Sodium alginate/poly (ethylene oxide) blend hydrogel membranes for controlled release ofvalganciclovir hydrochloride

B. Mallikarjunaa, K. Madhusudana Raoa, S. Siraja, A. Chandra Babua, K. Chowdoji Raob and M.C.S. Subhaa*

aDepartment of Chemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, India; bDepartment of Polymer Science &Technology, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, India

Sodium alginate (SA) and poly (ethylene oxide) PEO blend membranes were prepared by solvent casting method for thecontrolled release of valganciclovir hydrochloride, an antiHIV drug. The prepared membranes were thin, flexible,smooth, and characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimeter (DSC),X-ray diffraction (X-RD), scanning electron microscopy (SEM), and tensile strength measurement. FTIR was used tounderstand the formation of hydrogen bonding between SA and PEO. The DSC and X-RD studies were performed tounderstand the crystalline nature of drug after encapsulation into the membranes. SEM was used to study the surfacemorphology of the membranes. Tensile strength measurements revealed the mechanical strength of the membranes. Invitro release studies indicated a dependence of release rate on the extent of crosslinking, amount of drug loading, andthe amount of PEO, but slow release rates was extended up to 12 h. Cumulative release data were fitted onto to anempirical equation to compute diffusional exponent (n), which indicated the nonFickian trend for drug release.

Keywords: sodium alginate (SA); poly (ethylene oxide) (PEO); valganciclovir hydrochloride (VHCl); membranes; drugdelivery systems

Introduction

Controlled drug release technology emerged during the1980s as a commercially sound methodology of extend-ing existing ways of administering pharmaceutical thera-pies [1]. Conventional dosage forms often lead to wideswings in serum drug concentrations [2]. The safety andtherapeutic efficacy of current treatments may beimproved if their delivery rate, biodegradation, and site-specific targeting can be predicted, monitored, and con-trolled. In recent years, considerable research efforts havebeen directed towards the development of safe and effi-cient drug delivery systems with the use of polymers asagents for the controlled release of drugs from varioustypes of formulated products, such as tablets, implants,and adhesive strips etc. Evidence of the high degree ofinterest in the design of such dosage forms is providedby number of reviews [3–5] and books [6–8] that hasbeen concerned with these subjects. The release of drugs,absorbed or encapsulated by polymer, involves their slowand controlled diffusion from or through polymericmaterial. Drugs covalently attached to biodegradablepolymers or dispersed in a polymeric matrix of such

macromolecules may be released by erosion or degrada-tion of the polymer. Therapeutic molecules complexedby polymers may also be released from gels by diffu-sion.

Sodium alginate (SA), a natural polysaccharide, com-posed of D-mannuronic acid and D-guluronic acid, isderived from the brown seaweeds. SA is a biodegradablepolymer used extensively in drug delivery applications[9–12]. Earlier literature cites many applications of SAin agricultural applications after crosslinking with glutar-aldehyde (GA) [13–15]. SA is one of the most versatilenatural materials known to form hydrogels and films[16–22]. Drug-loaded films of SA are being used inpharmaceutical applications. In the literature, the numer-ous films controlled on sustained delivery systems havebeen described, whereby the active ingredient has beendispersed within these films [23].

Poly (ethylene oxide) (PEO) is a nontoxic and water-soluble polymer, widely used in chemical, cosmetic, andpharmaceutical industries. PEO gels produced in watercan be dehydrated and the material produced is extre-mely hydrophilic and possesses a good bioadhesive

*Corresponding author. Email: mcssubha3@gmail.com

Designed Monomers and PolymersVol. 16, No. 2, March 2013, 151–159

ISSN 1568-5551 online� 2012 Taylor & Francishttp://dx.doi.org/10.1080/15685551.2012.705503http://www.tandfonline.com

property [24]. Due to its properties, PEO is used invarious drug delivery systems. Christine et al. [25] havereported PEO blend copolymer micelles as a deliveryvehicle for dihydrotestosterone. Zeng and Pitt [26] havealso reported PEO blend nanoparticles with crosslinkedcores as drug carrier. PEO is a good drug delivery vehi-cle in pharmaceutical industries [27,28].

