Development and Characterization of Novel Floating-Mucoadhesive Tablets Bearing Venlafaxine ...

13 Pages·2016·2.98 MB·English

Hindawi Publishing Corporation
Scientifica
Volume 2016, Article ID 4282986, 13 pages
http://dx.doi.org/10.1155/2016/4282986
Research Article
Development and Characterization of
Novel Floating-Mucoadhesive Tablets Bearing
Venlafaxine Hydrochloride
RaghvendraMisra1andPeeyushBhardwaj2
1DepartmentofPharmacy,VivekCollegeofTechnicalEducation,UttarPradesh246701,India
2InstituteofPharmacy,BundelkhandUniversity,Jhansi,UttarPradesh284128,India
CorrespondenceshouldbeaddressedtoPeeyushBhardwaj;[email protected]
Received31December2015;Revised15March2016;Accepted29March2016
AcademicEditor:PaulO.Gubbins
Copyright©2016R.MisraandP.Bhardwaj.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttribution
License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly
cited.
The present investigation is concerned about the development of floating bioadhesive drug delivery system of venlafaxine
hydrochloride which after oral administration exhibits a unique combination of floating and bioadhesion to prolong gastric
residencetimeandincreasedrugbioavailabilitywithinthestomach.Thefloatingbioadhesivetabletswerepreparedbythewet
granulationmethodusingdifferentratiosofhydroxypropylmethylcellulose(HPMCK4MCR)andCarbopol934PNFaspolymers.
Sodiumbicarbonate(NaHCO3)andcitricacidwereusedasgas(CO2)generatingagents.Tabletswerecharacterizedforfloating
properties,invitrodrugrelease,detachmentforce,andswellingindex.Theconcentrationofhydroxypropylmethylcelluloseand
Carbopol934PNFsignificantlyaffectstheinvitrodrugrelease,floatingproperties,detachmentforce,andswellingpropertiesof
thetablets.Theoptimizedformulationshowedthefloatinglagtime72±2.49secondsanddurationoffloating24.50±0.74hr.
Theinvitroreleasestudiesandfloatingbehaviorwerestudiedinsimulatedgastricfluid(SGF)atpH1.2.Differentdrugrelease
kineticsmodelswerealsoapplied.Theinvitrodrugreleasefromtabletswassufficientlysustained(morethan18hr)andtheFickian
transportsofthedrugfromthetabletswereconfirmed.Theradiologicalevidencesuggeststhatthetabletsremainedbuoyantand
alteredpositioninthestomachofalbinorabbitandmeangastricresidencetimewasprolonged(morethan>6hr).
1.Introduction reuptake inhibitor (SNRI). It inhibits the serotonin trans-
porter at 30-fold lower concentration than norepinephrine
Depressionisachronic,recurring,andpotentiallylife-threat-
transporter (Ki = 82 and 2480nm), respectively [4]. It
eningillnessthataffectsupto20%ofthepopulationacross
displays differential effects on norepinephrine reuptake in
the globe [1, 2]. This disease is one of the top ten causes of
healthy versus depressed patients [5]. It is highly soluble
morbidityandmortalityworldwideandrepresentsahighcost
in 0.1N HCl; its solubility decreases with increasing pH
to country’s economy [2]. Available therapy for depression
treatment is often associated with several undesirable side overthephysiologicalrange.Bothvenlafaxineanditsactive
effects, and its effectiveness achieves only a certain portion metabolite, ODV (O-desmethyl venlafaxine), have weak
of the population [3]. Therefore, the identification of the inhibitoryeffectonthereuptakeofdopaminebut,unlikethe
alternativetherapeutictoolsforthetreatmentofdepression tricyclics and similar to SSRIs (selective serotonin reuptake
isofhighimportance. inhibitors)theyarenotactiveinhistaminergic,muscarinic,
Venlafaxine hydrochloride, (±)-1-[2-(dimethylamino)-1- or alpha(1)-adrenergic receptors [6–9]. The half-life of ven-
(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride, is a lafaxinehydrochlorideis5±2hr,necessitatingtheadminis-
highlywatersolubleandstructurallynovelantidepressantfor tration,twoorthreetimesdailytomaintainadequateplasma
oraladministration.Itisadualserotoninandnorepinephrine drugconcentration.
2 Scientifica
Various attempts have been made to develop floating Table 1: Formulation for optimization of drug: HPMC K4MCR
system to control drug release; among them is the so ratio.
called hydrodynamically balanced system (HBS). Floating
Formulationcode(FC)
drugdeliverysystem(FDDS)orhydrodynamicallybalanced Ingredients(inmg)
FC1 FC2 FC3 FC4
systems(HBS)haveabulkdensitylowerthanthegastricfluid
Venlafaxinehydrochloride 42.43 42.43 42.43 42.43
and thus remain buoyant in the stomach without affecting
HPMCK4MCR 130 135 140 145
the gastric emptying rate for a prolonged period of time
[10]. FDDS is suitable for those drugs which are having Carbopol934PNF 15 15 15 15
an absorption window in the stomach or the upper small Sodiumbicarbonate 15 15 15 15
intestine [11], for drugs, which act locally in the stomach Lactose 30 30 30 30
[12],andfordrugsthatarepoorlysolubleorunstableinthe Magnesiumstearate 2.57 2.57 2.57 2.57
intestinal fluid [13]; venlafaxine hydrochloride is one drug TabletWt.(mg) 235 240 245 250
fromthelattercategory.
