Evaluation of chitosan based vaginal bioadhesive gel formulations for antifungal drugs

18 Pages·2014·0.29 MB·English

ActaPharm.64(2014)139–156 Originalresearchpaper
DOI:10.2478/acph-2014-0013
Evaluation of chitosan based vaginal bioadhesive gel
formulations for antifungal drugs
ZEYNEPAYÞENYÝÐÝT1 Theaimofthepresentstudywastoevaluatechitosanas
SÝNEMYAPRAKKARAVANA1 avaginalmucoadhesivegelbaseforeconazolenitrateand
BAYRÝERAÇ2
ÖZGEGÜRSEL1 miconazolenitrate.Tothisaim,differenttypesofchitosan
MÝNEHOªGÖRLÝMONCU2 withdifferentmolecularmassesandviscosityproperties
ESRABALOÐLU1 [low molecular mass chitosan (viscosity: 20,000 mPa s),
mediummolecularmasschitosan(viscosity:200,000mPas),
1EgeUniversity,FacultyofPharmacy highmolecularmasschitosan(viscosity:800,000mPas)]
DepartmentofPharmaceuticalTechnology
havebeenused.First,rheologicalstudieswereconduct-
35100Bornova,Ýzmir,Turkey
edonchitosangels.Mechanical,syringeabilityandmu-
coadhesivepropertiesofchitosangelsweredetermined.
2EgeUniversity,FacultyofPharmacy
Releaseprofilesofeconazolenitrateandmiconazoleni-
DepartmentofMicrobiology
tratefromchitosangelswereobtainedandevaluatedkine-
35100Bornova,Ýzmir,Turkey
tically.Inaddition,anticandidalactivitiesofformulations
were determined. Finally, vaginal retention of chitosan
gelsinratswasevaluatedbyinvivodistributionstudies.
Based on the results, it can be concluded that gels pre-
pared with medium molecular mass chitosan might be
effectivelyusedfordifferentantifungalagentsinthetreat-
mentofvaginalcandidiosis,sinceithashighmucoadhe-
siveness,suitablemechanicalandreleasepropertieswith
goodvaginalretention.
Keywords:chitosan,vaginalgel,mucoadhesion,econazole
AcceptedDecember19,2013 nitrate,miconazolenitrate,vaginalretention
Vaginal yeast infections are among the most common reasons for women seeking
medical care; it has been estimated that 70–75 % of women have an episode of Candida
vaginitis at least once during their lifetime (1). Local administration of antimicrobial
agents has been favored in the treatment of vaginitis because of the numerous side ef-
fectsofsystemicallyapplieddrugs.Vaginaldosageformsusedforthispurposeinclude
solutions, gels, creams, ointments, foams, pessaries, tablets and vaginal inserts (1). To
achieveadesirabletherapeuticeffect,vaginaldeliverysystemsneedtohavetheability
to spread onto the vaginal mucosa surface and guarantee an intimate and prolonged
contact at the site of application (2). Therefore, localized mucoadhesive dosage forms
*Correspondence;e-mail:[email protected]
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Z.A.Þenyiðitetal.:Evaluationofchitosanbasedvaginalbioadhesivegelformulationsforantifungaldrugs,ActaPharm.64(2014)
139–156.
mayberegardedasasuitableformulationdesigntoimproveboththebioavailabilityof
the drug and patient compliance while traditional vaginal preparations might not en-
sure satisfactory therapy.
Mucoadhesive gels have a high capability of adhering to mucosal surfaces, which
cover various body cavities such as the vagina and prolong the residence time of the
drugdeliverysystemattheapplicationsiteanddecreasethenumberofapplicationsre-
quired(3).Useofnaturalpolymersisvaluableforthepreparationofmucoadhesivegel
formulationsowingtotheirprovenbiocompatibilityandsafety.Inthisrespect,thepoly-
saccharidechitosanhasreceivedparticularattentionoverthepast20years(4).Chitosan
isanaturalcopolymerconsistingofglucosamineandN-acetylglucosamineunits.Ithas
acationiccharacterbasedonitsprimaryaminogroups.Theseprimaryaminogroupsof
chitosan are responsible for various properties (i.e., controlled drug release, mucoadhe-
sion,insitugelationandpermeationenhancement).Inaddition,chitosananditsderiva-
tives have efflux pump inhibitory properties. They are able to reversibly inhibit efflux
pumpsandowingtothispropertythemucosaluptakeofvariouseffluxpumpsubstrates
(suchasanticancerdrugs,antimycoticdrugsandantiinflammatorydrugs)canbegreat-
lyimproved(4).Allofthesepropertiesmakechitosananidealcandidateforbeingused
in drug delivery systems (4, 5).
