]Barium sulphate (15%) was incorporated in the formulation by

replacing repaglinide and adjusting the concentration of lactose tomake the tablet visible under X-ray. This was done on male healthyalbino rabbits weighing between 2.5 and 3 kg and animal wasfasted for about 12 h. Initially X-ray of the abdomen was taken toconfirm nonexistence of any radio opaque materials. Check pointbatch ORF-1 was administered by using oral cannula along with15 ml of water. At every intervals (upto 6 h) 10 ml of water wasadministered throughout the study. X-ray photographs of abdomenwere taken by placing animal in upright posture and this was doneunder the guidance of radiologist.

2.10.2. Bioavailability studiesIn the bioavailability studies, ORF-1 was evaluated for Cmax, tmax,

AUCt, AUMCt, MRT and t1/2 etc by conducting the studies in healthyalbino rabbits (weighing 2.2e2.5 kg). The datawas calculated by PKSolver. PK Solver is a freely available menu-driven add-in programfor Microsoft Excel written in Visual Basic for Applications (VBA).Total of twelve rabbits were divided into two groups of six each.Among the two groups, one was provided with marketed productRepide (2 mg of repaglinide, Wallace pharmaceuticals, India) andsecond group was fed with test formulation ORF-1. 2 ml of Bloodsamples were collected at different intervals up to 24 h frommarginal vein and centrifuged by adding 0.4 ml of sodium citrate.The sample was analysed by using HPLC method as portrayed byJain et al. [23].

3. Results and discussion

3.1. Physico chemical characterization of okra mucilage

Table 3 demonstrates the physico chemical characterization ofextracted OG. OGwas appeared to be sparingly soluble inwater andinsoluble in acetone, ethanol and chloroform. Such characteristicnature along with swelling ability (swelling ratio-28%) will bebeneficial especially in designing of swellable dosage forms tocontrol the drug release. The pH of OG (1% w/v) solution was foundto be 5.6. Moisture content was observed as 15.09%. This boundmoisture, during compression forms a film on particles and alsolubricate the powder flow. OG shown elevated viscosity at a higherconcentration (Viscosity of 1% and 0.5% conc was found to be228.78 cP and 62.32 cP respectively). OG posses good flow propertyas evident from Angle of repose, Carr's index and Hausner's ratio.


The total ash and acid insoluble ash was found to be 5.65% and0.25% w/w respectively which confirms the low adulteration.Foreign matter and arsenic was observed as less than 0.1% and1 ppm.

3.2. Phytochemical screening of mucilage

Phytochemical tests carried out on OG confirms the presence ofcarbohydrates, mucilage and saponins. The results of phytochem-ical screening of OG are summarized in Table 4.

3.3. Drug excipient compatibility study

FTIR analyses of Repaglinide, OG, repaglinide-OG mixture andrepaglinide with all polymers are shown in Fig. 1. FTIR spectrum ofrepaglinide {Fig. 1-A (i)} showed characteristic band around3307 cm�1 due to stretching of NeH, band at 2966 cm�1 due toeCH stretching, C]O stretching at 1685 cm�1, amide stretching at1637 cm�1, 1043 cm�1 indicating CeOeC stretch, 1215 cm�1 indi-cating CeN stretching. FTIR spectrum of repaglinide with OG{Fig. 1-A (ii)} and repaglinide with all polymers (Fig. 1-C) confirmsall characteristic peaks of repaglinde without any significant al-terations. This confirms the compatibility of drug with excipients[24].


Fig. 1. FTIR spectra of A) Overlay of pure repaglinide (i) and repaglinide with OG (ii). B) OG C) FTIR spectrum of repaglinide and mixture of all polymers.

Table 5The Quantitative Factor Effects and Associated P Value for two Responses.

Factor Y1 Y2

Factor effect P value Factor effect P value

X1 25.83 0.0008 þ89.11 <0.0001X2 �28.28 0.0003 þ23.06 <0.0001X3 þ1.28 0.8500 þ14.83 <0.0001X1X2 �15.58 0.0698 þ1.17 0.5887X1X3 �11.00 0.1923 �1.58 0.4643X2X3 �2.75 0.7398 þ1.25 0.5625X12 þ26.24 0.0214 �0.31 0.9124

X22 þ16.58 0.1318 �3.47 0.2204

X32 þ10.58 0.3289 þ4.53 0.1144


3.4. Toxicity evaluations

Acute toxicity studies reveals the safety of OG even at a dose of4000 mg/kg body weight, no mortality and toxic syndromes wereobserved.