Floating dosage forms remain on the surface of gastric
fluidbecauseofitsrelativelylowerdensitythanthatofgastric Table2:Formulationforoptimizationofdrug:Carbopol934PNF
fluid. Floating single unit dosage form, also called hydro- ratio.
dynamically balanced systems (HBS), has been extensively
Formulationcode(FC)
studied[14]. Ingredients(inmg)
FC3 FC5 FC6 FC7
Mucoadhesive delivery systems were also proven to be
suitable for reduction of transit time of the dosage form Venlafaxinehydrochloride 42.43 42.43 42.43 42.43
throughthegastrointestinaltract.Adhesivenessofthedosage HPMCK4MCR 140 140 140 140
form is based on the bioadhesive power of the polymer. Carbopol934PNF 15 10 20 25
Various synthetic as well as natural polymers have been Sodiumbicarbonate 15 15 15 15
reportedforthisapproach[15]. Lactose 30 30 30 30
Venlafaxinehydrochlorideisselectedasadrugcandidate Magnesiumstearate 2.57 2.57 2.57 2.57
forthisstudyasitsbioavailabilityislowandhalf-liferanges
TabletWt.(mg) 245 240 250 255
in5±2hrnecessitatingfrequentadministrationtomaintain
theadequateplasmalevelofdrug.
Thepresentresearchendeavorinvolvesdevelopmentand Table3:Formulationforoptimizationofdrug:sodiumbicarbonate
characterization of newer floating-mucoadhesive tablets of ratio.
venlafaxine hydrochloride using HPMC K4MCR and Car-
Formulationcode(FC)
bopol 934PNF and investigation of the combined effect of Ingredients(inmg)
FC3 FC8 FC9 FC10
thesepolymersonthefloatingbehaviorandinvitrorelease
pattern of the drug. Here the synergism effect of mucoad- Venlafaxinehydrochloride 42.43 42.43 42.43 42.43
hesion with floatation may increase the gastric retention of HPMCK4MCR 140 140 140 140
drug,henceincreasingitsbioavailability. Carbopol934PNF 15 15 15 15
Sodiumbicarbonate 15 20 25 30
Lactose 30 30 30 30
2.MaterialsandMethods
Magnesiumstearate 2.57 2.57 2.57 2.57
2.1. Materials. Venlafaxine hydrochloride was a kind gift TabletWt.(mg) 245 250 255 260
fromRanbaxyResearchLab.Ltd.(Gurgaon,Haryana,India).
HPMCK4MCRwasobtainedasagiftsamplefromColorcon
Asia Pvt. (Goa, India), Carbopol 934PNF from Arihant Table4:Formulationforoptimizationofdrug:lactoseratio.
Trading Co. (Mumbai, India), and lactose and magnesium
Formulationcode(FC)
stearate were procured from Central Drug House (New Ingredients(inmg)
FC8 FC11 FC12 FC13
Delhi, India). Sodium bicarbonate was obtained from SD
Venlafaxinehydrochloride 42.43 42.43 42.43 42.43
Fine-ChemLtd.(Mumbai,India).Allotherreagentswereof
analyticalgrade,whichwereusedinpreparation. HPMCK4MCR 140 140 140 140
Carbopol934PNF 15 15 15 15
Sodiumbicarbonate 20 20 20 20
2.2.Methodology. Venlafaxinehydrochloridefloatingtablets
Lactose 30 20 40 50
werepreparedbythewetgranulationmethodusinghydrox-
ypropyl methyl cellulose (HPMC K4MCR), Carbopol 934P, Magnesiumstearate 2.57 2.57 2.57 2.57
lactose,andsodiumbicarbonate.Thecompositionsofdiffer- TabletWt.(mg) 250 240 260 270
entformulationcodesoffloatingtabletsareshowninTables
1–4.
accurately weighed. Then accurately weighed quantities of
2.2.1. Preparation of Granules. Granules were prepared by venlafaxine hydrochloride, HPMC K4MCR, lactose, and
wet granulation method. First of all, the ingredients were sodiumbicarbonateweremixedhomogeneouslyusingglass
Scientifica 3
Table5:Comparativestudyofvariousgranulescharacteristics.
Formulationcode Angleofrepose(𝜃∘) Flowrate(gm/second) Bulkdensity(gm/cm3) Tappeddensity Carr’sindex
FC1 24.70±1.82 1.18±0.02 0.672±1.26 0.826±1.06 18.64
FC2 25.98±1.74 1.13±0.17 0.651±0.28 0.817±1.02 20.32
FC3 26.89±1.02 0.98±0.11 0.681±0.40 0.887±0.80 23.22
FC4 28.12±1.16 0.91±0.13 0.648±0.16 0.862±0.50 24.82
FC5 31.09±0.82 1.10±0.12 0.624±1.08 0.801±0.18 22.10
FC6 31.47±1.11 0.99±0.09 0.667±0.30 0.907±1.20 26.46
FC7 37.39±1.73 0.95±0.05 0.662±0.24 0.901±0.30 26.53
FC8 32.15±1.04 0.98±0.03 0.652±1.01 0.807±1.08 19.21
FC9 27.08±1.32 1.07±0.07 0.664±0.36 0.823±0.45 19.32
FC10 30.07±1.51 1.05±0.19 0.694±0.50 0.852±0.16 18.54
FC11 31.09±0.86 1.21±0.16 0.701±0.30 0.905±0.10 22.54
FC12 26.06±0.87 1.22±0.10 0.721±0.18 0.910±1.23 20.77
FC13 22.29±0.85 1.20±0.08 0.736±0.10 0.899±0.35 18.13
Mean±SD;𝑛=3;FC:formulationcode.
mortar and pestle. The wet granulation was done with 2.2.3. Preparation of Floating Tablet. The homogeneously
ethanol (95%). Wet mass was passed through a 40-mesh lubricatedgranuleswithmagnesiumstearate(approximately
∘
screen and dried in a hot air oven at 40 C over night. The 1% w/w) were then compressed into tablets using nine mm
driedgranulesweresizedthrough40/60meshandblended die/punchsetonasinglepunchtabletcompressionmachine
withCarbopol934Pandmagnesiumstearate(approximately (Cadmach Machinery Ltd., Ahmedabad, India). Compres-
1% w/w). Lactose was used as filler and channeling agent. sion force was adjusted to obtain tablets with hardness in
Sodiumbicarbonatewasusedasagasgeneratingagent[16]. the range of 6.2–6.9kg/cm2 on a Monsanto tablet hardness
tester.