Valganciclovir hydrochloride (VHCl) is an antiviraldrug, used extensively for the treatment of cytomegalovi-rus (CMV) retinitis in patients with acquired immunode-ficiency syndrome (AIDS) through oral administration.The chemical name for VHCl is L-Valine,2 [(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypro-pylester hydrochloride. VHCl is a polar hydrophiliccompound with a solubility of 70mg/ml in water at25 °C. Valcyte is an oral prodrug of Cytovene, a cur-rently approved and widely prescribed antiCMV medica-tion. The active ingredient in Valcyte is valganciclovir,which exists as a mixture of two diastereomers (com-pounds with the same atoms, but in different arrange-ments). In the body, the diastereomers are converted toganciclovir, which inhibits the replication of humanCMV. CMV belongs to the family of herpes viruses. Thevirus remains inactive in individuals with normalimmune function; however, it can cause illness in thosewith compromised immune systems, such as individualswith AIDS or patients taking posttransplant immuno sup-pressants. In patients with HIV/AIDS, the most commonform of CMV is CMV retinitis, an infection of the eyethat can lead to blindness [29].

It is well known that blending is effective and conve-nient method to improve the performance of polymermaterials. Recently, our group is actively involved in thedevelopment of blend polymeric systems for the controlrelease of various types of drugs [30–34]. Earlier, Yer-riswamy et al. [35] have prepared blend microspheres forcontrolled release of ciprofloxin hydrochloride. Krishnarao et al. [36] have prepared SA and hydroxy ethyl cel-lulose blend beads for controlled release of diclofenacsodium and ibuprofen. In the present study, SA/PEO

hydrogel membranes were prepared and crosslinked withGA as crosslinking agent, using VHCl as model drug.The drug content, equilibrium degree of swelling, andVHCl release rate of membranes were investigated atpH-7.4. The effects of PEO, extent of crosslinking, andvariation of drug content on VHCl release from themembranes were discussed. The properties of the SA/PEO blend membranes were investigated with Fouriertransform infrared spectroscopy (FTIR), equilibriumswelling studies, differential scanning calorimeter (DSC),X-ray diffraction (X-RD) analysis, scanning electronmicroscopy (SEM), and in vitro drug-release studies. Thein vitro drug-release studies were carried out in buffermedium at pH 7.4 and the results are presented here.

Experimental

Materials

SA (viscosity [2W/V%], 1100–1900 cps) was purchasedfrom Merck, Mumbai, India, PEO (MW �70,000), GA,hydrochloric acid (HCl), and acetone are all of analargrade purchased from Sd.Fine, Mumbai, India. VHCl is agift sample received from Apotech Laboratory, Bangalore,India. Double distilled water collected in the laboratorywas used throughout this research work. All the chemicalswere used as received without further purification.

Preparation of membranes

The blend membranes of SA/PEO were prepared by asolvent-casting technique. The 2wt.% solutions of SAand PEO were dissolved separately in distilled water(PEO in hot water) under constant stirring (Remi motor)for overnight. The required ratios (Table 1) of SA, PEOwere taken in 100ml beaker to this solution, the antiHIVdrug VHCl (10, 15, and 20wt.%) was added slowlyunder constant stirring until a clear homogeneous solutionwas obtained. The obtained solution was filtered forremoving of undissolved particles and poured on a Teflonplate of 20 cm� 15 cm. The membranes were dried in an

Table 1. Various formulation parameters used in the preparation of membranes and data obtained from evaluation of membranes.

