Research Article A Mucoadhesive Electrospun Nanofibrous...

Hindawi Publishing CorporationJournal of NanomaterialsVolume 2013 Article ID 924947 19 pageshttpdxdoiorg1011552013924947

Research ArticleA Mucoadhesive Electrospun Nanofibrous Matrix for RapidOramucosal Drug Delivery

Clare Dott Charu Tyagi Lomas K Tomar Yahya E Choonara Pradeep KumarLisa C du Toit and Viness Pillay

Department of Pharmacy and Pharmacology Faculty of Health Sciences University of the Witwatersrand7 York Road Parktown Johannesburg 2193 South Africa

Correspondence should be addressed to Viness Pillay vinesspillaywitsacza

Received 15 July 2013 Accepted 29 August 2013

Academic Editor Tong Lin

Copyright copy 2013 Clare Dott et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

A nanofibrous matrix system (NFMS) consisting of a drug-loaded nanofiber layer was electrospun directly onto a polymericbacking film the latter of which was formulated and optimized according to a 3-level 3-factor Box-Behnken experimental designThe dependent variables fill volume hydroxypropylmethylcellulose (HPMC) concentration and glycerol concentration wereassessed for their effects on measured responses disintegration time work of adhesion force of adhesion dissolution area undercurve (AUC) at 1 minute and permeation AUC at 3 minutes Physicochemical and physicomechanical properties of the developedsystem were studied by rheology FTIR toughness determination mucoadhesion and nanotensile testing Data obtained from thephysicomechanical characterization confirmed the suitability of NFMS for application in oramucosal drug deliveryThe optimizedNFMS showed the drug entrapment of 23mg15 cm2 with disintegration time of 128 seconds Electrospinning of drug-loadedpolyvinylalcohol (PVA) fibers resulted in a matrix with an exceedingly high surface-area-to-volume ratio which enhanced the rateof dissolution for rapid oramucosal drug delivery To corroborate with the experimental studies the incorporation of glycerol withHPMC and PVA blend was mechanistically elucidated using computer-assisted modeling of the 3D polymeric architecture of therespective molecular complexes to envisage the likely alignment of the polymer morphologies affecting the performance of thenanofibrous device

1 Introduction

Electrospinning has gleaned considerable interest in the fieldof drug delivery due to its proficiency in producing fiberswitheminently small diameters The process of electrospinninginvolves applying an electrical potential to a polymer solutionin order to produce very fine fibers in the nano- andmicrom-eter size range When a drop of polymer solution at the endof a capillary tube is subjected to an electrical potential thedrop elongates becoming conical in shape and once theelectrical field exceeds surface tension a fiber jet is ejectedfrom the tip of the cone [1ndash3] As the fiber jet travels throughthe atmosphere the solvent evaporates and solid polymerfibers are deposited on a grounded collector closing the gapbetween the capillary and collector and hence completingthe circuit [3 4] If the polymer concentration and henceviscosity and chain entanglements is too low the jet willbreak up into droplets before reaching the collector [5 6]

However as the concentration is increased the viscosity willincrease and chain entanglements will become sufficient forfiber formation resulting in a whipping motion of the jetand stretching and thinning of the fiber on application ofa potential Electrospun fibers display a small diameter andextremely high surface area to mass ratio [7 8] This isadvantageous in drug delivery as it results in an increase in thetotal drug release from drug-loaded fibers when compared tocast films of the same composition which have a considerablysmaller surface area [9 10] Furthermore a large exposedsurface area can greatly improve the dissolution rate andhence bioavailability of a drug [11ndash14] For adequate drugabsorption to occur via the buccal mucosa it is necessaryfor the drug concentration within the oral cavity to behigh Accelerated disintegration of an orally dissolving drugdelivery system results in a high concentration of drug atthe surface of absorption and therefore rapid and extensiveabsorption [15 16] Furthermore rapid absorption leads to

2 Journal of Nanomaterials

expeditious blood levels and hence a prompt onset of action[17ndash20] It has been demonstrated that the in vivo availabilityof a drug administered via the oramucosal route is greatlydependent on the disintegration rate of the drug deliverysystem [15]

During electrospinning the polymer chain orientationthat occurs during fiber formation has a significant effecton the physicomechanical properties of the nanofibrousmatrix that is formed [21] The fiber diameter has beenfound to affect the mechanical properties of electrospunmaterials [22] where fibers with smaller diameters displayeda greater strength but were less pliable than larger fibers[23] The physicomechanical properties of a material have asignificant effect on drug release [24] patient acceptability[25] and residence time at the site of absorption [26 27]Due to the relatively short residence time of an oramucosallyadministered drug delivery system at the site of absorptionmucoadhesion is often required [15] Mucoadhesive drugdelivery systems are advantageous in that the entire system isrendered immobile an intimate contact between the systemand buccal mucosa is created and a high drug concentrationat the absorption surface is achieved [15 27] This results ina reduction in the required drug concentration as well as animproved bioavailability [27] Thin mucoadhesive films arefavorable for oramucosal drug delivery due to the flexiblenature and high contact surface area of such films [15 28]

Statistical optimization by experimental design employsmathematical equations and graphic analysis in order tocharacterize and assess the effects of independent variableson measured responses [29] and was applied to this investi-gation In contrast to traditional approaches to formulationoptimization where one variable is assessed at a time statis-tical optimization utilizes fewer experimental runs which isless time consuming and provides a true optimized formula-tion by a systematic approach [29]

In thework outlined in this study drug-loaded fiberswereelectrospun directly onto a statistically optimized polymericbacking film in order to form a porous rapidly disintegratingnanofibrous matrix system (NFMS) for oramucosal drugdeliveryThe polymeric backing filmwas produced accordingto a Box-Behnken experimental designThe polyvinylalcohol(PVA) electrospun fibers were loaded with model drug di-phenhydramine in order to assess drug entrapment releaseand permeation characteristicsDrug-loaded films serving asa comparison were also prepared according to the same for-mula as the backing film and using the same constituents asthe electrospinning solutionThe effects of varying polymericconstituents on drug release drug permeation mucoadhe-sion and disintegration were also investigated in order toproduce an optimized oramucosal drug delivery system

2 Materials and Methods

21 Materials Polyvinylalcohol (PVA) (87ndash89 hydrolyzedMw 13000ndash23000 gmoL) and diphenhydramine (DPH)were purchased from Sigma-Aldrich (St Louis MO USA)Propan-2-ol glycerol and citric acid were purchased from

Table 1 Polymer concentrations and volumes used in film prepara-tion according to a Box-Behnken design

Formulationnumber

Fillvolume(mL)

HPMC(wv)

Glycerol (ww ofPVA + HPMC)

D1 40 050 125D2 100 025 150D3 40 025 150D4 70 025 125D5 70 050 100D6 100 050 125D7 40 025 100D8 70 025 125D9 70 000 100D10 100 000 125D11 70 000 150D12 70 025 125D13 70 050 150D14 40 000 125D15 100 025 100

Rochelle Chemicals (Johannesburg South Africa) Hydrox-ypropylmethylcellulose (HPMC) was purchased from Color-con Limited (London England)

22 Preparation of Polymeric Backing Films by Film CastingFilms intended as backing and mucoadhesive layers forelectrospunfiberswere prepared according to aBox-Behnkenexperimental design Polymer solutions were prepared bydissolving glycerol PVA and HPMC in a 4 1 mixture ofdeionized water and propan-2-ol The concentrations andvolumes used were as outlined in Table 1 For all the formu-lations the PVA concentration was used at 1wv Solutionswere syringed into rectangular flat-bottomedmoulds and leftunder an extractor at 21∘C for 48 hours in order that completesolvent evaporation and film formation could occur Forcomparative purposes a DPH-loaded film (FD) containingthe samepolymeric andplasticizer constituentswas prepared

221 Experimental Design A 3-factor Box-Behnken experi-mental design was generated by Minitab V15 (Minitab IncPA USA) in order to statistically optimize the polymeric filmlayer and analyze the effect of formulation variables on systemdisintegration and drug release The independent variables1198831 1198832 and 119883

3are outlined in Table 2 119884

1through to 119884

5

the dependent variables were disintegration time work ofadhesion (WA) maximum detachment force (MDF) disso-lution area under the curve (AUC) at 1 minute (AUCD) andpermeation AUC at 3 minutes (AUCP) respectively [30ndash32]

23 Preparation of Nanofibers by Electrospinning A drug-loaded solution for electrospinning was produced by dissolv-ing PVA citric acid DPH and glycerol in a 2 1 mixtureof water and propan-2-ol at concentrations of 25wv

Journal of Nanomaterials 3

Table 2 Test parameters employed in biaxial extensibility testing

Parameter SettingTest mode CompressionPretest speed 1mmsTest speed 1mmsPosttest speed 1mmsTarget mode DistanceDistance 10mmTrigger force 05N

2wv 10wvand 05 vv respectivelyThese quantities

were based on optimal fiber production reproducibilityand drug-loading proficiencies as will be explained laterin the paper The solution was placed in a 5mL pipettewhich was fitted into the adjustable supporting bracket of anelectrospinning device Electrospinning of the solution wasperformed at 20 kV with a tip-to-collector distance of 11 cmusing a custom-built electrospinning device (RGC Engineer-ing Sales Division Johannesburg South Africa) equippedwith a voltmeter and MJ Series High Voltage Power Supply(GlassmanHighVoltage Inc NJ USA) Fibers were collectedon the polymeric backing film secured on aluminum foil-lined board which formed the complete NFMS Sampleswere cut into sections For comparative purposes a film(FE) was prepared with the same drugpolymer ratio as theelectrospinning solution

24 Characterization

241 Scanning Electron Microscopy of the Drug-Loaded FiberLayer The surface structure of the electrospun fibers wasanalyzed by images produced by scanning electronmicrosco-py (SEM) using a Phenom Microscope (FEI CompanyHillsboro OR USA) Samples were mounted on stubs andsputter-coated with gold prior to examination

242 FTIR Spectroscopy FTIR spectroscopy was performedin order to assess structural changes that may have occurredin the polymeric backbone due to interactions of excipientsdrugs or polymers during film or fiber formation A Spec-trum 100 FT-IR Spectrometer (PerkinElmer Inc WalthamMA USA) was used to assess vibration characteristics ofchemical functional groups of samples in response to reac-tions with infrared light