2.2.2.EvaluationofGranules. Granulesofdifferentformula-
tion codes are evaluated for angle of repose, flow rate, bulk 2.2.4.CharacterizationofFloatingTablet. Thepreparedfloat-
density,tappeddensity,Carr’sindex,andsoforthasperthe ing tablets were characterized for drug content, uniformity
method described by Aulton [17]. The angle of repose and of weight using 20 tablets, hardness (a Monsanto hardness
flowratesweredeterminedbythefunnelmethod.Thebulk tester),andfriability(Rochetypefriabilator).Thedrugcon-
density and tapped density were obtained by the cylinder tentofthetabletwasdeterminedusing0.1NHClasasolvent.
method.Consider The uniformity of drug content in each formulation was
ℎ determined by triturating20 tablets and powder equivalent
(angleofrepose)𝜃=tan−1(𝑟), (1) toaverageweightwasaddedto100mLof0.1Nhydrochloric
acid, followed by stirring for 30 minutes [18]. The solution
where𝜃istheangleofrepose,ℎisheightofthecone(orpile wasfilteredthroughaWhatmanfilterpapernumber41and
height),and𝑟isradiusofcone(orpile)orbaseradius: dilutedsuitablyandtheabsorbanceofresultantsolutionwas
measuredusingDoubleBeamUVspectrophotometer(Shi-
weightofgranules
flowrate= , madzu,UV-1700,Japan)at225.0nmusing0.1Nhydrochloric
timeinseconds
acidasblank.Theaveragedrugcontentiscalculated.
𝑤
bulkdensity(𝜌𝑏)= 𝑉 , (2)
𝑏 2.2.5.FloatingCharacteristics. Floatingcharacteristicsofthe
𝑤 tabletswerestudiedatthetemperature37±0.5∘C,in250mL
bulkdensity(𝜌𝑡)= 𝑉, of a 0.1N HCl solution (pH = 1.2) (Figure9). The time
𝑡
requiredforthe tablet to riseto thesurface ofthe solution,
where 𝑤 is weight of the sample in grams, 𝑉𝑏 is final bulk andtofloat,wastakenasthefloatinglagtime.Theduration
volumes of granules in cm3, and 𝑉𝑡 is final tapped volumes of time in which dosage form constantly remained on the
3
ofgranulesincm . surfaceofthemediumwasconsideredastotalfloatingtime
And Carr’s index of each formulation was calculated (Table9).
accordingtotheequationgivenbelow:
𝜌 −𝜌 2.2.6. In Vitro Dissolution Studies. The in vitro dissolution
Carr’sindex(% compressibility)= 𝑡𝜌 𝑏 ×100. (3) studies of venlafaxine hydrochloride from floating tablet
𝑡
were carried out using USP Dissolution Testing Apparatus
ExperimentalevaluationsofgranulesareshowninTable5. II (Paddle Type). The dissolution test was performed using
4 Scientifica
900mL of 0.1N HCl, at 37 ± 0.5∘C at 75rpm. One mL of uppervialwasthenconnectedtothebalance.Weights(W)
thealiquotwaswithdrawnfromthedissolutionapparatusat wereaddedataconstantratetothepanontheothersideof
different predetermined time intervals (1, 2, 3, 4, 5, 6, 8, 10, the modified balance of the device until the two vials were
12,14,16,and18hours)andthesampleswerereplacedwith separated.
thefresh dissolutionmedium.Then thesample was filtered Thebioadhesiveforce,expressedasthedetachmentstress
2
throughtheWhatmanfilterpapernumber41 andanalyzed in dyne/cm , was determined from the minimum weight
at225nmusingUVSpectrophotometer(ShimadzuUV-1700, requiredtodetachthetwovialsusingthefollowingequation:
Japan).Cumulative%drugreleasewascalculatedusing“PCP 𝑚𝑔
Dissov2.08”software. detachmentstress(dyne/cm2)= , (5)
𝐴
2.2.7. Mechanism of Drug Release. The drug release mech- where𝑚𝑔istheweightrequiredfordetachmentand𝐴isthe
anism was determined by fitting the data to the various surfaceareaofthetablet[20].Thedetachmentstressesofthe
kineticequationssuchaszero-order,first-order,Higuchi,and variousformulationcodesaregiveninTable8.
Korsmeyer-Peppas and finding the 𝑅 and 𝑛 values of the
releaseprofilecorrespondingtoeachmodel. 2.2.10. Scanning Electron Microscopy (SEM). The surface
topography of the floating tablet was examined using scan-
2.2.8. Swelling Properties (Hydration Behavior of Matrix ning electron microscopy (Philips FEI XL-30) at different
Tablets). The swelling of the polymer can be measured by magnificationandtheaccelerationvoltageof14.9KV.Tablet
theirabilitytoabsorbwaterandswell.Theswellingproperty samples were mounted on a scanning electron microscope
of the formulation was determined by various techniques; holder(aluminumsamplemount)usingadoublesideadhe-
here the hydration behavior or swelling properties were sivetapeandcoatedwithgoldpalladiumundervacuumand
determinedasperthemethoddescribedbyDeshpandeetal. thensurfacetopographywasinvestigated.