Samplecode

SA(w/w%)

PEO(w/w%) GA (ml)

Drug(w/w%)

Thickness ofmembrane (m)

% Encapsulationefficiency

Tensile strength(kg/cm2)

SP-1 80 20 3 10 130 ± 0.78 86.57 ± 0.35 2.63 ± 0. 95SP-2 80 20 3 15 160 ± 0.65 87.31 ± 0.67 2.81 ± 0.37SP-3 80 20 3 20 170 ± 0.47 90.62 ± 0.73 3.11 ± 0.53SP-4 80 20 1.5 15 160 ± 0.31 89.46 ± 0.26 3.42 ± 0.71SP-2 80 20 3 15 160 ± 0.65 87.31 ± 0.67 2.81 ± 0.37SP-5 80 20 4.5 15 170 ± 0.98 82.78 ± 0.15 3.98 ± 0.06SP-6 70 30 3 15 140 ± 0.15 89.21 ± 0.89 3.42 ± 0.59SP-2 80 20 3 15 160 ± 0.65 87.31 ± 0.67 2.81 ± 0.37SP-7 90 10 3 15 130 ± 0.27 84.36 ± 0.87 2.45 ± 0.28SP-8 100 – 3 15 127 ± 0.31 80.19 ± 0.41 2.10 ± 0.63

152 B. Mallikarjuna et al.

oven (GDW-250, Scientek services, Bangalore, India) at37 °C, until it shows constant weight. The dried mem-branes were dipped into acetone–water mixturecontaining different ratios of GA and 1N HCl for cross-linking up to 30min. Then the crosslinked membraneswere washed with distilled water to remove the excess ofunreacted GA and dried at 37 °C for 24 h. The preparedmembranes were stored in a closed container for furtherevaluation. The formulation details are given in (Table 1).The various formulations of SA/PEO designated as SP-1,SP-2, SP-3, SP-4, SP-5, SP-6, SP-7, and SP-8.

Swelling studies

Equilibrium water uptake by the membranes was deter-mined by measuring the extent of swelling of the mem-branes in distilled water at room temperature. To ensurecomplete equilibration, samples were allowed to swellfor 24 h. Excess surface adhered liquid drops wereremoved by blotting and the swollen membranes wereweighed to an accuracy of ±0.01mg on an electronicmicrobalance (Mettler, AT120, Greifensee, Switzerland).The membranes were dried in an oven at 60 °C for 5 huntil there was no change in the weight of the driedmass of samples. The % swelling ratio (% SR) was cal-culated by the following equation:

% SR ¼ Ws �Wd

Wd

� �� 100 (1)

Here, Wd and Ws were the weights of dried and swollenmembranes, respectively.

Characterization techniques

Measurement of thickness

Thickness of the membranes were measured at five dif-ferent places using digital micrometer (MDC-25S Mitu-toyo, Tokyo, Japan) having an accuracy of 0.001mm.

Drug content

The membranes of specified area (1 cm2) were cut intosmall pieces and added to 100ml of phosphate bufferpH 7.4 for complete swelling at 37 °C. The swollenmembranes were crushed in a glass mortar with pestle.The solution was then heated gently for 2 h to extract thedrug completely and centrifuged using a table-top centri-fuge (R-8C DX Remi, India) at 3000 rpm for 10min toremove polymeric debris. The clear supernatant solutionwas analyzed for drug content using UV spectrophotom-eter (LabIndia-UV3000+) (kmax) at 255 nm. The averageof three determinations was considered. The % encapsu-lation efficiency was calculated by the followingequation:

% Encapsulationefficiency

¼ Actual loading

Theoretical loading

� �� 100 (2)

FTIR analysis

The FTIR spectra of plain SA, plain membrane, anddrug-loaded membranes were recorded using FTIR spec-troscopy (Perkin Elmer, model Impact 410, Wisconsin,MI, USA). The samples were crushed with potassiumbromide (KBr) to make pellets under hydraulic pressureof 600 kg/cm2 and scanned between 4000 and 400 cm�1.