3.5. Estimation of quantitative effects of factors

From the 3 full level factorial design, a total of 27 experimentalruns were projected by Design expert software for three factors OG(X1), HPMC K 15M (X2) and Xanthan gum (X3), which were variedat three different levels (coded as �1, 0 and þ1). Floating lag time(Y1) and Swelling index (Y2) were investigated as response pa-rameters for this study.

ANOVA was performed for estimation of quantitative effects ofthe fact factors. A quadratic model was obtained after analysingdata. Values of p < 0.05 indicate model terms are significant. Apositive value indicates a synergistic effect that favours optimiza-tion, while a negative sign represents an antagonistic effect or in-verse effect of the factor on the selected response [24]. The residual


equations for two dependent variables in terms of coded factors arepresented below

FOR DEPENDENT VARIABLE 1 (FLOATING LAG TIME):

Final Equation in Terms of Coded Factors:

Floating Lag Time ¼ þ46:94þ 25:83 X1 � 28:28 X2 þ 1:28 X3

� 15:58 X1X2 � 11:00 X1X3 � 2:75 X2X3

þ 26:24 X21 þ 16:58 X2

2 þ 10:58 X23

Response Y1 (floating lag time) was significantly influenced by i)synergistic effect of quadratic term of OG concentration (X1

2) andOG concentration (X1) ii) inverse effect of HPMCK15 M (X2) with arespective probability value of 0.0214, 0.0008, and 0.0003 (Table 5).

FOR DEPENDENT VARIABLE 2 (SWELLING INDEX):

Final Equation in Terms of Coded Factors:

Swelling Index ¼ þ216:05þ 89:11X1 þ 23:06X2 þ 14:83X3

þ 1:17X1X2 � 1:58X1X3 þ 1:25X2X3

� 0:31X21 � 3:47X2

2 þ 4:53X23

The significant factors were identified as OG concentration (X1),HPMC K15M concentration (X2) and xanthan gum (X3) with a pvalue of <0.0001 and all factors having synergistic influence onsecond response Y2.

The effect of independent variables on responses investigated(floating lag time and swelling index) were further elucidated andanalysed by response surface methodology (RSM) [25]. In RSM,main effects and interaction effects can learn by utilizing three


Fig. 2. Contour plots and three dimensional response surface plots for floating lag time (Y1).


dimensional response surface graphs (RSG). Contour plots gives avisual representation of measured responses. The RSG (Fig. 2-B)and parallel contour plots (Fig. 2-A) relating floating lag timeindicate the decrease of response with i) decreasing both xanthangum and OG, ii) increasing xanthan gum and HPMC K15M and iii)decreasing OG and HPMC K 15M. Fig. 3B and A indicates theincrement of response (Swelling index) with i) increasing bothxanthan gum and OG, ii) increasing xanthan gum and HPMC K15M.On other hand, HPMC K 15M and xanthan gum doesn't shown anyremarkable influence on swelling index. On basis of desirabilitycriterion, the optimal values for responses were obtained by nu-merical analyses. Optimum concentrations of OG, HPMC K15M andxanthan gumwere found to be 32.93%, 15% and 13.91%. Solution for


33factorial design was shown in Table 6.

3.6. Evaluation of check point batch (ORF-1)

By using optimized concentrations, formulation (ORF-1) wasprepared and evaluated for hardness, friability swelling index andin vitro floatability. Hardness and friability were found to be 7 kg/cm2 and 0.06% ± 0.05 respectively. Floating duration for ORF-1 wasfound to be > 18 h. Swelling index at different time intervals wasshown in Fig. 4. Maximum swelling index for ORF-1 was found tobe 224.63% at the end of 6 h.

Validation of the experimental design was done quantitativelyby comparing practical and predicted values. The relative error (%)


Fig. 3. Contour plots and three dimensional response surface plots for swelling index (Y2).

Table 6Solution for 33 factorial design 99% population.