Miconazole nitrate (MN) and econazole nitrate (EN) are imidazole derivative anti-
fungal drugs used to treat topical fungal and yeast infections (6). The objective of this
study was to comprehensively evaluate chitosan as a vaginal gel base for EN and MN.
Forthispurpose,differenttypesofchitosanwithdifferentmolecularmassesandviscos-
ity properties have been used for the preparation of mucoadhesive gels. First of all, a
comprehensiverheologicalstudywasconductedonpreparedchitosangels.Mechanical,
syringeability and mucoadhesion properties of chitosan gels were determined with a
TA-XT Texture Analyzer (7). Release profiles of MN and EN were obtained and evalu-
atedkinetically.Inaddition,anticandidalactivitiesofformulationsweredeterminedby
theagarwelldiffusionmethod.Finally,thevaginalretentionofchitosangelsinratswas
evaluated by in vivo distribution studies.
EXPERIMENTAL
Materials
Lowmolecularmasschitosan[Brookfieldviscosity(1%,m/V,in1%aceticacidso-
lutionat25°C):20,000mPas,75–85%deacetylated],mediummolecularmasschitosan
[Brookfieldviscosity(1%,m/V,in1%aceticacidsolutionat25°C):200,000mPas,75–85
% deacetylated], high molecular mass chitosan [Brookfield viscosity (1 %, m/V, in 1 %
acetic acid solution at 25 °C): 800,000 mPa s, > 75 % deacetylated] and EN were pur-
chased from Sigma-Aldrich (GERMANY). MN was obtained from ÝLSAN-ÝLTAÞ Phar-
maceutical Company (TURKEY). All other materials were of analytical grade.
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139–156.
Preparation of formulations
Gelformulationswerepreparedusingchitosanofthreedifferentmolecularmasses.
Briefly,chitosanof2%(m/m)concentrationwasdissolvedindilutedlacticacidsolution
(1 %, V/V). Percent chitosan concentration was chosen according to literature findings
and preformulation studies (8). Chitosan concentration in gel formulations was kept
constanttoevaluatethedifferencebetweenchitosantypes.MNorENwasincorporated
intoformulationsat2%(m/m)and1%(m/m)concentrations,respectively.MNandEN
concentrationswerechoseninaccordancewiththeirconcentrationincommercialprod-
ucts. Compositions of gels are given below:
F1: Formulations prepared with low molecular mass chitosan (2 %)
F2: Formulations prepared with medium molecular mass chitosan (2 %)
F3: Formulations prepared with high molecular mass chitosan (2 %).
Determination of pH
ThepHvaluesofgelsweremeasuredwithapH-meter(WTWseriespH720)atroom
temperature.ThepHvaluesofformulationswerechecked24hoursuponpreparation.
Rheological studies
Rheological analysis of chitosan gels was performed at 37 ± 0.1 °C with a Haake
Marsrheometer(ThermoFisher,Germany).Analysiswasperformedinflowmodeand
in conjunction with parallel steel plate geometry (40 mm diameter) with a gap of 0.3
mm, as described previously (9). In continuous shear analysis, the upward and down-
ward flow curves for each formulation were measured over shear rates (10–2000 s–1).
Oscillatory analysis of each formulation was performed after determination of its
linearviscoelasticregionat37±0.1°C,wherestresswasdirectlyproportionaltostrain
andthestoragemodulusremainedconstant.Frequencysweepanalysiswasperformed
over the frequency range of 0.1–10.0 Hz following application of a constant stress. The
standardgapsizewas0.3mmforeachsample.Storagemodulus(G')andlossmodulus
(G“)oftheformulationsweredeterminedaspreviouslydescribed(10).Ineachcase,rhe-
ological properties of the formulations were examined at least six times.