243 Rheological Studies of the Components of the NFMSThe rheological properties of polymer solutions and hydratedNFMS FD and FE samples were determinedwith the use of aHaakeModularAdvancedRheometer System (ThermoFisherScientific Karlsruhe Germany)The stress-strain rheologicalparameters of the polymer solution have an influence on drugrelease electrospinning palatability and effect on saliva andthey are important factors when considering the desiredcharacteristics of the system Samples were analyzed byplacing the polymer solution or NFMSfilm sample hydratedin 1mL simulated saliva (pH 675) on the sample stageand immersing the spindle in the fluid The shear rate was

ramped from 0 to 500s and the shear forces and viscositiesof the samples were measured at 37∘C for the NFMS andfilm samples and at 25∘C for the electrospinning solutionThethixotropy of the 25wv PVA electrospinning solution wasdetermined by ramping the shear rate from 0 to 50s over 60seconds holding for 60 seconds and then decreasing back to0s over 60 seconds Oscillation studies were carried out bysubjecting samples to oscillating stresses or strains Oscilla-tion measurements were used to determine the storage mod-ulus 1198661015840 and the loss modulus 11986610158401015840 as a function of angularfrequency120596 Oscillation tests provide information on sampleelasticity and viscosity related to the applied frequency

244 Microenvironmental Surface pH Variation Studies ofthe NFMS Extreme changes in pH on the surface of thematrix can cause irritation to mucous membranes within theoral cavity [33] Measurement of the surface pH is thereforeessential Matrices were allowed to swell in contact with 1mLof simulated saliva (pH 675) The surface pH was measuredby glass microelectrode (Mettler Instruments Giessen Ger-many)Measurements were taken after thematrices had beenhydrated for 20 seconds and at 1 3 5 10 and 15 minutesthereafter

245 Toughness and Biaxial Extensibility Studies of theNFMSBiaxial extensibility was determined from force-distance pro-files generated using a TAXTplus Texture Analyser (StableMicro Systems London England) fitted with a 2mm flatcylindrical probe and a 5 kg load cell The method of testingthe extensibility was based on work by Sibeko and coworkers(2009) [34] The sample was secured onto a ring assemblywith a central hole (5mm diameter) which was attachedto a supportive hollow raised platform The setup wasplaced such that the cylindrical probe of the textural analyzerwas centralized over the hole The probe was lowered andembedded onto the sample according to the test parametersoutlined in Table 2

246 Mucoadhesion of the Optimized NFMS and Drug-Load-ed Films Mucoadhesion testing was performed on NFMSsections using a TAXTplus Texture Analyser (Stable MicroSystems London England) fitted with a cylindrical probePorcine buccal mucosal tissue was attached to the probeusing rubber bands and exposed to simulated saliva (pH675) The NFMS samples were attached to the stage directlybelow the probe Mucoadhesion was tested by measuringthe maximum detachment force (MDF) and the work ofadhesion (WA) (AUCFD) between the buccal mucosa and thesamples The pretest test and posttest speeds were 2 2 and10mms respectively An applied force of 50 g a trigger forceof 5 g and contact time of 5 seconds were used for the test

247 Tensile Studies of theOptimizedNFMSandDrug-LoadedFilms The tensile properties of samples weremeasured usinga nanoTensile 5000 (Hysitron Incorporated MinneapolisMN USA) Samples were cut into thin strips and mountedwith cyanoacrylate-based adhesive onto specially designedmounting brackets held together with rigid strips of card-board Once the sample had cured completely the width


length and thickness were measured with digital calipersThe sample and sample bracket were secured in the uppersample gripper on the nanoTensile (NT) head and the masswas measured The NT head was lowered and the axes werealigned in order to secure the bottom of the sample bracket inthe lower sample gripper The rigid cardboard supports wereeach cut on the marks in order to prevent the supports frominterfering with sample testing The mounting brackets weremoved apart at a constant rate of displacement and the tensileproperties of the sample were measured and recorded

25 Disintegration Time of the Optimized NFMS and Drug-Loaded Films The in vitro disintegration time of NFMSsamples and drug-loaded films (FD and FE) was determinedaccording to a modified method based on the United StatesPharmacopoeia (USP) method for tablet disintegration test-ing using a Type PTZ 1 basket-rack assembly disintegrationapparatus (Pharma Test Hainburg Germany) Accordingto the USP disintegration is considered to have occurredwhen there is no longer any solid residue left on the meshof the basket-rack assembly apparatus (USP 28 2005) Thedisintegration medium comprised 150mL simulated saliva(pH 675) placed in a glass jar submerged in a water bathmaintained at 37∘C Sampleswere cut into sections andplacedon the mesh of the basket rack assembly with a mesh discplaced on top The basket rack assembly was raised and low-ered through a distance of 55mm at a frequency of 25 cyclesper minute and the time taken for sample disintegration tooccur was determined by observation and recorded

26 Drug Entrapment of Optimized NFMS and Drug-LoadedFilms Samples of the NFMS and the two drug-loaded films(FD and FE) were cut into 15 cm2 sections dissolved in sim-ulated saliva (pH 675) and the drug content of each sectionwas analyzed by UV spectrophotometer (NanoPhotometerImplen GmbHMunchen Germany) at ambient temperature(25∘C) at lambda max of 260 nm

27 In Vitro Drug Release Standard USP tests and appara-tuses for in vitro dissolution and drug release testing requirelarge volumes of fluid which do not accurately reflect thein vivo conditions in the oral cavity where there is only asmall volume of fluid available for the dissolution of a drugdelivery system [35] A modified drug release testing methodwas therefore developed for the purposes of this study Invitro drug release was tested using a 10mm long magnetin a 35mm diameter petri-dish placed on a temperature-controlled magnetic stirrer 2mL of simulated saliva (pH675) was placed in the petri-dish maintained at 37∘C andstirred at a constant rate to ensure circulation of bufferNFMS FD and FE samples were cut into sections of samedimensions and placed in the buffer Samples were drawnat 0083 025 05 1 3 5 10 and 15 minutes analyzed byUV spectrophotometer and replaced by fresh buffer As abranded product comparison the in vitro dissolution testingof Sleepeze-PM tablets was performed using a rotating paddleapparatus (Model 7ST Caleva Frankfurt Germany) andemploying 900mL phosphate buffered saline (PBS) (pH 68

37∘C) Samples were drawn at 1 3 5 10 15 30 60 and90 minutes replaced with fresh buffer and analyzed byUV spectrophotometer (NanoPhotometer Implen GmbHMunchen Germany)

28 Ex Vivo Drug Permeation Studies Ex vivo drug per-meation testing was performed using porcine buccal tissuewhich is considered to have a closer resemblance to humanbuccal mucosa than other animal tissues [36] Porcine buccalmucosal tissue was obtained from a certified local abattoirand transported on ice to the laboratory within 1 hourExcess tissue was removed specimens were flash-frozen atminus40∘Cwith liquid nitrogen and stored atminus60∘Cuntil requiredfor use Frozen specimens were equilibrated in phosphatebuffered saline (PBS) (pH 74) at room temperature to thawSections of mucosa were mounted in Franz Type DiffusionCells (Perme Gear Inc Hellertown PA USA) and equili-brated for 05 hours at 37∘C by adding PBS (pH 74) to boththe acceptor and donor compartments After equilibrationthe PBS in the donor compartment was removed and wasreplaced with an NFMS FD or FE sample in simulated saliva(pH 675) A 2mgmL DPH in simulated saliva solution wasalso tested for comparative purposes Samples were drawnfrom the acceptor compartment at 033 1 2 3 5 10 15 and30 minutes and analyzed by UV spectrophotometry and theremoved volume was replaced with fresh PBS The apparentpermeability coefficient (119875app) and steady state flux (119869 ss ) val-ues were calculated using (1) and (2) respectively as follows

119875app =119876

119860 times 119888 times 119905 (1)

119869 ss =Δ119872

119860 times Δ119905 (2)

where 119876 is the total amount of drug permeated duringthe testing time (120583g) 119860 is the diffusional area (cm2) 119888 isthe initial drug concentration in the donor compartment(120583gmL) 119905 is the total time that the experiment was run for(seconds) andΔ119872 is the amount of drug that had permeatedthrough the mucosal tissue during time Δ119905

29 Atomistic Molecular Structural Mechanics SimulationsMolecular mechanics computations in vacuum which in-cluded the model building of the energy-minimized struc-tures of multipolymer complexes were performed usingthe HyperChem 808 Molecular Modeling System (Hyper-cube Inc Gainesville FL USA) and ChemBio3D Ultra110 (CambridgeSoft Corporation Cambridge UK) [37] ThePVA decamer was drawn using ChemBio3D Ultra in itssyndiotactic stereochemistry as a 3D model whereas thestructure of HPMC (4 saccharide units) was built fromstandard bond lengths and angles using sugar buildermoduleon HyperChem 808 The oligosaccharide length for thepolysaccharide chain was determined on the basis of equiva-lent grid surface area covered by the polysaccharide so thatthe inherent stereoelectronic factors at the interaction sitecan be perfectly optimizedThe set of low-energy conformersthat were in equilibrium with each other was identified and


portrayed as the lowest energy conformational model Thestructure of glycosylated mucopeptide analogue (MUC) wasgenerated using sequence editor module on HyperChem808 The glycosylation was carried out at the threonineand serine amino acid residues The structure of glycerol(GLY) was built up with natural bond angles as defined inthe Hyperchem software The models initially minimizedusing the MM+ Force Field were energetically optimizedusing the AMBER 3 (Assisted Model Building and EnergyRefinements) Force Field The conformer having the lowestenergy was used to create the polymer-polymer complexesA complex of one molecule with another was assembled bydisposing them in a parallel way and the same procedure ofenergy-minimizationwas repeated to generate the finalmod-els Full geometry optimizations were carried out in vacuumemploying the Polak-Ribiere conjugate gradientmethod untilan RMS gradient of 0001 kcalmoL was reached Force fieldoptions in the AMBER (with all hydrogen atoms explicitlyincluded) and MM+ (extended to incorporate nonbondedcut-offs and restraints) methods were the HyperChem 808defaults For calculations of energy attributes the force fieldswere utilized with a distance-dependent dielectric constantscaled by a factor of 1 The 1ndash4 scale factors are the followingelectrostatic 05 and van der Waals 05 Invariant factorscommon to mathematical description of binding energy andsubstituent characteristics have been ignored [37]

3 Results and Discussion

31 Response Optimization All the NFMS prepared throughinclusion of 15 different formulations of polymer backingfilm were analyzed in terms of disintegration time work ofadhesion (WA) maximum detachment force (MDF) areaunder the curve (AUCD) at 1minute and area under the curve(AUCP) at 3 minutes which are graphically represented inFigure 1

Response optimization was performed using MinitabV15 (Minitab Inc PA USA) The film formulation wasoptimized according to the measured responses Maximizingand minimizing responses where appropriate resulted in alow desirability for the optimized formulation and the valueswere therefore targeted within the limits of acceptability Thefinal optimization plot revealed a composite desirability of9523 Tables 3 and 4 display the fitted values acquired fromformulation optimization with the observed experimentalvalues for the various responses

For optimized film preparation polymer solutions wereprepared by dissolving 1365mg of glycerol 794mg ofpolyvinylalcohol (PVA) and 116mg of hydroxypropyl-methylcellulose (HPMC) in 7939mL of a 4 1 mixture ofdeionized water and propan-2-ol