Response Prediction 95% CI low 95% CI high 95% PI low 95% PI high 95% TI low 95% TI high

Y1 60.642 25.781 95.503 �7.6683 128.952 �65.653 186.937Y2 326.484 320.467 332.502 310.538 342.431 297.605 355.364


for both the responses were calculated and the values found to bewithin acceptable range of ±5%. The Anticipated results wererelatively comparable to the experimental results which illustrates


the preciseness of the design.Dissolution studies of ORF-1 shown that 96.23% of repaglinide

was released in a controlled manner by the end of 24 h. As OG is


Fig. 4. Swelling index for ORF-1 at different interval of time.

Fig. 6. a) X-ray radiograms before administering ORF-1 b), c), d), e) X-ray radiogramsshowing presence of floating tablet (ORF-1) in gastric region of rabbit at 1 h, 2 h, 4 hand 6 h respectively.


insoluble in acidic pH it swells enormously which in turn helps tocontrol the drug release. Mixing of OG with HPMC K 15M andxanthan gum further causes for increase in viscosity of swollenmatrix, which in turn decreases the water diffusion [26]. Thein vitro drug release data was evaluated kinetically using variousmathematical models such as zero order, first order, Higuchi andKorsmeyer- Peppas model (Fig. 5). The drug release profile of ORF-1follows diffusion as well as erosion mechanism (n value for peppasmodel-0.6979) and shown maximum regression value (r2) of0.9754 for Higuchi model.

3.7. In vivo evaluation studies of ORF-1

3.7.1. In vivo buoyancy studiesThe floating behaviour was observed in rabbit stomach using X-

ray technique. X-ray photograph was taken prior to administrationof formulation (Fig. 6-A). Next X-ray photographwas taken after 1 hof administration (Fig. 6-B). Obtained radiographic images at theend of 2 h revealed that the tablet had altered its position but

Fig. 5. Release kine


remain buoyant in the stomach. Swelling of the tablet visualisedwith translucent swelling layer around it at the end of 6 h. Thisstudy provides the evidence that tablets floated on the gastric fluidbut did not adhere to gastric mucosa (see Table 6 and 7).

tics of ORF-1.


Table 7Comparison between practical and predicted values.

Parameter Predicted values Practical Values (ORF-1)

1. Floating lag time (secs) 60.66 622. Swelling Index (%) 226.53 224.63

Table 8Phamracokinetic parameters for test (ORF-1) and marketed (Repide) repaglinideformulations.

Pharmacokinetic parameters ORF-1 Marketed product

Cmax (mg/ml) 0.194 0.207tmax (h) 4 1AUCt (mg/ml*h) 2.097 0.403AUMCt (mg/ml*h) 17.736 0.631MRTt (h) 8.458 1.564t1/2 (h) 3.773 0.780CL (l/h) 0.467 2.362Vd (l) 2.543 2.660Ke (1/h) 0.184 0.888Ka (1/h) 0.213 1.135


3.7.2. Pharmacokinetic studiesThe pharmacokinetic parameters of repaglinde following oral

administration of marketed and ORF-1 in rabbits were shown inTable 8. The comparison of pharmacokinetic data of ORF-1 withmarketed product clearly indicates that peak plasma concentrationof repaglinide from marketed product was reached very quicklyand more rapidly eliminated in contrast to ORF-1. AUC for ORF-1was increased almost five times, which indicates better absorp-tion in improving the relative bioavailability. Ka and Ke for ORF-1was reduced to 1/5th and 1/4th but Elimination half-life (t1/2)was increased by about 5.3 times, which is desirable for controlleddrug delivery systems. Vd is almost similar for both ORF-1 andmarketed product.

4. Conclusion

OG was proved as non toxic, compatible and has the potentialapplication in designing of floating drug delivery system. Repagli-nide gastroretentive tablets were developed by using 3-full levelfactorial design using naturally occurring plant based polymersalong with combination of synthetic polymer. The effect of inter-action of three dependent variables on two responses were studiedand optimized. This study concluded that all three variables hadsignificant effect on selected responses.

Check point batch ORF-1 showed desirable floatability, swellingindex and in vivo release characteristics. In vivo release studiesconfirms that there is decline in the Ka and Ke by formulating intofloating drug delivery system, which is desirable for control releaseand ability to alter pharmacokinetic behaviour in the desirablemode by formulating into floating system. The use of plant-basedpolymeric can be a good replacement for synthetic polymers inthe development of controlled release dosage forms.