Mechanical properties of formulations
Texturalanalysiswasperformedtodeterminemechanicalpropertiesoftheformu-
lationsusingasoftware-controlledpenetrometer(TA-TXPlus,StableMicroSystem,UK)
equipped with a 5 kg load cell. Formulations were initially transferred into glass vials
(20 mL). An analytical probe was twice compressed into each formulation to a defined
depth(15mm)andatadefinedrate(2mms–1),allowingadelayperiod(15s)between
theendofthefirstandbeginningofthesecondcompression.Experimentswerecarried
out at least six times. As a result of this study, a force-time curve was obtained (Fig. 1)
and mechanical parameters (hardness, compressibility, adhesiveness, cohesiveness and
elasticity) were calculated (11).
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139–156.
Hardnessistheforcerequiredtoattainagivendeformationandthealtitudeofthe
firstpeakgivesthehardnessvalue.Compressibilityistheworkrequiredtodeformthe
product during the first compression of the probe and the first area under the curve
(AUC) defines compressibility. Adhesiveness is the work necessary to overcome the at-
tractiveforcesbetweenthesurfaceofthesampleandthesurfaceoftheprobe.Thesec-
ond AUC defines adhesiveness. Cohesiveness is the ratio of the area under the force-
-time curve produced in the second compression cycle to that in the first compression
cycle.Elasticityistherateatwhichthedeformedsamplereturnstoitsundeformedcon-
ditionaftertheremovalofthedeformingforce.Cohesivenessandelasticityvalueswere
calculated according to the following equations:
Cohesiveness = AUC /AUC (1)
3 1
Elasticity = Time difference /Time difference (2)
3–4 1–2
Fig.1.Schematicrepresentationoftheforce-timecurveobtainedfromtexturalanalysis.
Syringeability of formulations
Theworkrequiredtoexpelformulationsfromasyringewithoutaneedlewasmea-
suredusingaTA-XTTextureAnalyzer(StableMicroSystems)incompressionmode,as
previously described in literature (12). Shortly, formulations were packed into 2 mL
plasticsyringeswithoutneedlestoaheightof25mm,avoidingairbubbles.Thesyringe
wasthenplacedinthemetallicsupportandimmobilizedwithaplasticclampingring.A
forcetransducerwasconnectedtothetextureanalyzerTA-XTtomeasuretheforcewith
which the arm of the texture analyzer moved and pushed the plunger of the syringe.
Theprobewasloweredataconstantspeed(2.0mms–1)overadistanceof30mm.The
resistancetoexpressionofsyringecontents(workdone)wasdeterminedfromthearea
undertheforce-timecurverecordedduringplungercompression.Allmeasurementswere
performed in at least six replicates (12).
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139–156.
Mucoadhesion studies
Mucoadhesion measurements were performed using a TA-XT Texture Analyzer
(Stable Micro Systems) equipped with a load cell of 1 kg. A/MUC measuring system
(mucoadhesion test ring) consisting of a ring in which the biological support can be
fixedandacylinderprobewithadiameterof1cmwereused.Inthisstudy,mucindis-
persion (mucin from porcine stomach, Type II, Sigma-Aldrich, Germany) was used in-
steadofabiologicalsupport.Afilterpaperdiscwaswettedwith10mLofmucindisper-
sion in phosphate buffer (8 %, m/m, pH 6.4). 20 mg of each sample was applied to the
cylinderprobe.Thesampleandbiologicsubstratewereputincontactwithapreloadof
6000mNfor3min.Thecylinderprobewasmovedupwardsatapredeterminedspeed
of2.5mmmin–1toseparatethemucoadhesiveinterface(mucin-sample).Themaximum
detachmentforce,asafunctionofdisplacement,wasrecordedandtheworkofadhesion
parameter(mNmm)wascalculatedastheareaundertheforcevs.displacementcurve.
The test was conducted at 37 °C and each experiment was carried out six times (13).