32 Physical Dimensions of the Films and Fiber Layer Thefilms produced were even thin transparent and pliable Thefibers formed a white layer on the films The NFMS backinglayer film was 80120583m thick while the complete NFMS was460 120583m thick and hence the fiber layer was 380 120583m thickThe

Table 3 Targeted responses for constrained optimization of the filmformulation

Response Lower Target UpperDisintegration time (seconds) 12 13 20Work of Adhesion (mJ) 03 04 07Maximum detachment force (N) 02 03 045AUCD at 1 minute 03 035 045AUCP at 3 minutes 16 19 2

Table 4 Fitted and experimental values for the optimizationresponses

Response Fittedvalue

Experimentalvalue Desirability

Disintegration time(seconds) 132457 128 966

Work of adhesion (mJ) 03885 0335 862MaximumDetachment force (N) 03043 02705 889

AUCD at 1 minute 03491 04179 835AUCP at 3 minutes 18885 20860 905

FE film was 110 120583m thick and the FD film was approximately90 120583m thick but was somewhat uneven in places

33 Scanning Electron Microscopy SEM analysis revealedthat the fibers produced were randomly arranged havinguniform diameters on average The fiber diameter wasapproximately 036 120583m and the average visible pore sizeranged between approximately 069 and 191 120583m as depictedin Figure 2

34 FTIR Spectroscopy FTIR analysis was performed inorder to determine whether any chemical changes occurredto the drug andor polymer during the process of elec-trospinning The FTIR spectra for the DPH-loaded fiberlayer (DF) DPH and non-drug-loaded PVA placebo fibers(PF) are depicted in Figure 3 The broad OndashH stretchingvibration of PVA can clearly be seen for both DF and PF at3295 cmminus1 DPHandDFboth show a small peak at 3033 cmminus1characteristic of the phenyl groups present in the DPHmolecule (Figure 3) The phenyl groups are also identified bythe presence of large peaks at 755 cmminus1 and 702 cmminus1 in bothprofiles where DPH was present The peak associated withthe stretching vibration of the alkoxy substituent in the DPHmolecule at 2955 cmminus1 is obscured by the slightly broaderband of the alkyl group of the PVA molecule at 2913 cmminus1 inthe DF spectrum which can also be seen in the PF spectrumThe broad peaks at 2594 cmminus1 2524 cmminus1 and 2487 cmminus1in the DPH spectrum representative of the tertiary aminegroup are also visible in the DF spectrum but not in the PFspectrum The peak at 1598 cmminus1 indicating the absorptionfrom the phenyl groups is visible in both the DPH and DFspectra From the FTIR data it can therefore be deduced thatno significant chemical changes occurred to the drug duringsolution preparation and electrospinning


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Figure 1The 15 experimental design formulations depicting (a) average disintegration times (b) average work of adhesion (WA) (c) averagemaximum detachment force (MDF) (d) AUCD at 1 minute and (e) AUCP at 3 minutes

35 Rheological Studies of the Components of the NFMS

351 Formulations The rheological properties of a hydratedsample play an important role in the retention of that samplewithin the buccal cavity The hydrated film and NFMSsamples were investigated for the effect of an increasing shearrate ( 120574) on shear force (120591) and viscosity (120578)The average valuesover the shear rate range for these parameters are outlined inTable 5 Linear rheological profiles are depicted in Figure 4The FE film (Figure 4(c)) exhibited an exceedingly largeraverage viscosity and shear force than theNFMS (Figure 4(a))and FD film (Figure 4(b)) which correlates with the greatermucoadhesive properties and slower disintegration rate

evinced by this filmHowever such a high viscositymay resultin an unpleasant mouthfeel in vivo [38] The large disparitybetween the parameters of the NFMS and FE film may bedue to the more rapid disintegration rate of the formerNevertheless the rheological properties of the NFMS suggestthat it would have an adequate retention time which is inagreement with the mucoadhesion data reported in a latersection

352 Electrospinning Solution The rheological properties ofa solution employed for electrospinning can have a substan-tial effect on the process of electrospinning as well as the


Figure 2 SEM image of the electrospun fiber layer showing averagefiber diameter of 036 120583m and visible pore size of between 069 and191 120583m

1000200030004000

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smitt

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DPH-loaded fibers Placebo fibers DPH

Figure 3 FTIR profiles of the drug-loaded fibers (DF) placebofibers (PF) and DPH

Table 5 Average rheological parameters of the NFMS FD film andFE film in 1mL simulated saliva (pH 675)

Sample Shear rate (1s) Shear force (Pa) Viscosity (mPasdots)NFMS 2543 744 3229FD 2523 739 3049FE 2532 8271 161667

quality and morphology of fibers that are formedThe degreeof polymer chain entanglements and hence the polymerconcentration has a considerable influence over the viscosityof a solution The actual conformation of individual polymerchains also has a significant influence on solution viscosityconsidering that solutions containing coiled chains have alower viscosity than those with extended chains [39] It istherefore important to investigate the rheological properties

of polymeric solutions employed in electrospinning The25wv PVA solution that was electrospun to form the fiberlayer of the NFMS was analyzed for responses to rheologicalstresses both linear and oscillating The average shear force(120591) and viscosity (120578) were 18640 Pa and 7375mPasdots respec-tively for an average shear rate ( 120574) of 2523s Figure 5 displaysthe rheological profile The linear rheological properties ofthe 25wv solution were deemed acceptable for electro-spinning because adequate fiber formation occurred at thatpolymer concentration

Thixotropy is observed when the viscosity of a materialthat was at rest decreases on exposure to a mechanical stressand consequently increases again upon removal of the stressThe thixotropy of the 25wv PVA electrospinning solutionwas determined by calculating the difference between theAUC values of the increasing shear and decreasing shearrate curves and was determined to be minus1229 Pasdotsminus1 Thisdifference is relatively small when compared to the averageAUC which was 7574 Pasdotsminus1 and it was deduced that theelectrospinning solution underwent adequate thixotropicrecovery Figure 5(b) displays the thixotropy curve for the25 PVA solution The curves of shear stress as a functionof shear rate (blue line) for both increasing and decreasingrates follow an almost identical path and appear as one thickline suggesting a favorable recovery of the sample

Viscoelasticity is an important factor to be consideredfor the electrospinning of a polymer solution as the polymeris required to be stretched in order to produce fibers Itis necessary for the elastic properties of a solution to begreat enough so that the fiber jet will not break up beforereaching the collector surface Oscillation rheology testing isa useful tool for assessing the viscoelastic behavior of mate-rials intended for electrospinning The yield stress (120591

119900) was

determined for the 25wv PVA electrospinning solutionat 25∘C by measuring the deformation (120574) over a range ofcontrolled stress (120591) The average yield stress was 03782 Paand the rheological plot is depicted in Figure 5(c) In orderto determine the viscoelastic region of the 25wv PVAelectrospinning solution a stress sweep was performed atvarious frequencies to ascertain the yield point The yieldpoint was found to be 636 Pa at a frequency of 01 Hz Afrequency sweep was performed in order to determine thestability of the 25wv PVA solution The frequency ofoscillations ranged from8 to 0008Hz at a constant stressTheresulting plot is presented in Figure 5(d)

36 Microenvironmental Surface pH Variation of the NFMSIt has been observed that extreme changes in surface pHmay cause damage to mucosal surfaces [40] The evaluationof surface pH variation is therefore an important factor toconsider for oramucosal drug delivery system The surfacepH values of NFMS ranged between 663 and 675 over the 15minutes in whichmeasurements were taken (Figure 6)Therewas an initial drop in pH to 663 at the 20 second time pointpossibly due to dissolution and subsequent solubilization ofcitric acid which was employed in the formulation as a taste-masking component At the 3 minute time point the pH had


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(c)

Figure 4 Linear rheological profiles of the (a) NFMS (b) FD film and (c) FE film

increased to 673 which may be due to the buffering effect ofthe simulated saliva or the dissolving of the polymeric com-ponents of the formulationThe variation of pHwas less than05 units and was considered acceptable for an oramucosallyadministered drug delivery system as it can be deduced thatminimal irritation to the buccal mucosa would occur

37 Toughness and Biaxial Extensibility Studies of the NFMSExtensibility is the degree of extension or stretching thata material can withstand before fracture occurs polymerlinkages have a substantial effect on the physicomechani-cal strength of materials The maximum force (119865max) anddistance (119863max) values for the NFMS optimized polymerbacking film of the NFMS (NFMS film) FD film and FEfilmwere plotted and are presented in Figure 7The complete

NFMS was found to be slightly stronger than the NFMS film(119865max = 529N and 517N resp) but also less extensible(119863max = 4435 and 4957mm resp) It can therefore bededuced that the presence of electrospun fibers resulted in aslight increase in film strength and a decrease in extensibilityWhen electrospunfibers are produced there is a thinning andextending process that takes place and this may result in thefibers being less extensible than the filmThe presence of drugin the polymer backing film (FD) brought about a decreasein both 119865max and 119863max This may also partially explain thereduction in extensibility with the presence of a drug-loadedfiber layer The FE film had a significantly larger 119865max and119863max than the NFMS whichmay be due to the absence of themore rigid polymer HPMC and formation by film castingwhich does not result in thinning of the former


0 100 200 300 400 500

120574 (1s)

400

350

300

250

200

150

100

50

0

120591(P

a)

743

742

741

740

739

738

737

736

120578(m

Pas)

25 PVA std flow C120591 = f(120574)

120578 = f(120574)

(a)

35

30

25

20

15

10

5

00 10 20 30 40 50

0

200

400

600

800

1000

1200

120591(P

a)

120578(m

Pas)

120574 (1s)25 PVA thixotropy A

120591 = f(120574)

120578 = f(120574)

(b)

1000000

100000

10000

10000

1000

1000

100

100

10

1001

01 Yieldstress

120574(mdash

)

120591 (Pa)Yield stress 25 PVA A

120574 = f(120591)

(c)

10000000

1000000

100000

010000

001000

000100

000010

000001

G998400

(Pa)

G998400998400

(Pa)

100001000100010001

120596 (rads)

G998400 = f(120596)G998400998400 = f(120596)

Frequency sweep PVA 25 8-0 008 S15

(d)

Figure 5 (a) Linear rheological profile of 25wv PVA electrospinning solution (b) thixotropy curve for the 25wv PVA solution usedfor electrospinning (c) rheology plot depicting the yield stress (at 03782 Pa) of a 25wv PVA solution intended for electrospinning and(d) stress sweep of 25wv PVA solution intended for electrospinning

Table 6 Experimental values obtained from nanotensile analysis

SampleYoungrsquosmodulus(MPa)

Yieldstress(MPa)

Ultimatestrength(MPa)

Ultimatestrain

Toughness(Jcm3)