Conflict of interest

None.

References

[1] Megha Sharma, Seema Kohli, Agnimitra Dinda, In-vitro and in-vivo evaluationof repaglinide loaded floating microspheres prepared from different viscositygrades of HPMC polymer, Saudi Pharm. J. 23 (2005) 675e682, http://dx.doi.org/10.1016/j.jsps.2015.02.013.

[2] Sharad S. Darandale, Pradeep R. Vavia, Design of a gastro retentive mucoad-hesive dosage form of furosemide for controlled release, Acta Pharm. 2 (2012)


509e517, http://dx.doi.org/10.1016/j.apsb.2012.05.004.[3] Lifang Yina, Chao Qin, Kaisheng Chen, et al., Gastro-floating tablets of ceph-

alexin: preparation and in vitro/in vivo evaluation, Int. J. Pharm. 452 (2013)241e248, http://dx.doi.org/10.1016/j.ijpharm.2013.05.011.

[4] Hemlata Patil, Roshan V. Tiwari, Michael A. Repka, Recent advancements inmucoadhesive floating drug delivery systems: a mini-review, J. Drug Deliv.Sci. Technol. 31 (2016) 65e71, http://dx.doi.org/10.1016/j.jddst.2015.12.002.

[5] Sujata Acharya, Sradhanjali Patra, Nihar Ranjan Pani, Optimization of HPMCand carbopol concentrations in non-effervescent floating tablet throughfactorial design, Carbohydr. Polym. 102 (2014) 360e368, http://dx.doi.org/10.1016/j.carbpol.2013.11.060.

[6] S. Peter Dio, Tivadar Pernecker, Sandor Nagy, Szilard Pa, Attila Devay, Influenceof different types of low substituted hydroxy propyl cellulose on tableting,disintegration, and floating behaviour of floating drug delivery systems, SaudiPharm. J. 23 (2015) 658e666, http://dx.doi.org/10.1016/j.jsps.2014.09.001.

[7] Rajani Shakya, Panna Thapa, Ranendra N. Saha, In vitro and in vivo evaluationof gastroretentive floating drug delivery system of ofloxacin, Asian J. Pharm. 8(2013) 191e198, http://dx.doi.org/10.1016/j.ajps.2013.07.025.

[8] Priyanka Sinha, U. Ubaidulla, Amit Kumar Nayak, Okra (Hibiscus esculentus)gum-alginate blend mucoadhesive beads for controlled glibenclamide release,Int. J. Biol. Macromol. 72 (2015) 1069e1075, http://dx.doi.org/10.1016/j.ijbiomac.2014.10.002.

[9] Gurpreet Kaur, Deepinder Singh, Vivekjot Brar, Bioadhesive okra polymer basedbuccal patches as platform for controlled drug delivery, Int. J. Biol.Macromol. 70(2014) 408e419, http://dx.doi.org/10.1016/j.ijbiomac.2014.07.015.

[10] V. Kontogiorgos, I. Margelou, N. Georgiadis, C. Ritzoulis, Rheological charac-terization of okra pectins, Food Hydrocoll. 29 (2012) 356e362, http://dx.doi.org/10.1016/j.foodhyd.2012.04.003.

[11] Muhammad U. Ghori, Katerina Alba, Alan M. Smith, Barbara R. Conway,VassilisKontogiorgos, Okra extracts inpharmaceutical and foodapplications, FoodHydrocoll. 42 (2014) 342e347, http://dx.doi.org/10.1016/j.foodhyd.2014.04.024.

[12] Priyanka Sinha, U. Ubaidulla, M. Saquib Hasnain, Amit Kumar Nayak,Bobba Rama, Alginate-okra gum blend beads of diclofenac sodium fromaqueous template using ZnSO4 as a cross-linker, Int. J. Biol. Macromol. 79(2015) 555e563, http://dx.doi.org/10.1016/j.ijbiomac.2015.04.067.

[13] S.I. Alqasoumi, Okra’ Hibiscus esculentus L.: a study of its hepatoprotectiveactivity, Saudi Pharm. J. 20 (2012) 135e141, http://dx.doi.org/10.1016/j.jsps.2011.10.002.