Release studies
The in vitro release studies of MN and EN from different chitosan gel bases were
carried out using Spectra/Por Regenerated Cellulose Dialysis Membrane Tubes
(12.000–14.000 MWCO). Membranes were soaked in distilled water for 24 hours before
theexperiment.Phosphatebuffer(pH4.5)withdioxane(65:35,V/V)wasusedasrecep-
tor medium (14). Each formulation was packed in dialysis bags, which were placed in
150 mLof buffer at 37 °C in sealed glass vials. The receptor medium was continuously
stirred.Atcertaintimeintervals,sampleswerewithdrawnandthedrugcontentofeach
samplewasanalyzedspectrophotometrically(ShimadzuUV-Vis1208spectrophotomet-
er). Samples were measured at 273 nm and 270 nm for MN and EN contents, respec-
tively. All the experiments were repeated at least three times.
Determination of release mechanism
The release mechanism from gels was investigated using the Ritger-Peppas equa-
tion (15, 16).
Mt/M¥ = k tn (3)
Inthisequation;Mtisthedrugreleasedattimet,M¥isthequantityofdrugreleasedat
infinite time, Mt/M¥ is fractional release, k is the diffusional constant and n is the
diffusional exponent that characterizes the drug release mechanism.
Determination of anticandidal activities of formulations
Anticandidalactivitiesofformulationsweredeterminedbytheagarwelldiffusion
method. The standard Candida albicans ATCC 90028 strain was inoculated onto a
Sabouraud Dextrose Agar (SDA, Oxoid) plate and incubated at 35 °C for 48 hours. A
suspension equal to the 0.5 McFarland turbidity standard was prepared in a sterile sa-
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139–156.
linesolution(8.5gL–1)fromthecandidacolonies.100µLofthesuspensioncontaining
approximately 1 × 106 – 5 × 106 colony forming units (CFU)/mL was spread on the
plateswithasterileswabandallowedtodryatroomtemperaturefor5minutes.Then,
20mmdiameterwellsweremadeinthecentersofSDAplateswithasterilescalpel.0.5
mLofformulationwithorwithoutMNandENwasputintothewellsaseptically.After
incubation for 24–48 hours at 35 °C, inhibition zone diameters formed around the for-
mulations were measured. To control the possible contamination of formulations, they
wereplacedonSDAplatesthatwerenotinoculatedwithC.albicansandincubated(17).
In vivo distribution studies
For in vivo distribution studies, the near-infrared dye IRDye 800RS Carboxylate
(LI-CORBiosciences,NE)wasloadedinchitosangels(10mg/10g,m/m).FemaleWistar
albinorats(200–250g)wereanesthetizedwithketamine.Vaginalandabdominalregions
of the rats were shaved and 0.2 mL of gels was given intravaginally using a syringe
without a needle. Rats were transferred to the MousePOD™ Adapter (model 9201-MP)
scanningsurfaceofanOdysseyInfraredImagingSystem(model9201-3;LI-CORBiosci-
ences, USA). The MousePOD™ adapter was equipped with temperature regulators to
maintainanimaltemperatureduringscanning.Vaginalregionsofanimalswerescanned
fromtailtoabdomenintwoinfraredchannelssimultaneously(700and800nm),where
one channel (700 nm channel) was used for normalization of the measured infrared in-
tensities.Theratswerescannedeveryhourfor8hand24hafteradministration.Thein-
tensitiesweredisplayedinpseudocolorsbytheOdysseysoftware(LI-CORBiosciences)
to isolate regions of interest (18). This in vivo study was performed following institu-
tionalapprovalfromtheEthicsCommitteeofAdnanMenderesUniversity(Aydýn,Tur-
key, No: B.30.2.ADU.0.00.00.00/050.04/2012/107). Experiments were carried out in ac-
cordance with the guidelines laid down by the Helsinki Declaration regarding the care
and use of animals for experimental procedures and in accordance with local laws and
regulations.
Statistical data analysis
StatisticaldataanalysiswasperformedusingtheStudentt-testwithp<0.05asthe
minimal level of significance.