[19].
TheswellingpropertiesofHPMCandCarbopolpolymer 2.2.11. Stability Studies. Stability studies were carried out
matricescontainingthedrugweredeterminedbyplacingthe accordingtoICHandWHOguidelinestoassessthedrugand
tabletmatricesintheUSPdissolutiontestapparatusII.The formulation stability. The prepared floating tablets of opti-
mediumusedwas0.1NHCl,900mLrotatedat75rpm.The mized formulation(FC8) containing hydroxypropyl methyl
mediumwasmaintainedat37±0.5∘Cthroughoutthestudy. cellulose (HPMC K4MCR) and Carbopol 934PNF (FC8)
The tablets were removed periodically from the dissolution were selected for stability studies based on in vitro drug
medium.Afterdrainingfreewatertheseweremeasuredfor release,floatinglagtime,totalfloatingtime,andtheirphysical
weightgain,thickness,anddiameter.Swellingcharacteristics properties.Theselectedtabletsofvenlafaxinehydrochloride
wereexpressedintermsofpercentagewateruptake(WU%) (FC8)weresealedinaluminumfoilpackagingcoatedinside
∘
accordingtothefollowingequation: with polyethylene and kept in a humidity chamber at 45 C
and75%RHforthreemonths[21].Attheendandduringthe
WU% study, samples were analyzed for the drug content, in vitro
dissolution, floating behavior, and other physicochemical
wt.ofswollentablet−initialwt.ofthetablet
= (4) parameters(Table9).
initialwt.ofthetablet
×100. 2.2.12.TabletPreparationforInVivoStudies. Theoptimized
formulation FC8 had shown good in vitro buoyancy and
sustained-release behavior and hence was finally selected
2.2.9.DetachmentStress. Piecesofsheepfundustissueswere
for in vivo study (i.e., radiography). The tablets of nine
broughtfrommarketandstoredfrozeninsalinesolutionand
mm diameter and 350mg in weight were prepared. To
thawedtoroomtemperatureimmediatelybeforeuse.Atthe
timeoftestingasectionoftissue(I)wastransferred,keeping make the tablet X-ray opaque, incorporation of BaSO4 was
the mucosal side out, to the upper glass vial (G) using a necessary.Bariumsulphate(BaSO4)hashighrelativedensity
3
rubberbandandanaluminumfoilcap.Thediameterofeach (4.4777g/cm )andpoorfloatingproperties.Theamountof
exposed mucosal membrane was 1.1cm. The vials with the the X-ray opaque material in these tablets was sufficient to
fundustissue were stored at 37∘C for10min. Next, onevial ensurevisibilitybyX-rays,butatthesametimethisamount
withasectionoftissue(I)wasconnectedtothebalance(B), ofbariumsulphatewaslowenoughtoenabletabletstofloat.
andtheothervialwasfixedonaheight-adjustablepan(P). For this purpose, the amount of venlafaxine hydrochloride
A bioadhesive tablet (F) was applied to the lower vial with intheformulation,FC8,wasreplacedwith40mgofbarium
thehelpoftwopiecesofadhesivetape.Theheightofthevial sulphate,andallotheringredientswerekeptconstant.These
wasadjustedsothatthetabletcouldadheretothemucosal tablets were analyzed for hardness and floating properties.
tissues in the vial. The mucoadhesive forces of the floating Theanalysisconfirmedthatthesetabletsweresimilartothe
tablets were determined by the measuring device shown in tabletsforinvitrotesting.
Figure5.
Aconstantweight(10g)wasplacedontheuppervialand 2.2.13. In Vivo Radiographic Studies. Nowadays, radio-
appliedfortwominutes,afterwhichitwasremovedandthe graphic study is a very popular evaluation parameter for
Scientifica 5
floating dosage form. It helps to locate dosage form in the Optimization of the HPMC K4MCR
120.000
GIT by which one can predict and correlate the gastric
retentiontime,floatingbehavior,andpassageofthedosage
e100.000
formintheGIT.Heretheinclusionofradio-opaquematerial as
e
into a solid dosage form enables it to be visualized by X- g rel 80.000
rays. It is also important that dosage forms are nondisin- dru
tegrating units, and animal subjects are young and healthy % 60.000
e
[22]. v
ati 40.000
The animal protocol to carry out in vivo radiographic ul
m
studies was reviewed and approved by the Institutional u
C 20.000
Animals Ethical Committee of Bundelkhand University,
India (registration number 716/02/a/CPCSEA). The in vivo 0.000
radiographic studies were conducted in young and healthy 0 5 10 15 20
malealbinorabbitsweighing2.0to2.2kg.Theanimalswere Time (hr)
keptunderstandardlaboratoryconditions(temperature:25
±2∘C).Rabbitswerekeptforoneweekintheanimalhouse FC1 FC3
FC2 FC4
to acclimatize them and fed a fixed standard diet. The 4
Figure1:Releaseprofileofvenlafaxinehydrochloridein0.1NHCl
healthy male albino rabbits were used to monitor the in
(pH1.2)forformulationcodesFC1,FC2,FC3,andFC4.
vivo transit behavior of the floating tablet. None of them
hadsymptomsorhistoryofgastrointestinal(GI)disease.In
ordertostandardizetheconditionsofGImotility,theanimals
werefastedfor12hourspriortothecommencementofeach The floating tablets of venlafaxine hydrochloride were
experiment. In each experiment, the first radiograph of the preparedbywetgranulationmethodusingHPMCK4MCR,
animal subjects was made to ensure the absence of radio- Carbopol 934PNF, sodium bicarbonate, and lactose. The
opaque material in the GIT. One of the tablets prepared magnesiumstearatewasusedasthelubricant.
for radiography was orally administered to rabbits with the Theoptimizationoftheformulationwasdonebasedon
sufficientamountofwater.Duringthestudytherabbitswere adjustingthedrug-polymerratio,floatinglagtime,duration
notallowedtoeat,butwaterwasavailableadlibitum. offloating,gasgeneratingagents,invitrodrugreleaserate.