[14] P. Suresh Babu, V. Krishna, K.R. Maruthi, K. Shankarmurthy, Ramesh K. Babu,Evaluation of acute toxicity and hepatoprotective activity of the methanolicextract of Dichrostachys cinerea (Wight and Arn.) leaves, Pharmacogn. Res. 3(1) (2011) 40e43, http://dx.doi.org/10.4103/0974-8490.79114.

[15] Govikari Koteshwar Rao, Praveen Kumar Mandapalli,Rajendraprasad Manthri, Veerareddy Prabhakar Reddy, Development andin vivo evaluation of gastro retentive delivery systems for cefuroxime axetil,Saudi Pharm. J. 21 (2013) 53e59, http://dx.doi.org/10.1016/j.jsps.2012.01.003.

[16] Longmei Wang, Ruihua Feng, Jinhua Gao, Yanwei Xi, Guihua Huang, Genericsustained release tablets of trimetazidine hydrochloride: preparation andin vitroein vivo correlation studies, Asian J. Pharm. 11 (2016) 417e426,http://dx.doi.org/10.1016/j.ajps.2015.10.001.

[17] A.K. Nayak, D. Pal, K. Santra, Development of calcium pectinate-tamarindseedpolysaccharide mucoadhesive beads containing metformin HCl, Carbohydr.Polym. 101 (2014) 220e230, http://dx.doi.org/10.1016/j.carbpol.2013.09.024.

[18] J. Malakar, A.K. Nayak, Formulation and statistical optimization of multiple-unit ibuprofen-loaded buoyant system using 23-factorial design, Chem. Eng.Res. Des. 9 (2012) 1834e1846, http://dx.doi.org/10.1016/j.cherd.2012.02.010.

[19] Meka Venkata Srikanthn, Nali Sreenivasa Rao, Songa Ambedkar Sunil, BattuJanaki Ram, Venkata Ramana Murthy Kolapalli, Statistical design and evalu-ation of a propranolol HCl gastric floating tablet, Acta Pharm. 2 (2012) 60e69,http://dx.doi.org/10.1016/j.apsb.2011.12.008.

[20] Liang Li, Linlin Wang, Yang Shao, et al., Elucidation of release characteristics ofhighly soluble drug trimetazidine hydrochloride from chitosan-carrageenanmatrix tablets, J. Pharm. Sci. 102 (2013) 2644e2654, http://dx.doi.org/10.1002/jps.23632.

[21] Simon Herrlich, Sven Spieth, Stephan Messner, Roland Zengerle, Osmoticmicropumps for drug delivery, Adv. Drug Deliv. Rev. 64 (2012) 1617e1627,http://dx.doi.org/10.1016/j.addr.2012.02.003.

[22] S. Saisivam, M. Rahamath Ulla, F. Shakeel, Development of floating matrixtablets of losartan potassium: in vitro and in vivo evaluation, J. Drug Del. Sci.Tech. 23 (2013) 611e617, http://dx.doi.org/10.1016/S1773-2247(13)50093-1.

[23] Sunil K. Jain, Govind P. Agrawal, Narendra K. Jain, A novel calcium silicatebased microspheres of repaglinide: in vivo investigations, J. Control Release113 (2006) 111e116, http://dx.doi.org/10.1016/j.jconrel.2006.04.005.

[24] Amit Kumar Nayak, Dilipkumar Pal, Kousik Santra, Ispaghula mucilage-gellanmucoadhesive beads of metformin HCl:Development by response surfacemethodology, Carbohydr. Polym. 107 (2014) 41e50, http://dx.doi.org/10.1016/j.carbpol.2014.02.022.

[25] Aashima Hooda, Arun Nanda, Manish Jain, Vikash Kumar, Permender Rathee,Optimization and evaluation of gastroretentive ranitidine HCl microspheresby using design expert software, Int. J. Biol. Macromol. 51 (2012) 691e700,http://dx.doi.org/10.1016/j.ijbiomac.2012.07.030.

[26] A.J. Rajamma, H.N. Yogesha, S.B. Sateesha, Natural gums as sustained releasecarriers: development of gastroretentive drug delivery system of ziprasidoneHCl, DARU J. Pharm. Sci. 20 (2012) 58, http://dx.doi.org/10.1186/2008-2231-20-58.


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Prof. Chakka Gopinath