Fiber layer 2609 049 298 0227 038NFMSfilm 3601 1675 333 0242 062

NFMS 3031 118 279 0238 048FD 5635 113 273 0314 071FE 2034 110 352 0731 210

38 Tensile Properties by Nanotensile Testing The stress-strain relationship of a material is highly dependent on theflexibility of the polymer chains and the strength of thematerial When only a small amount of stress is required toproduce a large amount of strain thematerial is considered tobe flexible and Youngrsquosmodulus which is the slope of the lin-ear portion of the stress-strain curve will be relatively smallThe average experimental values for Youngrsquos modulus (119864)yield stress (120590

119910) ultimate strength (120590

119906) ultimate strain (120576

119906)

and toughness (119906119891) are outlined inTable 6The samples tested

were the fiber layer of theNFMS (Figure 8(a)) theNFMSfilm(Figure 8(b)) the complete NFMS (Figure 8(c)) the FD film(Figure 8(d)) and the FE film (Figure 8(e))The drug-loadedfiber layer exhibited the smallest yield stress ultimate strain


Time (min)0 2 4 6 8 10 12 14

pH

65

66

67

68

69

70

Figure 6 Average pH variation over time for the NFMS hydratedin simulated saliva (pH 675) (119899 = 3 SD lt 001)

FMS film FMS FD FE

Max

imum

forc

e (N

)M

axim

um d

istan

ce (m

m)

0

2

4

6

8

10

12

Force Distance

Figure 7 Vertical bar chart outlining average maximum forceand distance values for the film of the nanofibrous matrix system(NFMS) the complete NFMS drug-loaded NFMS film (FD) andcomparator film containing the same components as the electro-spinning solution (FE)

and toughness (Figure 8(a)) Youngrsquos modulus of the fiberlayer was greater than that of the FE film (Figure 8(e)) butsmaller than the other tested samples suggesting that it wasmore flexible than the film onto which it was incorporatedbut less flexible than the FE film When compared to theFE film which was prepared using the same components atthe same ratios the fiber layer was found to have a largerYoungrsquos modulus and a considerably smaller yield stressultimate strength ultimate strain and toughness as well asa smaller elastic region (green portion of nanotensile profile)which may be attributed to the elongating forces experiencedby polymer chains during electrospinning [21 41] When apolymer is exposed to greater elongating forces the fibers thatare formed will have smaller diameters which have also beenassociated with a larger Youngrsquos modulus and hence a greaterstiffness It can therefore be deduced that the differencesbetween the tensile properties of the fiber layer and the

FE film are due to polymer chain stretching during fiberformation The NFMS film revealed slightly larger valuesthan the fiber layer for the various responses determinedduring nanotensile testing (Figure 8(b)) This may be dueto the presence of the more rigid polymer HPMC in thefilm The profile for the NFMS revealed two distinct pointsof fracturemdashthe first one being the point at which the fiberlayer fractured and the second where the film layer fractured(Figure 8(c)) The FD film (Figure 8(d)) which is the DPH-loaded NFMS film featured a substantially larger Youngrsquosmodulus than the NFMS film suggesting that the presenceof DPH in the formulation enhanced the rigidity of the film

The results of nanotensile testing were in agreement withthe extensibility results in the previous section Howeverthe two tests were performed disparately and with varyingsensitivity The extensibility test utilized a large sample areaimbedded a probe into the sample until fracture and mea-sured the force-distance relationship whereas the nanotensiletest employed only a small sample area pulled the sampleapart until fracture and measured the stress-strain relation-ship from which various parameters such as Youngrsquos mod-ulus yield stress and toughness could be calculated Whileboth tests are useful the nanotensile test was more applicablefor this particular formulation due to the method of testingtype of results produced and the augmented sensitivity of thetest

39Mucoadhesive Properties Theaveragemaximumdetach-ment force (MDF) and work of adhesion (WA) were deter-mined from the peak and AUC respectively of the force-distance profiles generated by mucoadhesive testing Table 7outlines the values of MDF and WA for the NFMS filmnanofibrous layer and the drug-loaded films (FD and FE)The backing film of the NFMS exhibited an adequate MDFandWAThe nanofibrous layer was observed to be somewhatmore mucoadhesive than the film however due to the rapiddisintegration rate of the fibers the backing film is requiredto hold the system in place and ensure that the released drugis detained at the buccal mucosa until absorption occursTheFE film was found to have a considerably larger MDF thanthe nanofibrous layer of the NFMS This may be attributedto the rapid disintegration rate of the fibers resulting in lessof the formulation being available in its original form at thepoint in time whenmucoadhesion wasmeasured as opposedto the slower disintegration rate of the FE film In comparisonto the NFMS film layer the FD film displayed an exceedinglysmaller MDF and WA From this it can be deduced that theaddition of drug to the film formulation resulted in a reduc-tion in mucoadhesiveness The disparity between the MDFand WA values of the NFMS backing film and the FE filmmay be due to the presence of HPMC in the NFMS film for-mulationHPMChas poorly flexible chains due to a high glasstransition temperature and is therefore poorly mucoadhesive[42] and hence the addition ofHPMC to the film formulationwill decrease the mucoadhesive strength of the resulting film

310 Disintegration Time of the Optimized NFMS and Drug-Loaded Films The time taken for the NFMS and the FDand FE films to disintegrate was 128 seconds 158 seconds


3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)

Figure 8 Stress-strain nanotensile profiles of the (a) drug-loaded fiber layer of NFMS (b) film of NFMS (c) complete NFMS (d) FD film(drug-loaded) and (e) FE film (drug-loaded)


Table 7 MDF and WA for the matrix and different films understudy

Formulation MDF WANFMS film 02705 0335NFMS nanofibrous layer 02982 0601FD 00468 0041FE 03867 0599

FMS Fiber layer FD FE

Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60

Figure 9 Disintegration times of the nanofibrous matrix system(NFMS) fiber layer of the NFMS drug-loaded optimized film (FD)and film formed from the same components as the electrospinningsolution (FE) (119899 = 3 SD lt 1)

and 526 seconds respectively and is depicted graphically inFigure 9 The DPH-loaded fiber layer of the NFMS took anaverage of 36 seconds to disintegrate which is considerablyshorter than the time taken for the drug-loaded films orthe NFMS to disintegrate This very short time period ofdisintegration may not suffice or correlate with the optimumtime required for the absorption of the released drug throughoramucosa and may result in poor bioavailability of thedrug due to swallowing of major drug content In orderto keep the drug at the surface of absorption and preventswallowing the backing film layer in NFMS should remainintact for a longer period of time than the fiber layerHowever if the film remains intact for too long it mayresult in poor mouthfeel and affect patient acceptability Thepolymer backing film supports the fiber layer and retains itfor an optimum extended period of time as seen in Figure 9ensuring maximum drug absorption without compromisingthe patient compliance

311 Drug Entrapment and InVitroDrugRelease Theaveragedrug entrapment of the NFMS FD and FE films was deter-mined as 23mg plusmn 044mg 88mg plusmn 011mg and 55mg plusmn048mg respectivelyThe optimized NFMS exhibited a rapiddissolution rate with an average of 63 of the loaded dosereleasing in 1 minute and 86 in 3 minutes In comparisonthe FD and FE films released 27 and 17 of the loadeddose in 1 minute and 48 and 46 at 3 minutes respec-tively The drug release profiles are depicted in Figure 10(a)It is apparent that the dissolution rate of the NFMS is

significantly more rapid than that of either of the drug-loaded films owing to the extremely high surface area of thenanofibrous layer in comparison with films [8 10] whichenhances the rate of disintegration and dissolution [14]Figure 10(b) compares the drug release profiles of the NFMSand the branded comparator product Sleepeze-PM the laterdisplaying a relatively rapid drug release with 31 and 55 ofthe loaded dose releasing after 1 and 3 minutes respectivelyHowever the optimized NFMS exhibited a superior drugrelease profile in a considerably smaller volume of bufferwhich makes it preferable to the conventional system on themarket in terms of its rapid action

The area under the curve (AUCD) at 1 minute wascalculated forthe NFMS FD and FE films and Sleepeze-PMtablets and it is illustrated in Figure 10(c) The AUCD of theNFMS is nearly 3 times greater than that of the FD film andSleepeze-PM tablets and approximately 5 times greater thanthe AUCD of the FE film Hence it can be deduced that drugrelease from the NFMS occurs more rapidly than from any ofthe tested comparison formulations

312 Ex Vivo Drug Permeation Studies Ex vivo drug per-meation where conditions are as similar as possible toin vivo circumstances is a valuable study to conduct inorder to determine the expediency of employing a particulardrug or drug delivery system for buccal administration[43] Figure 11(a) depicts the flux profiles of the NFMS a2mgmL DPH solution and the drug-loaded films FD andFE The DPH solution exhibited a slightly greater flux thanthe NFMS with 79 and 78 of the loaded dose permeatedat 3 minutes respectively The FD and FE films displayeda lower flux than the NFMS where 74 and 55 of theloaded dose had permeated after 3 minutes respectivelyThisis in agreement with the in vitro dissolution data PermeationAUC (AUCP) at 3 minutes was calculated for the testedformulations and plotted as in Figure 11(b) AUCP of the2mgmL DPH solution was slightly greater than that for theNFMS suggesting that the rate of permeation of drug fromsolution was onlymarginally faster than that from theNFMSThe FE film exhibited the smallest AUCP value and the valuefor the FD film was between that of the NFMS and FE filmThe rate of drug permeation from the DPH-loaded filmswas somewhat slower than that from the NFMS or the drugsolution

The apparent permeability coefficient (119875app) and steadystate flux (119869ss) values were calculated for the tested formu-lations and are outlined in Table 8 These values were inaccordance with those for AUCP of the various formulationswith the FE film exhibiting the smallest119875app and 119869ss values andthe DPH solution having the largest 119875app and 119869ss values

313 Molecular Mechanics Assisted Model Building and Ener-gy Refinements Molecular mechanics energy relationship(MMER) a method for analytico-mathematical represen-tation of potential energy surfaces was used to provideinformation about the contributions of valence terms non-covalent Coulombic terms and noncovalent van der Waals


10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FMSSleepeze-PM tables

(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)

Figure 10 (a) Drug release profiles of the nanofibrous matrix system (NFMS) and the drug-loaded films FD and FE (119899 = 3 SD lt 004)(b) Comparative drug release profiles of the nanofibrous matrix system (NFMS) and Sleepeze-PM tablets (119899 = 3 SD lt 004) and (c) AUCDcomparison between the NFMS comparator DPH-loaded film formulations (FD and FE) and Sleepeze-PM tablets (119899 = 3 SD lt 002)

interactions for the plasticizerpolysaccharideprotein mor-phologies and interactions TheMMERmodel for the poten-tialsteric energy factors in various molecular complexes canbe written as

119864moleculecomplex = 119881Σ = 119881b + 119881120579 + 119881120593 + 119881ij + 119881hb + 119881el (3)