Forradiographicimaging,allfourlegsoftherabbitwere Results indicated that the low-density polymers like
tiedoverapieceofplywood(20×20inch),andlocationof HPMC K4MCR and Carbopol 934PNF affects the floating
the formulation in the stomach was monitored by keeping behavior of the venlafaxine hydrochloride floating tablet.
the subjects in front of X-ray machine (Allengers, Bharat HPMCK4MCRandCarbopol934PNFareselectedbecause
Electricals, India, Model number E 080743). The distance oftheirhighviscosities,whicharedesiredforthesustained
between the source of X-rays and the object was the same release. For optimizing the concentration ratio of the drug,
for all the imaging. This allowed us to see the tablet in the polymers and several formulations of the different batches
body of the stomach, antrum, and/or pyloric part of the were formulated randomly in which only drug to the poly-
stomachsothatobservationsofthetabletmovementscould mer ratio varied and remaining ingredients of formulation
bemade.Gastricradiographywasdoneat1hr,3hr,and6hr. remained constant. Then floating behavior and release rate
Inbetweentheradiographicimaging,theanimalswerefreed study of these formulations were determined in the 0.1N
andallowedtomoveandcarryoutnormalactivitiesbutwere HCl(pH1.2).Thenacertainratioofdrugtopolymergives
notallowedtotakeanyfood.Themeangastricresidencetime satisfactoryfloatingbehaviorandinvitrodrugreleasein0.1N
ofthedrugwascalculated. HCl.Atthisstageofoptimization,fewbatchesofformulation
codes FC1, FC2, FC3, and FC4 were prepared for the opti-
3.ResultsandDiscussion mizing concentration of the polymer for obtaining the best
floatationbehaviorandinvitrodrugrelease.Floatinglagtime
Thegranulespreparedforthecompressionoffloatingtablets anddurationoffloatingwasfoundtobe112,99,88,and74
were evaluated for their flow properties (Table5). Granules secondsandapproximately17,18,23,and27hr,respectively.
of matrix tablets of different formulation codes showed the Thecumulative%drugreleasewasfoundtobe97.34,97.43,
angle of repose from 22.29∘ ± 0.85 to 37.39∘ ± 1.73 and 94.43,and90.65in18hrfortheformulationcodesFC1,FC2,
flowratesfrom0.91±0.13to1.22±0.10gm/secandCarr’s FC3,andFC4(Figure1).ButthereleasepatternoftheFC3
indexwasfoundintherangeof18.13to26.53.Theseresults showedbetterinvitroreleaseofdruginthesustainedmanner
indicate that as the concentration of the HPMC K4MCR inpredeterminedtimeintervalsthanformulationsFC1,FC2,
and Carbopol 934PNF increased in the formulations the and FC4. Formulation FC3 also showed better floatation
angleofreposeandCarr’sindexwerefoundtobeincreased behavior (i.e., floating lag time 88 seconds and duration of
while their flow rate was found to be decreased. Thus the floating approximately 23hr). Therefore, formulation FC3
angleofreposeandCarr’sindexvalueofdifferentbatchesof has been selected in order to obtain the optimum HPMC
granules indicate satisfactory flow behavior. Other granules loading level, because it has better in vitro release pattern
parameters were also determined and found to be within and floatation behavior. Results also indicate that as the
acceptablelimits. concentrationoftheHPMCincreased,thecumulative%drug
6 Scientifica
Optimization of Carbopol 934PNF 120.000 Optimization of sodium bicarbonate
120.000
100.000
100.000
ug release 80.000 ug release 80.000
% dr 60.000 % dr 60.000
ulative 40.000 ulative 40.000
m m
u u
C C 20.000
20.000
0.000
0.000
0 5 10 15 20
0 5 10 15 20
Time (hr)
Time (hr)
FC3 FC9
FC3 FC6
FC8 FC10
FC5 FC7
Figure3:Releaseprofileofvenlafaxinehydrochloridein0.1NHCl
Figure2:Releaseprofileofvenlafaxinehydrochloridein0.1NHCl
(pH1.2)forformulationcodesFC3,FC8,FC9,andFC10.
(pH1.2)forformulationcodesFC3,FC5,FC6,andFC7.
release behavior and floating lag time were also decreased 120.000 Optimization of lactose
to a certain value. After optimizing the concentration of
HPMC K4MCR, next optimization was done for Carbopol ase100.000
e
cFoCn5cefnortrmatuiolanti.oAnsdtehcerecaosnecde,ntthraetniotnheofinthveitCroarbdorupgolrienletahsee ug rel 80.000
patternoftheformulation(FC5)wasincreasedcomparedto % dr 60.000
thatoftheFC3formulationfor18hrdissolutionstudy.Itwas e
v
foundthatastheconcentrationoftheCarbopolincreasedin ati 40.000
ul
the formulation (i.e., FC6 (20mg) and FC7 (25mg)), then m
u
in vitro drug release was also decreased compared to that C 20.000
of FC3 (15mg). Because the release and floatation behavior
0.000
exhibitedbytheFC3weremuchbetterthanFC5,FC6,and
0 5 10 15 20
FC7 (Figure2), the formulation FC3 remained selected for
Time (hr)
thefurtherstudy.