RESULTSANDDISCUSSION
Results of pH measurements
ThevaginalpHofhealthywomenofreproductiveageisacidic(4.5–5.5).Itismain-
tained by Lactobacilli present in the healthy vagina that play an important role in the
controlofinfectionbycommonpathogens.Theseorganismsalsoproduceotherbacteri-
cidal compounds such as hydrogen peroxide, bacteriocin-like substances and possibly
biosurfactants (19). The pH of formulations is one of important parameters for vaginal
compatibility. Therefore, the pH values of chitosan gels were determined first in this
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TableI.pHvaluesofformulations
Formulationcode pH±SD
F1 5.34±0.04
F2 5.44±0.06
F3 4.98±0.03
F1+MN 4.82±0.07
F2+MN 4.67±0.08
F3+MN 4.53±0.04
F1+EN 3.85±0.06
F2+EN 3.92±0.09
F3+EN 3.79±0.07
study.Theresultsshowedthatalltheformulationsweresuitableforvaginalapplication
astheycouldmaintaintheacidicpHvalueofthevagina(TableI).Itwasalsoobserved
thatthepHvalueofthegelsdidnotchangesignificantlywhenusingdifferenttypesof
chitosan.AdditionofENandMNintogelformulationssignificantlydecreasedpHval-
ues in all formulations (p < 0.05).
Results of rheological studies
Rheologicalpropertiesaffecttheinvivobehaviorofformulationsinthevaginasuch
as application, spreadability and retention time. Spreadability of gels increased with a
decreaseinviscosity.Also,theretentiontimeofchitosangelswasaffectedbytheirvis-
cosity and rheological behavior. Therefore, were evaluated the rheological behavior of
chitosan gels and determined if the flow types of the formulations were Newtonian or
non-Newtonian.
ItcanbeseenfromFig.2thatthegelsexhibitedflowbehaviorindependenceonthe
chitosantype.F1formulationshowedNewtonianflowduetoitslowviscosity.Thisflow
behavior is common in diluted gel and emulsion formulations. The reason for Newto-
nian flow behavior is that the molecules or micelles of this formulation did not get en-
tangled.Further,theformulationdidnotundergoaphasechangetoturnintoageland
was still an easily flowing liquid, similar to pure water displaying typical Newtonian
flowbehavior(20,21).Solutionsbegantoflowaftershearstressreacheditsyieldpoint.
Therefore, the flow curve for these solutions, under physiological conditions, exhibited
pseudoplasticbehaviorwithhysteresis.Thehysteresisphenomenonindicatedthepres-
enceofanelasticcomponent.Thus,stronggelsformedwiththesepolymerscanbechara-
cterizedasviscoelasticmaterials.Viscoelasticmaterialsnormallyshowhysteresisunder
cyclic deformation. Viscoelastic materials are preferable to viscous materials because
theyflowmoreeasilyandarelesssusceptibletodeformationduetostress(21).Onthe
other hand, F2 and F3 formulations exhibited plastic flow. Plastics are shear thinning,
their curve begins with a yield value and their viscosity decreases with an increase in
shearrate(20,21).Itisclearthatthetypeofchitosanaffectstheflowbehaviorofafor-
mulation.
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Fig.2.Flowcurvesofchitosangels.
Oscillatory studies determine the viscoelastic property of the formulation by sub-
jectingthesampletosinusoidalshearstress.Theeffectsofchitosantypeandadditionof
an active substance on the viscoelastic properties, namely, storage modulus (G', a mea-
sure of elasticity) and loss modulus (G“, viscous components) of the formulations, are
displayedinFig.3.Ascanbeseen,thesechitosangelsarecharacterizedbylowerG'and
higher G“ values, pointing to a mainly viscous polymer solution containing a network
establishedbyphysicalentanglements.Also,atallfrequencyvaluesaliquid-likebehav-
iorisobserved,sotheviscouspropertiesaremorepronouncedthantheelasticones(22).
Similarliquidtypebehaviorhasbeenreportedforchitosangelsintheliterature(22–24).
ResultsofourrheologicalstudiesalsoshowedthattheadditionofMNorENhadno
significant effect on the flow behavior or viscosity values for all formulations (p > 0.05).
Mechanical properties of formulations
Vaginal semi-solid formulations should have appropriate mechanical properties
(e.g.,mucoadhesiveproperties,easeofapplication,lowhardness,andgoodretentionat
theapplicationsite)toprovidemaximumbenefitoftheformulationtothepatient(12).
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Fig.3.Effectsofchitosantypeandadditionofanactivesubstanceonstoragemodulus(G')and
lossmodulus(G“).
Therefore, vaginal bioadhesive gel formulations were evaluated according to their me-
chanical properties and the results are given in Table II.