119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb

[Δ119864 = minus10565 kcalmoL]

(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593

minus 29066119881ij minus 7096119881hb minus 261649119881el

(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)

FMS DPH solution FD FE

24

22

20

18

16

14

AUC

Pat3min

(b)

Figure 11 (a) Drug permeation profiles of the matrix system (NFMS) the drug solution and the drug-loaded film formulation (FD andFE) (119899 = 3 SD lt 01 in all cases) and (b) plot depicting AUCP at 3 minutes for the nanofibrous matrix system (NFMS) DPH solution andDPH-loaded film formulation (FD and FE) (119899 = 3 SD lt 002 in all cases)

119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb

minus 276724119881el [Δ119864 = minus39028 kcalmoL] (11)

119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)

119864HPMCPVAMUC = minus170567119881Σ = 8098119881b + 91792119881120579

+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)

where 119881Σis related to total steric energy for an optimized

structure 119881b corresponds to bond stretching contributions(reference values were assigned to all of structurersquos bondlengths) 119881

120579denotes bond angle contributions (reference

values were assigned to all of structurersquos bond angles)119881120593rep-

resents torsional contribution arising from deviations fromoptimum dihedral angles 119881ij incorporates van der Waalsinteractions due to nonbonded interatomic distances 119881hbsymbolizes hydrogen-bond energy function and 119881el standsfor electrostatic energy In addition the total potential energydeviation Δ119864total was calculated as the difference betweenthe total potential energy of the complex system and the sumof the potential energies of isolated individual molecules asfollowsΔ119864Total (119860119861) = 119864Total (119860119861) minus (119864Total (119860) + 119864Total (119861)) (14)

Table 8 Calculated apparent permeability coefficient (119875app) andsteady state flux (119869ss) values for the formulations under study

Formulation 119875app 119869ss

NFMS 49 times 10minus4 588DPH solution 50 times 10minus4 595FD 47 times 10minus4 560FE 34 times 10minus4 411

Themolecular stability can then be estimated by compar-ing the total potential energies of the isolated and complexedsystems If the total potential energy of complex is smallerthan the sum of the potential energies of isolated individualmolecules in the same conformation the complexed form ismore stable and its formation is favoured [44]

3131 Energy Computations for PolymerPlasticizer Com-plexes Using Atomistic Simulations Themolecular confirma-tions obtained from the simulation of HPMC PVA and glyc-erol (GLY) are represented by Figure 12 Table 9 and (4)ndash(9)The effects of blending PVA with HPMC (HPMCPVA) andglycerol with HPMC (HPMCGLY) and blending all threealtogether are elucidated herein It is evident from the energycomputations that all the three complexes are well stabilizeddue to minusve Δ119864 ((4)ndash(9)) HPMC contains interactive oxygencontaining groups in the form of ndashCndashOndashCndash (both in thering and the methyl side chain) and hydroxyl group for pos-sible association with glycerine molecules Specifically theoxofunctionalities of HPMC and the hydroxyl functionalityof glycerine may interact with directional orientation actingat adequately short distances (Figure 12(a)) H-bonding andvanderWaals attractive interactions resulting in energymini-mization of 28318 kcalmol Similarly in case ofHPMCPVAthe hydroxyl group of PVA interacted with ndashCndashOndashCndashmoiety


Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)

Figure 12 Visualization of geometrical preferences of (a) HPMCglycerol complex (b) HPMCPVA complex and (c) HPMCPVAGlycerolcomplex and (d) connolly molecular electrostatic potential surfaces in translucent display mode showcasing the trimolecular complex aftermolecular simulationThe atoms involved in H-bonding are emphasized by space filling model (dots) Color codes for elements are C (cyan)O (red) and H (white)

Table 9 Molecular mechanics evaluation of the surface-to-volume ratio and density of pure polymers and blends

Molecular complex Surface area (A2) Volume (A3) SVR Mass (amu) Density (amuA3)HPMC 137470 265535 05177 99315 03740PVA 78580 132724 05920 44255 03334Glycerol 98204 133336 07365 36836 02762HPMCPVA 154878 347673 04454 143569 04129HPMCGLY 143669 324783 04423 136153 04192HPMCPVAGLY 162486 405257 04009 180407 04452SVR surface-to-volume ratio

of HPMC with an energy minimization of 10565 kcalmoL(Figure 12(b)) Furthermore we carried out the full simula-tion of HPMCPVAGLY to see whether the individual blendinteractions still persist or not It is evident from Figure 12that apart from all the previous H-bonding interactions PVAalso interacted with GLY forming a GLY-HPMC-GLY-PVA-GLY complex (Figure 12(c)) resulting in an even higher stabi-lization of potential energy (Δ119864 = minus42515 kcalmoL) In allthree blend simulations the nonbonding London dispersion

hydrophobic forces dominated the overall contribution fromall the energy terms further explaining the vigorous geomet-rical conformational requirements desirable for the networksbetween these polymerplasticizer fragments (Figure 12(d))

In addition the molecular attributes in terms of surface-to-volume ratio (SVR) and final density corroborated withthe above findings with HPMCPVAGLY having lowestSVR followed by HPMCGLY and HPMCPVA (Table 9)The lower the surface-to-volume ratio the more stable


MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)

Figure 13 Visualization of geometrical preferences of (a) PVAMUC complex (b) HPMCMUC complex and (c) HPMCPVAMUClcomplex aftermolecular simulationThe atoms involved inH-bonding are emphasized by space fillingmodel (dots) Color codes for elementsC (cyan) O (red) N (blue) and H (white)

the structure In this study initial models were developedemploying a derivative approach based on average-densityfunction of the pure systems Considering the polymer-polymerpolymer-plasticizer system a substantial increasein the network density was detected as compared to theaverage of the component individual molecules with densityvalues ranging from 04129 through 04192 to 04452 amuA3for HPMCPVA HPMCGLY and HPMCPVAGLYrespectively Interestingly these density increments are incorroboration with the appearance of specific interchainnetworking forming a miscible interphase in between thethree molecules [45] Thus we conclude that the energy

stabilization low SVR and high density lead to highlyefficient plasticization of the HPMCPVA backing film byglycerol The observations so obtained were in accordancewith previously reported results by Sakellariou et al 1993where the plasticizerrsquos efficiency was defined in relation tothe tendency of the polymer-plasticizer set to form polar aswell as hydrogen-bonding interactions [46]

3132 Prediction of Mucoadhesive Potential of the BackingLayer The bioadhesive or mucoadhesive potential of theNFMS was determined by measuring the detailed chemicalinterfaces between the individual polymers (HPMC and


PVA) or polymeric matrix (HPMCPVA) and the glycosy-lated oromucopeptide analogue after geometrical optimiza-tion using energyminimizations HPMC and PVA are knownto bemucoadhesive polymers andmay impart bioadhesion tothe drug delivery system [47]

As per the energy consideration a collective phenome-non comprising van der Waals forces electrostatic interac-tions andH-bonding in the form of nonbonding interactionswas reported ((4) (5) and (10)ndash(13)) This contributed to astress transduction necessitating the establishment of con-nectivity between chemically conformed regions via inter-active surface generation Interestingly the inherent bindingenergies of the polymer matrices with MUC were quite highranging from minus14028 through minus39028 to minus58641 kcalmoLin case of PVAMUC HMPCMUC and HPMCPVAMUCconfirming the significant interactions among the polymerentities and the oromucopeptide (Figure 13 and Table 9) Theminimized energy increased significantly after introducingboth the polymers together in the MUC-polymer systemleading to a comparatively stabilized conformation Addi-tionally the H-bonds formed between the polymer matrixand the MUC were increased in case of trimolecular system(Figure 13) A deeper inspection revealed the existence ofhydrophobic interactions in the form of methyl groups (frommucopeptide residues) networkingwith oxofunctionalities ofthe constituent polymers (Figure 13)

The experimental mucoadhesion studies can be corre-lated to these in silico findings As explained earlier in thepaper the mucoadhesion due to hydrophilic polymers isusually accompanied by a ldquoregion of maximumrdquo where itis dependent on the concentration of the polymer such asHPMC in the present case The contour plot depicted aninitial increase in mucoadhesion with increase in the amountof polymers up to the intermediate levels and decreases there-after The possible explanation to this is that the HPMCPVAbacking film may readily absorb water while in contact withhydrated mucous membrane leading to swelling of the poly-mer matrix and may progressively become rubbery becauseof extensive uncoiling of polymeric chains Furthermore thismay result in an increase in the mobility of the polymerfragments producing a wide-spread adhesive surface whichmay thus present with maximum contact area for mucosa tointeract and may additionally provide flexibility to the poly-mer chains for mucosal interpenetration [48] On contrary afurther increase in the amount of these hydrophilic polymersmay render the network structure too dense and less flexible(due to high glass transition temperature as described inmucoadhesion section) to hold the tethered mucous chainsthereby decreasing the mucoadhesion [48] Glycerol mayfurther enhance the mucoadhesion by providing a stabilizedand flexible system as postulated in the polymerplasticizercomplexes and also by providing additional hydroxyl bondsto form H-bonds with the mucopeptide

4 Conclusions

Mucoadhesive drug-loaded electrospun fibers were incor-porated directly onto polymeric backing films of PVA andHPMC which were successfully prepared and optimized

according to a 3-level 3-factor Box-Behnken experimen-tal design The effects of the independent variables onthe dependent response variables were analyzed and anoptimized formulation was mathematically produced Thephysicochemical and physicomechanical characteristics ofthe optimized NFMS were assessed The FTIR analysis eluci-dated no significant chemical interactions occurring betweendrug polymer and excipients during the process of formu-lation preparation The complete NFMS exhibited rapid andoptimum disintegration time Although the disintegrationand drug release of the fiber matrix alone was high enoughthe backing film holds the system in place for an optimumtime length ensuring the retention of released drug at buccalmucosa until the absorption occurs The optimized NFMSthus displayed rapid disintegration and drug release withgood mucoadhesion oramucosal retention flexibility andminimal mucosal irritation due to pH variation The NFMSmay therefore be deemed suitable for rapid oramucosaldrug delivery Furthermore molecular mechanics techniqueafforded unique understanding on the miscibility profilingand mucoadhesive properties of specific polymerplasticizerand polymermucopeptide complexes respectively

Conflict of Interests

The authors declare that they have no conflict of interests

Acknowledgments

This research was funded by the National Research Foun-dation (NRF) and Technology Innovation Agency (TIA) ofSouth Africa

References

[1] J Doshi andD H Reneker ldquoElectrospinning process and appli-cations of electrospun fibersrdquo Journal of Electrostatics vol 35no 2-3 pp 151ndash160 1995

[2] D Liang B S Hsiao and B Chu ldquoFunctional electrospun na-nofibrous scaffolds for biomedical applicationsrdquoAdvancedDrugDelivery Reviews vol 59 no 14 pp 1392ndash1412 2007