For the floating drug delivery system, the ideal matrix FC8 FC12
should be highly permeable for the dissolution media in FC11 FC13
order to initiate rapid generation of the carbon dioxide gas Figure4:Releaseprofileofvenlafaxinehydrochloridein0.1NHCl
(CO2) and also should be permeable for CO2 to promote (pH1.2)forformulationcodesFC8,FC11,FC12,andFC13.
floating.Thebuoyancylagtimeofthetabletsdependsonthe
concentrationofthesodiumbicarbonate(NaHCO3)involved
in the CO2 formation. In the trial study, in vitro release of
drug from the different formulation batches was studied to drugwasincreasedinthemorecontrolledmannerthanthat
determinetheoptimumconcentrationofthegasgenerating ofFC3.
agent.ItwasobservedfromtheformulationsFC8,FC9,and Here,thelactoseactsaschannelingagentwhichissoluble
FC10 that as the concentration of the sodium bicarbonate inthedissolutionmedium;therefore,thematrixintegritygets
increased in these formulations, the floating lag time was broken and showed faster in vitro drug dissolution. Results
found to be decreased, but their corresponding release of indicate from the formulations (i.e., FC11, FC12, and FC13)
drug was increased (Figure3). The trial study also showed thatreleaserateofdrugisdirectlyproportionaltothecon-
that,athigherconcentrationofthesodiumbicarbonate,FC10 centrationofthelactose(Figure4).Astheconcentrationof
(30mg) causes bursting and rapid disintegration of tablet. thelactoseincreased,invitrodrugreleaseswerealsofoundto
Hence it was desirable to use optimum concentration of beincreasedbutiftheconcentrationofthelactoseincreased
sodium bicarbonate to get the least floating lag time with morethan50mgthenthetabletwillstartdisintegrationby
minimum bursting effect and desired floating time with- the erosion mechanism. Therefore, optimum concentration
out rapid disintegration. So FC8 with sodium bicarbonate of the lactose is required for getting the maximum in vitro
(20mg) was optimized and selected to achieve optimum in drugreleasewithoutcausingerosion.Fromtheaboveresults,
vitrobuoyancywithlessburstingeffect.TheformulationFC8 FC8 was found to be the best formulation which showed
was preferred over the FC3, because the in vitro release of betterinvitrodrugreleaseandfloatationbehavior.
Scientifica 7
Table6:Physiochemicalcharacterizationofvenlafaxinehydrochloridetablets.
2 %drugcontent Floatinglag Totalfloating
Code %weightvariation Hardness(kg/cm ) %friability
uniformity time(sec) time(hr)
FC1 ±3.0% 6.40±0.16 0.524 99.21±1.46 112±2.87 17.33±2.05
FC2 ±4.5% 6.37±0.45 0.564 98.47±0.34 99±2.49 18.50±1.87
FC3 ±3.5% 6.53±0.57 0.572 98.86±1.24 88±2.87 23.33±0.62
FC4 ±4.0% 6.63±0.58 0.482 97.20±0.18 74±3.27 27.08±0.95
FC5 ±2.5% 6.93±0.52 0.458 98.53±0.52 94±3.27 12.75±2.08
FC6 ±3.0% 6.70±0.70 0.545 99.08±2.21 82±2.94 26.50±1.02
FC7 ±4.0% 6.43±0.33 0.584 97.40±1.02 76±2.45 29.25±0.74
FC8 ±4.0% 6.67±0.98 0.580 98.91±0.18 72±2.49 24.50±0.74
FC9 ±2.5% 6.70±0.49 0.495 98.00±0.24 64±2.94 26.50±1.54
FC10 ±3.0% 6.47±0.90 0.457 97.56±1.32 54±2.45 26.25±1.87
FC11 ±3.0% 6.80±0.43 0.530 98.43±0.64 67±3.74 28.25±0.69
FC12 ±4.5% 6.27±0.41 0.572 99.02±1.45 81±2.87 20.52±0.92
FC13 ±4.5% 6.67±0.66 0.592 98.74±0.82 93±3.27 18.00±0.82
Mean±SD;𝑛=3;FC:formulationcode.
and the matrix gained more water. Drug diffusion signif-
B
icantly depends on the water content of the tablet. This
may be because the mobility of the polymer chains is very
dependent on the water content of the system. In case of
G
high-water content, polymer chain relaxation takes place
I with volume expansion resulting in marked swelling of the
T F W system. Also, higher water content could lead to greater
G󳰀 penetration of the gastric fluid into the tablet leading to
quickercarbondioxidegasgeneration,therebyreducingthe
P
floatinglagtime.Consequently,quickerandgreaterswelling
of the tablet would lead to an increase in the diffusion
pathwayand,thus,areductionindiffusionrate.Sothedrug
󳰀 release was found to be high initially and then gradually
B: modified balance;W: weights;GandG: glass vial
F:bioadhesive tablet;I: fundus tissue decreased.