Adhesiveness is the work required to detach the probe from the sample and is re-
lated to bioadhesion. Cohesiveness provides information on the effects of repeated
shearing stresses on the structural properties of formulations. Hardness expresses the
applicability of the gel to the desired site. Compressibility determines the extraction of
thegelfromthecontainerandthesimplicityofitsspreadabilityontheapplicationsite.
Elasticity represents the rate at which the deformed sample returns to its undeformed
condition.LowernumericalvaluesasdeterminedbytheTextureProfileAnalysis(TPA)
in elasticity mode indicate higher product elasticity (11). Formulations should have
goodadhesivenesspropertiestoremainonthevaginalmucosaforalongperiodoftime
and thereby decrease application frequency. On the other hand, compressibility and
hardnessvaluesoftheformulationsshouldbelowtofacilitateproductremovalfromthe
container and provide product comfort within the vaginal cavity.
As can be seen from Table II, increase in chitosan molecular mass and viscosity al-
tered the mechanical properties of all formulations. Formulations prepared with high
molecular mass hitosan exhibited the highest adhesiveness values. On the other hand,
thehardnessandcompressibilityvaluesoftheseformulationswere,asexpected,higher
than the others, which might be disadvantageous for their spreadibility on the vagina
and patient compliance. Hardness and compressibility of formulations prepared with
low molecular mass chitosan are low compared to other formulations. Nevertheless,
their adhesiveness is comparatively low, which might cause leakage during the use of
the formulation and restrict patient compliance.
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Briefly, the compressibility and hardness values of formulations should be low
whileadhesivenessandcohesivenessvaluesshouldbehigh.Also,formulationsshould
show lower numerical values of elasticity, which indicate higher product elasticity.
Based on the results of mechanical properties, gels prepared with medium molecular
masschitosanappearedtooffermoresuitablemechanicalpropertiesthangelsforvagi-
nal application prepared with low and high molecular mass chitosan.
In addition, the results showed that the addition of active substances in 1 or 2 %
concentrations did not significantly affect the adhesiveness, cohesiveness, hardness,
compressibility and elasticity of the formulations.
Results of syringeability studies
Theworkrequiredtoexpelsamplesfromasyringeisanotherimportantparameter
for practical administration of gels with a syringe. This parameter shows the force re-
quiredfortheapplicationofaformulationandaffectsclinicalpractice.Previously,Jones
et al., reported that increased product viscoelasticity (particularly elasticity) offered in-
creased resistance to product deformation in TPA. In syringeability analysis, this situa-
tioncausesanincreaseinworkrequiredforcompression/expulsionoftheformulation
(25).Ourresultsonelasticity,hardnessandsyringeabilitywereinaccordwiththisstudy
andtherankingwas:F3>F2>F1(TableII).Inaddition,significantincreasesinsyring-
ingworkwereobservedasthemolecularweightandviscosityofchitosanincreased(p<
0.05).F3requiredmostworktoexpeltheliquidformulationfromthesyringe(orappli-
cator),whichmightbedisadvantageousfortheeaseofadministeringformulationswith
asyringeorapplicator.Inaddition,theresultsshowedthatincorporationof2%MNor
1 % EN into chitosan gels had no significant effect on work required to expel formula-
tions from the syringe.
Results of mucoadhesion studies
Mucoadhesivepropertiesofformulationsplayanimportantroleinprolongingthe
residence time and mucoadhesion should be determined sensitively. ATA-XTplus tex-
ture analyzer can be used to measure mucoadhesion of formulations under simulated
vaginal conditions, based on the principle of applying tensile strength and shear stress
tobreaktheadhesivebondbetweenthetestsampleandamodelmembrane(26).There-
fore, the mucoadhesive properties of chitosan gels were determined with a TA-XTplus
texture analyzer equipped with the A/MUC measuring system.
The results of mucoadhesion studies are presented in Table II. Chitosan is a
well-known bioadhesive polysaccharide and its mucoadhesive properties are likely to
be based on its cationic character. The mucus layer exhibits anionic structures in sialic
acid and sulfonic acid form. Based on ionic interactions between the cationic primary
aminogroupsofchitosanandtheseanionicsubstructuresofthemucus,mucoadhesion
can be achieved. In addition, hydrophobic interactions might contribute to chitosan
mucoadhesive properties (4).
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