[3] T J Sill and H A von Recum ldquoElectrospinning applications indrug delivery and tissue engineeringrdquo Biomaterials vol 29 no13 pp 1989ndash2006 2008

[4] J M Deitzel J Kleinmeyer D Harris and N C B Tan ldquoTheeffect of processing variables on the morphology of electrospunnanofibers and textilesrdquo Polymer vol 42 no 1 pp 261ndash2722001

[5] M G McKee G L Wilkes R H Colby and T E Long ldquoCor-relations of solution rheology with electrospun fiber formationof linear and branched polyestersrdquoMacromolecules vol 37 no5 pp 1760ndash1767 2004

[6] S L Shenoy W D Bates H L Frisch and G E Wnek ldquoRole ofchain entanglements on fiber formation during electrospinningof polymer solutions good solvent non-specific polymer-polymer interaction limitrdquo Polymer vol 46 no 10 pp 3372ndash3384 2005

[7] A Frenot and I S Chronakis ldquoPolymer nanofibers assembledby electrospinningrdquo Current Opinion in Colloid and InterfaceScience vol 8 no 1-2 pp 64ndash75 2003


[8] D H Reneker and A L Yarin ldquoElectrospinning jets and poly-mer nanofibersrdquo Polymer vol 49 no 10 pp 2387ndash2425 2008

[9] X Zong K Kim D Fang S Ran B S Hsiao and B ChuldquoStructure and process relationship of electrospun bioabsorb-able nanofiber membranesrdquo Polymer vol 43 no 16 pp 4403ndash4412 2002

[10] S Agarwal J H Wendorff and A Greiner ldquoUse of electrospin-ning technique for biomedical applicationsrdquo Polymer vol 49no 26 pp 5603ndash5621 2008

[11] L Bruner and St Tolloczko ldquoUber die Auflosungsgeschwin-digkeit fester Korperrdquo Zeitschrift fur Anorganische Chemie vol28 no 1 pp 314ndash330 1901

[12] E Sjokvist and C Nystrom ldquoPhysicochemical aspects of drugrelease XI Tableting properties of solid dispersions using xyl-itol as carrier materialrdquo International Journal of Pharmaceuticsvol 67 no 2 pp 139ndash153 1991

[13] G Verreck I Chun J Peeters J Rosenblatt andM E BrewsterldquoPreparation and characterization of nanofibers containingamorphous drug dispersions generated by electrostatic spin-ningrdquo Pharmaceutical Research vol 20 no 5 pp 810ndash817 2003

[14] A Dokoumetzidis and P Macheras ldquoA century of dissolutionresearch from Noyes and Whitney to the biopharmaceuticsclassification systemrdquo International Journal of Pharmaceuticsvol 321 no 1-2 pp 1ndash11 2006

[15] G Ponchel ldquoFormulation of oralmucosal drug delivery systemsfor the systemic delivery of bioactive materialsrdquoAdvanced DrugDelivery Reviews vol 13 no 1-2 pp 75ndash87 1994

[16] S Rossi G Sandri and CM Caramella ldquoBuccal drug deliverya challenge already wonrdquo Drug Discovery Today Technologiesvol 2 no 1 pp 59ndash65 2005

[17] M J Rathbone B K Drummond and I G Tucker ldquoThe oralcavity as a site for systemic drug deliveryrdquo Advanced DrugDelivery Reviews vol 13 no 1-2 pp 1ndash22 1994

[18] J Abrams ldquoNew nitrate delivery systems buccal nitroglycerinrdquoThe American Heart Journal vol 105 no 5 pp 848ndash854 1983

[19] O A Scholz A Wolff A Schumacher et al ldquoDrug deliveryfrom the oral cavity focus on a novel mechatronic deliverydevicerdquo Drug Discovery Today vol 13 no 5-6 pp 247ndash2532008

[20] DM Simpson JMessina F Xie andMHale ldquoFentanyl buccaltablet for the relief of breakthrough pain in opioid-tolerantadult patients with chronic neuropathic pain a multicenterrandomized double-blind placebo-controlled studyrdquo ClinicalTherapeutics vol 29 no 4 pp 588ndash601 2007

[21] A Baji YWMai S CWongM Abtahi and P Chen ldquoElectro-spinning of polymer nanofibers effects on oriented morphol-ogy structures and tensile propertiesrdquo Composites Science andTechnology vol 70 no 5 pp 703ndash718 2010

[22] E P S Tan andC T Lim ldquoMechanical characterization of nano-fibersmdasha reviewrdquo Composites Science and Technology vol 66no 9 pp 1102ndash1111 2006

[23] E P S Tan S Y Ng and C T Lim ldquoTensile testing of a singleultrafine polymeric fiberrdquo Biomaterials vol 26 no 13 pp 1453ndash1456 2005

[24] T Coviello F Alhaique C Parisi PMatricardi G Bocchinfusoand M Grassi ldquoA new polysaccharidic gel matrix for drug de-livery preparation and mechanical propertiesrdquo Journal of Con-trolled Release vol 102 no 3 pp 643ndash656 2005

[25] S N R Adhikari B S Nayak A K Nayak and B MohantyldquoFormulation and evaluation of buccal patches for delivery ofatenololrdquo AAPS PharmSciTech vol 11 no 3 pp 1038ndash10442010

[26] M A Zaman G P Martin and G D Rees ldquoMucoadhesionhydration and rheological properties of non-aqueous deliverysystems (NADS) for the oral cavityrdquo Journal of Dentistry vol36 no 5 pp 351ndash359 2008

[27] G P Andrews T P Laverty and D S Jones ldquoMucoadhesivepolymeric platforms for controlled drug deliveryrdquo EuropeanJournal of Pharmaceutics and Biopharmaceutics vol 71 no 3pp 505ndash518 2009

[28] L Perioli V Ambrogi F Angelici et al ldquoDevelopment ofmucoadhesive patches for buccal administration of ibuprofenrdquoJournal of Controlled Release vol 99 no 1 pp 73ndash82 2004

[29] B Singh R Kumar and N Ahuja ldquoOptimizing drug deliverysystems using systematic ldquodesign of experimentsrdquomdashpart I fun-damental aspectsrdquo Critical Reviews inTherapeutic Drug CarrierSystems vol 22 no 1 pp 27ndash105 2005

[30] S L C Ferreira R E Bruns H S Ferreira et al ldquoBox-Behnkendesign an alternative for the optimization of analytical meth-odsrdquo Analytica Chimica Acta vol 597 no 2 pp 179ndash186 2007

[31] G E P Box and D W Behnken ldquoSome new three level designsfor the study of quantitative variablesrdquo Technometrics vol 2 no4 pp 455ndash475 1960

[32] S Chopra S K Motwani Z Iqbal S Talegaonkar F J Ahmadand R K Khar ldquoOptimisation of polyherbal gels for vaginaldrug delivery by Box-Behnken statistical designrdquo EuropeanJournal of Pharmaceutics and Biopharmaceutics vol 67 no 1pp 120ndash131 2007

[33] V M Patel B G Prajapati and M M Patel ldquoFormulationevaluation and comparison of bilayered and multilayeredmucoadhesive buccal devices of propranolol hydrochloriderdquoAAPS PharmSciTech vol 8 no 1 pp E147ndashE154 2007

[34] B SibekoV Pillay Y E Choonara et al ldquoComputationalmolec-ular modeling and structural rationalization for the design of adrug-loaded PLLAPVA biopolymeric membranerdquo BiomedicalMaterials vol 4 no 1 Article ID 015014 2009

[35] S Azarmi W Roa and R Lobenberg ldquoCurrent perspectivesin dissolution testing of conventional and novel dosage formsrdquoInternational Journal of Pharmaceutics vol 328 no 1 pp 12ndash212007

[36] A Figueiras J Hombach F Veiga and A Bernkop-SchnurchldquoIn vitro evaluation of natural and methylated cyclodextrins asbuccal permeation enhancing system for omeprazole deliveryrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol71 no 2 pp 339ndash345 2009

[37] P Kumar V Pillay Y E Choonara G Modi D Naidooand L C du Toit ldquoIn silico theoretical molecular modelingfor Alzheimerrsquos disease the nicotine-curcumin paradigm inneuroprotection and neurotherapyrdquo International Journal ofMolecular Sciences vol 12 no 1 pp 694ndash724 2011

[38] M EMalone I AMAppelqvist and I TNorton ldquoOral behav-iour of food hydrocolloids and emulsionsmdashpart 1 lubricationand deposition considerationsrdquo Food Hydrocolloids vol 17 no6 pp 763ndash773 2003

[39] S Ramakrishna K FujiharaW E Teo T C Lim and ZMaAnIntroduction to Electrospinning andNanofibersWorld ScientificLondon UK 2005

[40] P Bottenberg R Cleymaet C de Muynck et al ldquoDevelopmentand testing of bioadhesive fluoride-containing slow-releasetablets for oral userdquo Journal of Pharmacy and Pharmacology vol43 no 7 pp 457ndash464 1991

[41] J W Lu Z P Zhang X Z Ren Y Z Chen J Yu and Z X GuoldquoHigh-elongation fiber mats by electrospinning of polyoxym-ethylenerdquoMacromolecules vol 41 no 11 pp 3762ndash3764 2008


[42] E Karavas E Georgarakis and D Bikiaris ldquoApplication ofPVPHPMC miscible blends with enhanced mucoadhesiveproperties for adjusting drug release in predictable pulsatilechronotherapeuticsrdquo European Journal of Pharmaceutics andBiopharmaceutics vol 64 no 1 pp 115ndash126 2006

[43] Y Sudhakar K Kuotsu and A K Bandyopadhyay ldquoBuccalbioadhesive drug deliverymdasha promising option for orally lessefficient drugsrdquo Journal of Controlled Release vol 114 no 1 pp15ndash40 2006

[44] B Y Yu J W Chung and S Y Kwak ldquoReduced migrationfrom flexible poly(vinyl chloride) of a plasticizer containing 120573-cyclodextrin derivativerdquo Environmental Science and Technologyvol 42 no 19 pp 7522ndash7527 2008

[45] H Abou-Rachid L Lussier S Ringuette X Lafleur-LambertM Jaidann and J Brisson ldquoOn the correlation between misci-bility and solubility properties of energetic plasticizerspolymerblends modeling and simulation studiesrdquo Propellants Explo-sives Pyrotechnics vol 33 no 4 pp 301ndash310 2008

[46] P Sakellariou A Hassan and R C Rowe ldquoPlasticization ofaqueous poly(vinyl alcohol) andhydroxypropylmethylcellulosewith polyethylene glycols and glycerolrdquo European PolymerJournal vol 29 no 7 pp 937ndash943 1993

[47] N K Mongia K S Anseth and N A Peppas ldquoMucoadhesivepoly(vinyl alcohol) hydrogels produced by freezingthawingprocesses applications in the development of wound healingsystemsrdquo Journal of Biomaterials Science Polymer Edition vol7 no 12 pp 1055ndash1064 1996