SEM studies

The membranes were mounted onto stubs using double-sided adhesive tape and sputter coated with platinumusing a sputter coater (Edward S 150, UK). The coatedmembranes were observed under SEM (JEOL, JSM-6360, Kyoto, Japan) at the required magnification atroom temperature. The acceleration voltage used was10 kV with the secondary electron image as a detector.

DSC studies

The sample membranes were heated from 0 to 400 °C ata heating rate of 10 °C/min under nitrogen atmosphere(flow rate, 20ml/min) using a DSC (Model-SDT Q600,USA) and then thermograms were obtained.

X-RD studies

The X-RD patterns of SA, plain membrane, and drug-loaded membranes were carried on a Shimadzu Lab-XRD-6000X diffractometer (Japan), using Nickel-filteredCu Kα radiation at 40 kV and 50mA in the 2h range of0–50o.

Tensile strength of the membrane

The membranes of 15 cm� 15 cm size were firmly fixedto the jaws of tensile tester (Instron, UK) and tensilestrength (TS) of the membranes was measured with anextension speed of 20mm/min.

In-vitro release study

In vitro drug release study was performed in phosphatebuffer pH 7.4 (PBS) using tablet dissolution tester (Lab-India, Mumbai, India) equipped with eight baskets at thestirring speed of 100 rpm. The membranes of 4.0 cm2

area were mounted. The amount of drug release wasdetermined by withdrawing 10ml samples at a specifictime intervals for 12 h. The volume withdrawn was

Designed Monomers and Polymers 153

replaced with an equal volume of fresh PBS; the sampleswere analyzed in a UV spectrophotometer (LabIndia-UV3000+) (kmax) at 271 nm using PBS as blank.

Results and discussions

Swelling studies

The membranes swelling properties were influenced bythe amount of PEO and crosslinker (GA). As the amountof PEO increases, the SR of membranes increases; itmay be due to the enhancement of hydrophilic polymerchains by increase with PEO concentration. In the caseof GA crosslinker variation, the SR decreases with anincrease in crosslinker; it may be due to the formation ofpolymeric chains which becomes rigid network as aresult of contraction of microvoids. The various formula-tions and their SRs are shown in the Figure 1.

Fourier transform infrared spectroscopy

Results of FTIR spectra of (a) plain SA, (b) plainmembrane, and (c) drug-loaded membrane are shown inFigure 2. The FTIR spectra of plain SA showed a peakat 3475 cm�1 indicating the –OH stretching frequency;the two characteristic peaks at 1638 and 1427 cm�1

showed the asymmetric and symmetric stretching fre-quency of –COO group, respectively [37]. The peak1031 cm�1 indicated the –C–O–C symmetric stretchingfrequency. From Figure 2(b), the strong intense peaks1627 and 1419 cm�1 showed the asymmetric and sym-metric stretching frequency of –COO group, the intensepeak at 1017 cm�1 indicated the ether linkage of –C–O–C symmetric stretching, and the 3442 cm�1 (Figure 2(b))broad peak indicated the stretching frequency of –OH.The lower shifting of –OH stretching frequency from3475 to 3442 cm�1 clearly, indicated the formation ofintermolecular hydrogen bonding between SA and PEO.The same peaks were also observed in the drug-loadedmembrane.

SEM studies

The SEM photomicrographs of (a) plain membrane and(b) drug-loaded membrane are presented in Figure 3.The plain membrane has shown a smooth surface,while drug-loaded membrane has shown rough anddense surface. The appearance of the dense surfacemay be due to the presence of crosslinker, it shrinksthe membrane.

Figure 1. Variation of % SR with concentration of PEO and crosslinker.

Figure 2. FTIR spectra of (a) plain SA, (b) plain membrane,and (c) drug-loaded membrane.

154 B. Mallikarjuna et al.

DSC studies

DSC thermograms of (a) plain drug, (b) plain membrane,and (c) drug-loaded membranes are presented in Figure 4.In the case of plain drug, (Figure 4(a)) showed the peakat 177.21 °C indicates the melting peak. This meltingpeak was not found in the drug-loaded membrane. Thisindicates the molecular dispersion of VHCl drug into themembranes.