T: supportive adhesive tape;P:height-adjustable pan The % swelling index of all formulations from FC1 to
FC10 at 24hr was found to be between 136.03 and 170.99,
Figure 5: Mucoadhesion measuring device for obtaining detach-
respectively. The percentage water uptake was found to be
mentstress.
improved as the concentration of the HPMC K4MCR and
Carbopol 934PNF increased in the formulation. The result
indicates, from Table7, that swelling index was increased
ThediameteroftheformulationsFC1toFC13wasfound muchmoreincaseofCarbopolcomparedtoHPMCbecause
intherangeof8.97±0.01to8.99±0.03andthicknesswas Carbopolisbearingverygoodwatersorptionproperty.Itwas
in the range of 3.96 ± 0.01 to 3.99 ± 0.02. The variation alsoobservedthatastheconcentrationoftheCarbopolinthe
in the weight was found in the range of ±5% complying formulationdecreased,the%wateruptakewasalsofoundto
withpharmacopoeialspecifications.Thehardnessofdifferent bedecreased(i.e.,FC5).
formulation was found to be between 6.27 ± 0.41 and Table8 clearly indicates that the value of bioadhesive
6.93 ± 0.52kg/cm2 indicating good mechanical strength. force was found to be increased significantly as the con-
The friability was below 1% for all formulations which is centration of the mucoadhesive polymer HPMC and Car-
an indication of good mechanical resistance of tablet. The bopolincreased.Allfloatingformulationsshowedmucoad-
2
drugcontentvariedbetween98.00%and99.21%indifferent hesive forces in the range of 110.42 to 167.80 dynes/cm .
formulationwithlowstandarddeviation(Table6). ResultsindicatethatastheconcentrationofHPMCK4MCR
Theswellingofthepolymersused(i.e.,HPMCK4MCR increased in the formulations FC1 to FC4, then the value
and Carbopol 934PNF) was determined by swelling index of detachment forces also increased from 123.45 to 156.72
2
of the tablet. Hydrophilic matrices (i.e., HPMC K4MCR dynes/cm , respectively. It was also observed that as the
and Carbopol 934PNF) in contact with water swell and concentration of Carbopol 934PNF increased, the values of
increase their volume due to water diffusion through the detachment forces were increased from the 159.65 to 167.00
2
matrix.Thepolymerchainscontinuethehydrationprocess, dynes/cm forformulationsFC6toFC7,respectively,butas
8 Scientifica
x
e
d
ellingin136.03140.84148.67154.78141.45159.45166.72161.52166.78170.99
w
S
)
m
m
meter(±0.38±1.20±1.48±0.92±1.34±0.88±1.53±0.67±0.25±1.44
aldia18.1618.5218.7318.8518.6218.8918.9318.9919.1419.27
n
Fi
)
m
m
kness(±1.08±0.74±0.89±1.21±1.42±1.27±0.54±0.28±0.78±0.38
thic4.424.504.564.614.534.634.664.624.644.68
al
n
Fi
s. g)
ofmatrixtablet Finalweight(m±552.593.11±578.521.32±607.105.06±637.223.40±578.482.25±648.864.13±681.682.67±654.253.28±678.171.44±703.672.87
r
o
vi
ha m)
e
b m
welling meter(±0.01±0.02±0.01±0.01±0.02±0.02±0.01±0.01±0.01±0.02
S a8797897987
able7: nitialdi8.98.98.98.98.98.98.98.98.98.9
T I
)
m
m
ness(0.010.020.010.020.010.010.020.020.010.02
k±±±±±±±±±±
hic97989799989697999899
alt3.3.3.3.3.3.3.3.3.3.
niti
I
)
g
ght(m±3.05±4.35±1.69±1.71±1.01±1.89±3.29±1.23±3.53±4.42 code.
Initialwei234.11240.20244.18250.10239.58250.09255.58250.17254.21259.67 ormulation
f
C:
de F
o 3;
c =
n
o 𝑛
ulati ±SD;
ormC1C2C3C4C5C6C7C8C9C10 ean
FFFFFFFFFFF M
Scientifica 9
Table8:Detachmentforcesofdifferentformulations.
2
S.numberFormulationcode(FC) Detachmentforce(dynes/cm )
1 FC1 123.45
2 FC2 131.74
3 FC3 147.53
4 FC4 156.72
5 FC5 110.42
6 FC6 159.65
7 FC7 167.80
Figure6:Scanningelectronmicroscopyofoptimizedformulation
8 FC8 142.18 FC8oftabletsurfacebeforedissolution.
9 FC9 140.21
10 FC10 136.24
11 FC11 143.78
12 FC12 145.26
13 FC13 140.65
theconcentrationofCarbopoldecreased,valueofforceswas
decreased(i.e.,FC5).Hence,itwasalsoconcludedfromthe
results that the values of detachment forces were increased
muchmoreincaseofCarbopol934PNFcomparedtoHPMC
Figure7:Scanningelectronmicroscopyofoptimizedformulation
K4MCR, because the Carbopol was highly bioadhesive as
FC8oftabletsurfaceafterdissolution.
comparedtoHPMC.
Bioadhesionisasurfacephenomenoninwhichamaterial
120.000
ofsyntheticornaturaloriginadheresorstickstoabiological
surface, usually mucus membrane. Many hydrophilic poly-
100.000
mers adhere to mucosal surfaces as they attract water from e
as
tthheesmimucpulessgtemlleacyhearnaidsmheorifnagdthoesthioene,painthdeiltiahlassubrfeaecne.dThefiniseids g rele 80.000
u
as “adhesion by hydration.” The hydrogen bonding present dr
% 60.000
between the adherent polymer and mucus is involved in e
v
mucoadhesionatthemolecularlevel.Astheconcentrationof ati 40.000
bioadhesivepolymersincreased,thenthehydrogenbonding mul
u
betweenthemucusmembraneandadherentpolymeratthe C 20.000
molecularlevelincreased;therefore,detachmentforceswere
alsofoundtobeincreased. 0.000
Surface morphology of the optimized formulation FC8 0 5 10 15 20
wasexaminedbyscanningelectronmicroscopy(SEM).Itwas Time (hr)
observedfromtheSEMphotographsthatthedrugisreleased
FC8 Marketed-2
fromthematrixtabletbythediffusionprocess.Thesurface Marketed-1
morphology of the matrix tablet after dissolution showed
Figure8:Comparisonof%drugreleaseofoptimizedformulation
that the solvent front enters the matrix and moves slowly
(FC8)versusmarketedformulationsfor18hr.
towardthecenterofthetablet.Thedrugdiffusesoutofthe
matrix after it comes in contact with dissolution medium.