[48] P Kumar and M Bhatia ldquoFunctionalization of chitosanmeth-ylcellulose interpenetrating polymer network microspheres forgastroretentive application using central composite designrdquoPDA Journal of Pharmaceutical Science and Technology vol 64no 6 pp 497ndash506 2010

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of



CeramicsJournal of


CompositesJournal of

NanoparticlesJournal of



International Journal of

Biomaterials


NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research



MetallurgyJournal of


BioMed Research International

MaterialsJournal of


Nano

materials


Journal ofNanomaterials


expeditious blood levels and hence a prompt onset of action[17ndash20] It has been demonstrated that the in vivo availabilityof a drug administered via the oramucosal route is greatlydependent on the disintegration rate of the drug deliverysystem [15]

During electrospinning the polymer chain orientationthat occurs during fiber formation has a significant effecton the physicomechanical properties of the nanofibrousmatrix that is formed [21] The fiber diameter has beenfound to affect the mechanical properties of electrospunmaterials [22] where fibers with smaller diameters displayeda greater strength but were less pliable than larger fibers[23] The physicomechanical properties of a material have asignificant effect on drug release [24] patient acceptability[25] and residence time at the site of absorption [26 27]Due to the relatively short residence time of an oramucosallyadministered drug delivery system at the site of absorptionmucoadhesion is often required [15] Mucoadhesive drugdelivery systems are advantageous in that the entire system isrendered immobile an intimate contact between the systemand buccal mucosa is created and a high drug concentrationat the absorption surface is achieved [15 27] This results ina reduction in the required drug concentration as well as animproved bioavailability [27] Thin mucoadhesive films arefavorable for oramucosal drug delivery due to the flexiblenature and high contact surface area of such films [15 28]

Statistical optimization by experimental design employsmathematical equations and graphic analysis in order tocharacterize and assess the effects of independent variableson measured responses [29] and was applied to this investi-gation In contrast to traditional approaches to formulationoptimization where one variable is assessed at a time statis-tical optimization utilizes fewer experimental runs which isless time consuming and provides a true optimized formula-tion by a systematic approach [29]

In thework outlined in this study drug-loaded fiberswereelectrospun directly onto a statistically optimized polymericbacking film in order to form a porous rapidly disintegratingnanofibrous matrix system (NFMS) for oramucosal drugdeliveryThe polymeric backing filmwas produced accordingto a Box-Behnken experimental designThe polyvinylalcohol(PVA) electrospun fibers were loaded with model drug di-phenhydramine in order to assess drug entrapment releaseand permeation characteristicsDrug-loaded films serving asa comparison were also prepared according to the same for-mula as the backing film and using the same constituents asthe electrospinning solutionThe effects of varying polymericconstituents on drug release drug permeation mucoadhe-sion and disintegration were also investigated in order toproduce an optimized oramucosal drug delivery system

2 Materials and Methods

21 Materials Polyvinylalcohol (PVA) (87ndash89 hydrolyzedMw 13000ndash23000 gmoL) and diphenhydramine (DPH)were purchased from Sigma-Aldrich (St Louis MO USA)Propan-2-ol glycerol and citric acid were purchased from

Table 1 Polymer concentrations and volumes used in film prepara-tion according to a Box-Behnken design

Formulationnumber

Fillvolume(mL)

HPMC(wv)

Glycerol (ww ofPVA + HPMC)

D1 40 050 125D2 100 025 150D3 40 025 150D4 70 025 125D5 70 050 100D6 100 050 125D7 40 025 100D8 70 025 125D9 70 000 100D10 100 000 125D11 70 000 150D12 70 025 125D13 70 050 150D14 40 000 125D15 100 025 100

Rochelle Chemicals (Johannesburg South Africa) Hydrox-ypropylmethylcellulose (HPMC) was purchased from Color-con Limited (London England)

22 Preparation of Polymeric Backing Films by Film CastingFilms intended as backing and mucoadhesive layers forelectrospunfiberswere prepared according to aBox-Behnkenexperimental design Polymer solutions were prepared bydissolving glycerol PVA and HPMC in a 4 1 mixture ofdeionized water and propan-2-ol The concentrations andvolumes used were as outlined in Table 1 For all the formu-lations the PVA concentration was used at 1wv Solutionswere syringed into rectangular flat-bottomedmoulds and leftunder an extractor at 21∘C for 48 hours in order that completesolvent evaporation and film formation could occur Forcomparative purposes a DPH-loaded film (FD) containingthe samepolymeric andplasticizer constituentswas prepared

221 Experimental Design A 3-factor Box-Behnken experi-mental design was generated by Minitab V15 (Minitab IncPA USA) in order to statistically optimize the polymeric filmlayer and analyze the effect of formulation variables on systemdisintegration and drug release The independent variables1198831 1198832 and 119883

3are outlined in Table 2 119884

1through to 119884

5

the dependent variables were disintegration time work ofadhesion (WA) maximum detachment force (MDF) disso-lution area under the curve (AUC) at 1 minute (AUCD) andpermeation AUC at 3 minutes (AUCP) respectively [30ndash32]

23 Preparation of Nanofibers by Electrospinning A drug-loaded solution for electrospinning was produced by dissolv-ing PVA citric acid DPH and glycerol in a 2 1 mixtureof water and propan-2-ol at concentrations of 25wv






24 Characterization
















119875app =119876

119860 times 119888 times 119905 (1)

119869 ss =Δ119872

119860 times Δ119905 (2)






















D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

Disi

nteg

ratio

n tim

e (s)

50

40

30

20

10

0

(a)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

00

02

04

06

08

10

Wor

k of

adhe

sion

(mJ)

(b)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

00

01

02

03

04

05

06

Max

imum

det

achm

ent f

orce

(N)

(c)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

050

045

040

035

030

025

020

015

010

AUC

Dat1min

(d)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

19

18

17

16

15

14

13

AUC

Pat3min

(e)








1000200030004000

Tran

smitt

ance

()

0

20

40

60

80

100










119900) was




10

9

8

7

6

5

4

3

2

1

0

60

50

40

30

20

10

0

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(a)

12

10

8

6

4

2

00 100 200 300 400 500

32

31

30

29

28

27

26

25

24

23

22

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

350

300

250

200

150

100

50

0

20

15

10

5

0

times103

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(c)






0 100 200 300 400 500

120574 (1s)

400

350

300

250

200

150

100

50

0

120591(P

a)

743

742

741

740

739

738

737

736

120578(m

Pas)

25 PVA std flow C120591 = f(120574)

120578 = f(120574)

(a)

35

30

25

20

15

10

5

00 10 20 30 40 50

0

200

400

600

800

1000

1200

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

1000000

100000

10000

10000

1000

1000

100

100

10

1001

01 Yieldstress

120574(mdash

)


120574 = f(120591)

(c)

10000000

1000000

100000

010000

001000

000100

000010

000001

G998400

(Pa)

G998400998400

(Pa)

100001000100010001

120596 (rads)

G998400 = f(120596)G998400998400 = f(120596)


(d)




Yieldstress(MPa)


Ultimatestrain

Toughness(Jcm3)


NFMS 3031 118 279 0238 048FD 5635 113 273 0314 071FE 2034 110 352 0731 210




119906)




Time (min)0 2 4 6 8 10 12 14

pH

65

66

67

68

69

70


FMS film FMS FD FE

Max

imum

forc

e (N

)M

axim

um d

istan

ce (m

m)

0

2

4

6

8

10

12

Force Distance








3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)






Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials








24 Characterization
















119875app =119876

119860 times 119888 times 119905 (1)

119869 ss =Δ119872

119860 times Δ119905 (2)






















D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

Disi

nteg

ratio

n tim

e (s)

50

40

30

20

10

0

(a)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

00

02

04

06

08

10

Wor

k of

adhe

sion

(mJ)

(b)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

00

01

02

03

04

05

06

Max

imum

det

achm

ent f

orce

(N)

(c)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

050

045

040

035

030

025

020

015

010

AUC

Dat1min

(d)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

19

18

17

16

15

14

13

AUC

Pat3min

(e)








1000200030004000

Tran

smitt

ance

()

0

20

40

60

80

100










119900) was




10

9

8

7

6

5

4

3

2

1

0

60

50

40

30

20

10

0

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(a)

12

10

8

6

4

2

00 100 200 300 400 500

32

31

30

29

28

27

26

25

24

23

22

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

350

300

250

200

150

100

50

0

20

15

10

5

0

times103

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(c)






0 100 200 300 400 500

120574 (1s)

400

350

300

250

200

150

100

50

0

120591(P

a)

743

742

741

740

739

738

737

736

120578(m

Pas)

25 PVA std flow C120591 = f(120574)

120578 = f(120574)

(a)

35

30

25

20

15

10

5

00 10 20 30 40 50

0

200

400

600

800

1000

1200

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

1000000

100000

10000

10000

1000

1000

100

100

10

1001

01 Yieldstress

120574(mdash

)


120574 = f(120591)

(c)

10000000

1000000

100000

010000

001000

000100

000010

000001

G998400

(Pa)

G998400998400

(Pa)

100001000100010001

120596 (rads)

G998400 = f(120596)G998400998400 = f(120596)


(d)




Yieldstress(MPa)


Ultimatestrain

Toughness(Jcm3)


NFMS 3031 118 279 0238 048FD 5635 113 273 0314 071FE 2034 110 352 0731 210




119906)




Time (min)0 2 4 6 8 10 12 14

pH

65

66

67

68

69

70


FMS film FMS FD FE

Max

imum

forc

e (N

)M

axim

um d

istan

ce (m

m)

0

2

4

6

8

10

12

Force Distance








3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)






Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials










119875app =119876

119860 times 119888 times 119905 (1)

119869 ss =Δ119872

119860 times Δ119905 (2)






















D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

Disi

nteg

ratio

n tim

e (s)

50

40

30

20

10

0

(a)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

00

02

04

06

08

10

Wor

k of

adhe

sion

(mJ)

(b)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

00

01

02

03

04

05

06

Max

imum

det

achm

ent f

orce

(N)

(c)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

050

045

040

035

030

025

020

015

010

AUC

Dat1min

(d)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

19

18

17

16

15

14

13

AUC

Pat3min

(e)








1000200030004000

Tran

smitt

ance

()

0

20

40

60

80

100










119900) was




10

9

8

7

6

5

4

3

2

1

0

60

50

40

30

20

10

0

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(a)

12

10

8

6

4

2

00 100 200 300 400 500

32

31

30

29

28

27

26

25

24

23

22

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

350

300

250

200

150

100

50

0

20

15

10

5

0

times103

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(c)






0 100 200 300 400 500

120574 (1s)

400

350

300

250

200

150

100

50

0

120591(P

a)