X-RD studies

The X-ray diffractograms of (a) plain drug, (b) plain SAmembrane, (c) plain membrane, and (d) drug-loadedmembrane are presented in Figure 5, where plain drughas shown characteristic intense peaks at the 2h of 9.6o,

12o, 15.8o, and 26.9o due to its crystalline nature.Whereas, in case of drug-loaded membrane, no intensepeaks related to drug was observed. This indicates themolecular dispersion of the drug after incorporation intothe membranes.

Tensile strength of the membrane

The improved mechanical strength of the membraneswas confirmed by TS measurement. As the PEO contentincreases the TS of the membranes increases (SP-6 > SP-2 > SP-7), this may be due to formation of large numberof links among the polymer chains as a result of forma-tion, thereby increasing strength of the matrix. Amongthe membranes, TS increased with an increase in

Figure 4. DSC thermograms of (a) plain drug, (b) plain membrane, and (c) drug-loaded membrane.

Figure 3. SEM photographs of (a) plain membrane and (b) drug-loaded membrane.

Designed Monomers and Polymers 155

concentration of GA (SP-5 > SP-2 > SP-4), indicating anincreased strength of matrix with increasing crosslinking.The mechanical strength values of membranes are shownin Table 1.

In-vitro release study

Drug-release kinetic parameters of different formulations

Drug-release kinetics was analyzed by plotting the cumu-lative release data vs. time by fitting the data to a simpleexponential equation [37]:

(Mt=M1) ¼ ktn (3)

where Mt and M∞ represent the fractional drug release attime t, k is a constant characteristic of the drug–polymersystem, and n is an empirical parameter characterizingthe release mechanism. Using the least square procedure,we have the values of n and k for all the formulationsand these values are given in Table 2. If n= 0.5, the drug

diffuses and release from the polymer matrix following aFickian diffusion. For n > 0.5, anomalous or nonFickiandrug diffusion occurs. If n= 1, a completely nonFickianor case-II release kinetics is operative. The intermediaryvalues ranging between 0.5 and 1.0 are attributed to ananomalous type diffusive transport [37].

In the present study, the values of k and n showed adependence on the extent of crosslinking, drug loading,and PEO content in the membranes. The values of n formembranes prepared by using various amounts of PEO(10, 20, and 30wt.%) while keeping VHCl (15%) andGA (3ml) constant, ranged from 0.487 to 0.712 leadingto a shift of transport from Fickian to the anomaloustype. The VHCl-loaded membranes exhibited n valuesranging from 0.463 to 0.675 (see Table 2), indicating theshift from erosion type release to a swelling controlled,nonFickian type mechanism. This may be due to thereduction in the regions of low microviscosity and clo-sure of microcavities in the swollen state of the polymer.Similar findings have been observed elsewhere, where inthe effect of different polymer ratios on dissolution kinet-ics was studied [38]. Correlation coefficients, r, obtainedwhile fitting the release data are in the range from of0.934 to 0.997.

Effect of drug variation

Figure 6 shows the release profile of VHCl-loaded mem-branes SP-1, SP-2, and SP-3 at different amounts of drugloading (10, 15, and 20wt.%, respectively) in phosphatebuffer solution pH 7.4 (PBS) at 37 °C. The release datashow that the membrane containing higher amount ofVHCl drug (SP-3) displayed faster and higher releaserates than those formulations containing lower amount of

Table 2. The release kinetic parameters of k, n, and r valuesat pH 7.4.

Formulationcodes k n

Correlationcoefficient, r

SP-1 0.060 0.463 0.992SP-2 0.077 0.524 0.986SP-3 0.134 0.675 0.971SP-4 0.178 0.692 0.934SP-5 0.118 0.586 0.964SP-6 0.037 0.712 0.997SP-7 0.048 0.487 0.996SP-8 0.091 0.383 0.972

Figure 5. XRD patterns of (a) plain drug (b) plain SA, (c) plain membrane, and (d) drug-loaded membrane.