The images of the tablet showed a network in the swollen
polymerthroughwhichthedrugdiffusedtothesurrounding Thedrugreleasewasfoundtofollowfirst-orderkinetics
medium. Thus it was concluded that the drug was released with 𝑟 = 0.9935 and 0.9904 for marketed-1 (tablet) and
from a matrix by diffusion mechanism (Figures 6 and marketed-2(capsule),respectively,whileoptimizedformula-
7). tionFC8followedthePeppasmodelwithvalueof𝑟=0.9962,
A comparative study was performed on the available 𝑛=0.4473,and𝑘=25.2788.Sothebest-fitmodelwasfound
marketedformulationofextendedreleasetabletandcapsule tobethePeppasmodelforoptimizedformulationFC8.The
containingvenlafaxinehydrochlorideequivalenttovenlafax- marketed formulations of tablet and capsule showed more
ine37.5mg.Theresultsobtainedfromtheinvitrodrugrelease than90%ofdrugreleasein14hrwhileoptimizedformulation
study showed that optimized formulations FC8 showed FC8showedonly82.58%ofdrugreleasein14hr.
moresustained-releaseactionthanthatoftablet(marketed- Thedataobtainedfrominvitrodissolutionstudieswere
1) and capsule (marketed-2) with respect to time of 18hr fitted to zero-order, first-order, Higuchi, and Korsmeyer-
(Figure8). Peppas equations. All release kinetic models were applied
10 Scientifica
Table9:Stabilitystudiesofvenlafaxinehydrochloridefloatingtabletsofoptimizedformulation(FC8).
Characteristic Initial 1stmonth 2ndmonth 3rdmonth
Hardness(kg/cm2) 6.67±0.98 6.02±0.56 6.42±0.20 6.30±0.88
Drugcontent(%) 98.91±0.18 98.34±0.02 98.12±1.42 98.00±0.27
Floatinglagtime(seconds) 72±2.65 76±1.26 84±2.45 90±3.26
Totalfloatingtime(hours) 24.50±0.74 24.16±1.12 24.18±2.26 24.08±0.34
Swellingindex(%) 161.52 160.82 160.64 160.18
Buoyancyondisturbing Float Float Float Float
Matrixintegrity Verygood Verygood Verygood Verygood
%invitrorelease18hours 96.92±0.83 94.43±1.38 93.98±0.42 93.00±1.56
Mean±SD;𝑛=3;FC:formulationcode.
(a) (b)
Figure9:Invitrofloatingstudiesofoptimizedformulation(FC8)(a)after80secand(b)after24hr.
on the formulation codes FC1, FC2, FC3, FC4, FC5, FC6, aluminumfoilpackagingforthreemonths.Theincreasedlag
FC7, FC8, FC9, FC10, FC11, FC12, and FC13 due to their timeindicatesthepossibilityofreactionofsodiumbicarbon-
satisfactoryreleasebehavior.Thebest-fitmodelwasfoundto ate with moisture during the study period. However, there
bethematrixforformulationcodesFC1,FC2,andFC5and wastheverylittleeffectonthedurationofthefloatingand
PeppasforformulationcodesFC3,FC4,FC6,FC7,FC8,FC9, matrix integrity of the tablets. Some drug degradation was
FC10,FC11,FC12,andFC13.Theselectioncriteriaforthebest found,butitwasnotstatisticallysignificant.Decreaseddrug
modelwerebasedongoodnessoffitofthedataandresidual release was found from the formulation but drug released
sumofsquares.Thedetailsofthebest-fitmodelofdifferent compiled the official standard of release, since more than
formulationcodesaregiveninTable10. 80% of the drug was released (Table9). Thus, it was found
For confirming the diffusion mechanism of optimized that the floating tablets of venlafaxine hydrochloride were
formulation FC8, the data was fitted to the Korsmeyer almoststableunderthesestorageconditionsforatleastthree
equation, which showed the exponent value 𝑛 = 0.4473. months.
Because the optimized formulation FC8 had the exponent The in vitro studies, with BaSO4-containing floating
value (𝑛) less than 0.5, it was suggested that the release tablets,showedafloatinglagtimeof112±2.00seconds,hard-
mechanism of venlafaxine hydrochloride indicates swelling nessof6.60±0.03kg/cm2,andthicknessof3.99±0.01mm.
anddiffusionmechanismoffloatingtablets,whichfollowed The intragastric behavior of the BaSO4-loaded tablet in the
the Fickian diffusion (Case, I transport). This kinetic data albinorabbitwasobservedbyusingaradiographicimaging
analysis was done by using “PCP Disso V2.08” Software technique. Radiographic images were taken after 1, 3, and
(PoonaCollegeofPharmacy,Pune,India). 6hr showing that the tablet had altered its position in the
TheoptimizedformulationFC8wassuggestedforstabil- stomach.Thisprovidedevidencethatthetabletswerefloating
itystudybasedoninvitrofloatinglagtime,totalfloatingtime, on the gastric fluid. After 4hr of the tablet administration,
invitrodrugdissolutionstudies,anditsphysicalproperties. theswellingofthetabletisvisualizedverywelltogetherwith
∘
The floating tablets were investigated at 400 C/75% RH in the white dry core and translucent swelling layer around it