743

742

741

740

739

738

737

736

120578(m

Pas)

25 PVA std flow C120591 = f(120574)

120578 = f(120574)

(a)

35

30

25

20

15

10

5

00 10 20 30 40 50

0

200

400

600

800

1000

1200

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

1000000

100000

10000

10000

1000

1000

100

100

10

1001

01 Yieldstress

120574(mdash

)


120574 = f(120591)

(c)

10000000

1000000

100000

010000

001000

000100

000010

000001

G998400

(Pa)

G998400998400

(Pa)

100001000100010001

120596 (rads)

G998400 = f(120596)G998400998400 = f(120596)


(d)




Yieldstress(MPa)


Ultimatestrain

Toughness(Jcm3)


NFMS 3031 118 279 0238 048FD 5635 113 273 0314 071FE 2034 110 352 0731 210




119906)




Time (min)0 2 4 6 8 10 12 14

pH

65

66

67

68

69

70


FMS film FMS FD FE

Max

imum

forc

e (N

)M

axim

um d

istan

ce (m

m)

0

2

4

6

8

10

12

Force Distance








3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)






Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials






















D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

Disi

nteg

ratio

n tim

e (s)

50

40

30

20

10

0

(a)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

00

02

04

06

08

10

Wor

k of

adhe

sion

(mJ)

(b)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

00

01

02

03

04

05

06

Max

imum

det

achm

ent f

orce

(N)

(c)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

050

045

040

035

030

025

020

015

010

AUC

Dat1min

(d)

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

19

18

17

16

15

14

13

AUC

Pat3min

(e)








1000200030004000

Tran

smitt

ance

()

0

20

40

60

80

100










119900) was




10

9

8

7

6

5

4

3

2

1

0

60

50

40

30

20

10

0

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(a)

12

10

8

6

4

2

00 100 200 300 400 500

32

31

30

29

28

27

26

25

24

23

22

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

350

300

250

200

150

100

50

0

20

15

10

5

0

times103

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(c)






0 100 200 300 400 500

120574 (1s)

400

350

300

250

200

150

100

50

0

120591(P

a)

743

742

741

740

739

738

737

736

120578(m

Pas)

25 PVA std flow C120591 = f(120574)

120578 = f(120574)

(a)

35

30

25

20

15

10

5

00 10 20 30 40 50

0

200

400

600

800

1000

1200

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

1000000

100000

10000

10000

1000

1000

100

100

10

1001

01 Yieldstress

120574(mdash

)


120574 = f(120591)

(c)

10000000

1000000

100000

010000

001000

000100

000010

000001

G998400

(Pa)

G998400998400

(Pa)

100001000100010001

120596 (rads)

G998400 = f(120596)G998400998400 = f(120596)


(d)




Yieldstress(MPa)


Ultimatestrain

Toughness(Jcm3)


NFMS 3031 118 279 0238 048FD 5635 113 273 0314 071FE 2034 110 352 0731 210




119906)




Time (min)0 2 4 6 8 10 12 14

pH

65

66

67

68

69

70


FMS film FMS FD FE

Max

imum

forc

e (N

)M

axim

um d

istan

ce (m

m)

0

2

4

6

8

10

12

Force Distance








3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)






Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





1000200030004000

Tran

smitt

ance

()

0

20

40

60

80

100










119900) was




10

9

8

7

6

5

4

3

2

1

0

60

50

40

30

20

10

0

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(a)

12

10

8

6

4

2

00 100 200 300 400 500

32

31

30

29

28

27

26

25

24

23

22

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

350

300

250

200

150

100

50

0

20

15

10

5

0

times103

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(c)






0 100 200 300 400 500

120574 (1s)

400

350

300

250

200

150

100

50

0

120591(P

a)

743

742

741

740

739

738

737

736

120578(m

Pas)

25 PVA std flow C120591 = f(120574)

120578 = f(120574)

(a)

35

30

25

20

15

10

5

00 10 20 30 40 50

0

200

400

600

800

1000

1200

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

1000000

100000

10000

10000

1000

1000

100

100

10

1001

01 Yieldstress

120574(mdash

)


120574 = f(120591)

(c)

10000000

1000000

100000

010000

001000

000100

000010

000001

G998400

(Pa)

G998400998400

(Pa)

100001000100010001

120596 (rads)

G998400 = f(120596)G998400998400 = f(120596)


(d)




Yieldstress(MPa)


Ultimatestrain

Toughness(Jcm3)


NFMS 3031 118 279 0238 048FD 5635 113 273 0314 071FE 2034 110 352 0731 210




119906)




Time (min)0 2 4 6 8 10 12 14

pH

65

66

67

68

69

70


FMS film FMS FD FE

Max

imum

forc

e (N

)M

axim

um d

istan

ce (m

m)

0

2

4

6

8

10

12

Force Distance








3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)






Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




10

9

8

7

6

5

4

3

2

1

0

60

50

40

30

20

10

0

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(a)

12

10

8

6

4

2

00 100 200 300 400 500

32

31

30

29

28

27

26

25

24

23

22

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

350

300

250

200

150

100

50

0

20

15

10

5

0

times103

120591(P

a)

120578(m

Pas)

0 100 200 300 400 500


120591 = f(120574)

120578 = f(120574)

(c)






0 100 200 300 400 500

120574 (1s)

400

350

300

250

200

150

100

50

0

120591(P

a)

743

742

741

740

739

738

737

736

120578(m

Pas)

25 PVA std flow C120591 = f(120574)

120578 = f(120574)

(a)

35

30

25

20

15

10

5

00 10 20 30 40 50

0

200

400

600

800

1000

1200

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

1000000

100000

10000

10000

1000

1000

100

100

10

1001

01 Yieldstress

120574(mdash

)


120574 = f(120591)

(c)

10000000

1000000

100000

010000

001000

000100

000010

000001

G998400

(Pa)

G998400998400

(Pa)

100001000100010001

120596 (rads)

G998400 = f(120596)G998400998400 = f(120596)


(d)




Yieldstress(MPa)


Ultimatestrain

Toughness(Jcm3)


NFMS 3031 118 279 0238 048FD 5635 113 273 0314 071FE 2034 110 352 0731 210




119906)




Time (min)0 2 4 6 8 10 12 14

pH

65

66

67

68

69

70


FMS film FMS FD FE

Max

imum

forc

e (N

)M

axim

um d

istan

ce (m

m)

0

2

4

6

8

10

12

Force Distance








3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)






Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




0 100 200 300 400 500

120574 (1s)

400

350

300

250

200

150

100

50

0

120591(P

a)

743

742

741

740

739

738

737

736

120578(m

Pas)

25 PVA std flow C120591 = f(120574)

120578 = f(120574)

(a)

35

30

25

20

15

10

5

00 10 20 30 40 50

0

200

400

600

800

1000

1200

120591(P

a)

120578(m

Pas)


120591 = f(120574)

120578 = f(120574)

(b)

1000000

100000

10000

10000

1000

1000

100

100

10

1001

01 Yieldstress

120574(mdash

)


120574 = f(120591)

(c)

10000000

1000000

100000

010000

001000

000100

000010

000001

G998400

(Pa)

G998400998400

(Pa)

100001000100010001

120596 (rads)

G998400 = f(120596)G998400998400 = f(120596)


(d)




Yieldstress(MPa)


Ultimatestrain

Toughness(Jcm3)


NFMS 3031 118 279 0238 048FD 5635 113 273 0314 071FE 2034 110 352 0731 210




119906)




Time (min)0 2 4 6 8 10 12 14

pH

65

66

67

68

69

70


FMS film FMS FD FE

Max

imum

forc

e (N

)M

axim

um d

istan

ce (m

m)

0

2

4

6

8

10

12

Force Distance








3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)






Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Time (min)0 2 4 6 8 10 12 14

pH

65

66

67

68

69

70


FMS film FMS FD FE

Max

imum

forc

e (N

)M

axim

um d

istan

ce (m

m)

0

2

4

6

8

10

12

Force Distance








3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)






Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




3

3

2

1

0minus00025 00500 01000 01500 02000 02733

Strain

Stre

ss (M

Pa)

(a)

3

2

1

0minus00184 00500 01000 01500 02000 02500 03000 03500

Strain

Stre

ss (M

Pa)

(b)

2

1

000000 01000 02000 03000 04025

Strain

Stre

ss (M

Pa)

(c)

3

2

1

0minus00003 01000 02000 03000

Strain

Stre

ss (M

Pa)

(d)

4

3

2

1

000000 02000 04000 06000

Strain

Stre

ss (M

Pa)

(e)






Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials







Disi

nteg

ratio

n tim

e (s)

0

10

20

30

40

50

60










10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)

FDFE

FMS

(a)

10

08

06

04

02

00

Frac

tiona

l dru

g re

leas

e

0 5 10 15 20 25 30

Time (min)


(b)

FMS FD FE

05

04

03

02

01

00

AUC

Dat1min

Sleepeze-PM

(c)




119864HPMC = 49713119881Σ = 2089119881b + 18821 + 22360119881120593

+ 6776119881ij minus 0335119881hb(4)

119864PVA = 5173119881Σ = 0615119881b + 1652119881120579 + 0881119881120593

+ 4895119881ij minus 2871119881hb(5)

119864HPMCPVA = 44321119881Σ = 2582119881b + 19911119881120579

+ 27276119881120593minus 2740119881ij minus 2709119881hb


(6)

119864GLY = 2624119881Σ = 0096119881b + 1121119881120579

+ 0375119881120593+ 1031119881ij

(7)

119864HPMCGLY = 31891119881Σ = 2261119881b + 21937119881120579

+ 27007119881120593minus 19097119881ij minus 0217119881hb


(8)

119864HPMCPVAGLY = 22867119881Σ = 2689119881b + 21701119881120579

+ 30849119881120593minus 30181119881ij minus 2192119881hb


(9)

119864MUC = minus166812119881Σ = 5474119881b + 70351119881120579 + 55173119881120593


(10)


60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




60

50

40

30

20

10

00 5 10 15 20 25 30

Flux

Time (min)

FMSSolution

FDFE

(a)


24

22

20

18

16

14

AUC

Pat3min

(b)


119864HPMCMUC = minus156127119881Σ = 6888119881b + 88277119881120579

+ 84268119881120593minus 51281119881ij minus 7555119881hb


119864PVAMUC = minus175667119881Σ = 6486119881b + 72435119881120579 + 66468119881120593


[Δ119864 = minus14028 kcalmoL] (12)


+ 78881119881120593minus 63968119881ij

minus 9755119881hb minus 275615119881el


(13)












Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Glycerol

HPMC

(a)

HPMC PVA

(b)

Glycerol

Glycerol

HPMC

PVA

(c) (d)








MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




MUC

PVA

(a)

MUC

HPMC

(b)

MUC

HPMC

PVA

(c)









4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials







4 Conclusions





Acknowledgments


References


























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





















































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



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