156 B. Mallikarjuna et al.

VHCl. A prolonged release was observed in the SP-1membrane, because it contains lower amount of drug.Notice that the release rate becomes quite slower at thelower amount of drug in the membrane, due to the avail-ability of more free void spaces through which a lesserno of drug molecules will transport.

Effect of crosslinking agent

The cumulative release vs. time curves for varyingamounts of GA (1.5, 3, and 4.5ml) at a fixed amount ofdrug (15wt.%), SP membranes SP-2, SP-4, and SP-5 aredisplayed in Figure 7. The % of cumulative release isquite faster and larger at lower amount of GA (1.5ml)(SP-4), whereas the release is quite slower at higheramount of GA (i.e. 4.5ml) (SP-5), The cumulativerelease is slower when the membrane containing higheramount of GA was used, it may be due to the polymeric

chains become rigid due to the contraction of microv-oids, thus decreasing the % cumulative release of VHClthrough the membrane.

Effect of PEO

To understand the release profiles of VHCl from thecrosslinked membranes SP-8, SP-2, SP-6, and SP-7 withdifferent PEO concentrations (0, 20, 30, and 10wt.%)were studied in pH 7.4 at 37 °C. From Figure 8, it wasobserved that the highest cumulative release is obtainedin SP-6 formulation, which has 30wt.% of PEO. On theother hand, the least cumulative release was observed,the formulation containing lower amount (10wt.%) ofPEO. Compared to the all formulations the lowest cumu-lative release was observed in the case of pure SA mem-brane (SP-8). This is due to the hydrophilic nature ofPEO. When the amount of PEO increased in the mem-brane, the drug release was increased and a lower cumu-lative release was observed for the formulationcontaining lower amount of PEO. It may be due to theincrease of hydrophilic nature and looses the polymernetwork by the increase of PEO concentration in themembrane. Hence, with an increase in PEO concentra-tion, the hydrophilic nature of the membrane increasedand the cumulative release also increased.

Conclusions

VHCl drug-loaded membranes based on SA/PEO wereprepared by a solvent/casting evaporation method. Theprepared membranes were thin, flexible, and smooth. Westudied the membrane characteristics, especially itspotential capacity in drug delivery system. The morpho-logical characterizations showed a good compatibilitybetween the membrane and drug. The results of

Figure 7. % cumulative release of VHCl drug through themembrane containing different amounts of crosslinker 1.5ml(SP-4), 3ml (SP-2), and 4.5ml (SP-5) at pH 7.4.

Figure 8. % cumulative release of VHCl drug through themembrane containing different amounts of PEO 0wt.% (SP-8),10wt.% (SP-7), 20wt.% (SP-2), and 30wt.% (SP-6) at pH 7.4.Figure 6. % cumulative release of VHCl drug through

the membrane containing different amounts of drug 10wt.%(SP-1), 15wt.% (SP-2), and 20wt.% (SP-3) at pH 7.4.

Designed Monomers and Polymers 157

controlled release tests showed that the amount of VHClrelease increased with an increase of PEO, amount ofdrug and decreased with an increase in crosslinker. Thus,we can controlled the drug release rate through changingsome influence factors, amount of the drug loaded,amount of PEO, and amount of crosslinker. The mechan-ical property is also good. By observing all the results,the membrane was a quite promising for controlledrelease of VHCl drug. The prolonged release rates ofVHCl were observed up to 12 h. The membrane can leadto a successful application for localized drug deliveryin vivo or in vitro environment.

AcknowledgmentsOne of the authors (B. Mallikarjuna) thanks the Council ofScientific and Industrial Research for providing financialsupport under the CSIR-JRF (File No. 09/383 (0043)/2009-EMR-1), Government of India, New Delhi.

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